CN110799245B - 用于治疗具有非典型braf突变的癌症的组合物和方法 - Google Patents

用于治疗具有非典型braf突变的癌症的组合物和方法 Download PDF

Info

Publication number
CN110799245B
CN110799245B CN201880040655.8A CN201880040655A CN110799245B CN 110799245 B CN110799245 B CN 110799245B CN 201880040655 A CN201880040655 A CN 201880040655A CN 110799245 B CN110799245 B CN 110799245B
Authority
CN
China
Prior art keywords
ser
leu
gly
pro
ala
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201880040655.8A
Other languages
English (en)
Other versions
CN110799245A (zh
Inventor
G·德克雷斯森佐
D·威尔施
S·萨哈
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biomed Valley Discoveries Inc
Original Assignee
Biomed Valley Discoveries Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biomed Valley Discoveries Inc filed Critical Biomed Valley Discoveries Inc
Priority to CN202210881186.0A priority Critical patent/CN116036278A/zh
Publication of CN110799245A publication Critical patent/CN110799245A/zh
Application granted granted Critical
Publication of CN110799245B publication Critical patent/CN110799245B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/131—Amines acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/195—Chemokines, e.g. RANTES
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2046—IL-7
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/208—IL-12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/45—Transferases (2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1135—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against oncogenes or tumor suppressor genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Wood Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Analytical Chemistry (AREA)
  • Mycology (AREA)
  • Pathology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • Oncology (AREA)
  • Biophysics (AREA)
  • Pain & Pain Management (AREA)
  • Inorganic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Endocrinology (AREA)
  • Plant Pathology (AREA)
  • Optics & Photonics (AREA)

Abstract

本发明尤其提供了用于在携带非典型BRAF突变(即非V600E/K BRAF突变)的受试者中治疗或缓解癌症的影响的方法、药物组合物和试剂盒，所述方法、药物组合物和试剂盒包含ERK抑制剂。还提供了用于鉴定将从包含ERK抑制剂的疗法中受益的患有非典型BRAF突变癌症的受试者的方法。

Description

用于治疗具有非典型BRAF突变的癌症的组合物和方法
相关申请的交叉引用
本申请要求2017年5月16日提交的美国临时专利申请号62/506,995的权益，其全部内容通过引用并入本文。
公开领域
本公开涉及使用一种或多种抗癌剂治疗或缓解具有非典型基因突变的癌症的影响的方法、试剂盒和药物组合物。
通过参考并入序列表
本申请包含对氨基酸和/或核酸序列的参考，所述氨基酸和/或核酸序列已经同时提交为序列表文本文件“2391211.txt”，文件大小为246KB，于2018年5月15日创建。根据37C.F.R.§1.52(e)(5)，上述序列表通过引用全文并入本文。
发明背景
丝裂原活化蛋白激酶(MAPK)或RAS/RAF/MEK/ERK信号传导负责涉及控制增殖、分化和细胞凋亡的几种细胞信号传导途径。发现MAPK细胞信号传导途径在人类癌症中被破坏，通常是由于KRAS、NRAS或BRAF基因的活化突变。已经开发出选择性BRAF抑制剂，例如维罗非尼(vemurafenib)和达拉非尼(dabrafenib)，以靶向BRAF突变肿瘤。例如，维罗非尼被批准用于具有BRAF V600E突变的不可切除或转移性黑色素瘤，并且对BRAF V600E突变的检测已成为预测对维罗非尼、达拉非尼和曲美替尼(trametinib)治疗有应答的护理标准。
尽管V600E突变是在许多肿瘤类型中观察到的最常见的BRAF突变，但是Catologof Somatic Mutations in Cancer(COSMIC)数据库已经报道了BRAF基因的外显子11和15内的100多个其他突变。在V600密码子以外的BRAF突变的临床重要性在很大程度上尚不清楚。
鉴于上述情况，需要新颖的治疗剂，该治疗剂将靶向携带除V600E以外的BRAF突变的细胞类型中的MAPK途径。本申请旨在满足这些和其他需求。
发明内容
根据一个方面，本公开提供了用于在具有非V600E/K BRAF突变的受试者中治疗或缓解癌症的影响的方法，该方法包括向受试者施用有效量的ERK抑制剂或其药学上可接受的盐。
根据一些实施方案，ERK抑制剂选自BVD-523、SCH-722984(Merck&Co.)、SCH-772984(Merck&Co.)、SCH-900353(MK-8353)(Merck&Co.)、LY3214996(Lilly)、AEZS-140(Aeterna Zentaris)、AEZS-131(Aeterna Zentaris)、AEZS-136(Aeterna Zentaris)、LTT-462(Novartis)、RG-7842(Genentech)、CC-90003(Celgene)、KIN-4050(Kinentia)及其组合。
根据一些实施方案，ERK抑制剂是BVD-523。
根据一些实施方案，非V600E/K BRAF突变是激酶活化的突变、激酶受损的突变或激酶未知的突变及其组合。
根据一些实施方案，激酶活化的突变选自R462I、I463S、G464E、G464R、G464V、G466A、G469A、N581S、E586K、F595L、L597Q、L597R、L597S、L597V、A598V、T599E、V600R、K601E、S602D、A728V及其组合。
根据一些实施方案，激酶受损的突变选自G466E、G466R、G466V、Y472C、K483M、D594A、D594E、D594G、D594H、D594N、D594V、G596R、T599A、S602A及其组合。
根据一些实施方案，激酶未知的突变选自T440I、S467L、G469E、G469R、G469S、G469V、L584F、L588F、V600_K601delinsE、S605I、Q609L、E611Q及其组合。
根据一些实施方案，非V600E/K BRAF突变选自D594、G469、K601E、L597、T599重复、L485W、F247L、G466V、BRAF融合、BRAF-AGAP3重排、BRAF外显子15剪接变体及其组合。
根据一些实施方案，受试者是哺乳动物。
根据一些实施方案，哺乳动物选自人、灵长类动物、农场动物和家养动物。
根据一些实施方案，哺乳动物是人。
根据一些实施方案，癌症是实体瘤癌症或血液癌症。
根据一些实施方案，癌症选自胶质母细胞瘤、黑素瘤、胆管癌、小细胞肺癌、结肠直肠癌、前列腺癌、阴道癌、血管肉瘤、非小细胞肺癌、阑尾癌、鳞状细胞癌、唾液管癌、腺样囊性癌、小肠癌和胆囊癌。
根据一些实施方案，癌症选自小肠癌、非小细胞肺癌、胆囊癌和鳞状细胞癌。
根据一些实施方案，该方法进一步包括向受试者施用选自MEK抑制剂、RAF抑制剂、HDAC抑制剂及其组合的至少一种另外的治疗剂。
根据一些实施方案，MEK抑制剂选自炭疽毒素、蒽醌(Golden Biotechnology)、ARRY-142886(6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺)(Array BioPharma)、ARRY-438162(Array BioPharma)贝美替尼(binimetinib)(MEK162，ARRY-1662)、AS-1940477(Astellas)、AS-703988(Merck KGaA)、bentamapimod(Merck KGaA)、BI-847325(Boehringer Ingelheim)、E-6201(Eisai)、GDC-0623(Hoffmann-La Roche)、GDC-0973(考比替尼(cobimetinib))(Hoffmann-La Roche)、L783277(Merck)、炭疽毒素的致死因子部分、MEK162(Array BioPharma)、PD 098059(2-(2'-氨基-3'-甲氧苯基)-氧萘-4-酮)(Pfizer)、PD 184352(CI-1040)(Pfizer)、PD-0325901(Pfizer)、PD318088(Pfizer)、PD334581(Pfizer)、6-甲氧基-7-(3-吗啉-4-基-丙氧基)-4-(4-苯氧基-苯基氨基)-喹啉-3-甲腈、4-[3-氯-4-(1-甲基-1H-咪唑-2-基硫烷基)-苯基氨基]-6-甲氧基-7-(3-吗啉-4-基-丙氧基)-喹啉-3-甲腈、pimasertib(pimasertib)(SantheraPharmaceuticals)、RDEA119(Ardea Biosciences/Bayer)、瑞美替尼(refametinib)(AstraZeneca)、RG422(Chugai Pharmaceutical Co.)、R0092210(Roche)、R04987655(Hoffmann-La Roche)、R05126766(Hoffmann-La Roche)、司美替尼(selumetinib)(AZD6244)(AstraZeneca)、SL327(Sigma)、TAK-733(Takeda)、曲美替尼(trametinib)(Japan Tobacco)、U0126(1,4-二氨基-2,3-二氰基-1,4-双(2-氨基苯硫基)丁二烯)(Sigma)、WX-554(Wilex)、YopJ多肽(Mittal等人，2010)、其药学上可接受的盐及其组合。
根据一些实施方案，RAF抑制剂选自AAL881(Novartis)、AB-024(AmbitBiosciences)、ARQ-736(ArQule)、ARQ-761(ArQule)、AZ628(Axon Medchem BV)、BAY 43-9006索拉非尼、BeiGene-283(BeiGene)、BUB-024(MLN 2480)(Sunesis&Takeda)、b-raf抑制剂(Sareum)、BRAF激酶抑制剂(Selexagen Therapeutics)、BRAF siRNA 313(tacaccagcaagctagatgca)和523(cctatcgttagagtcttcctg)(Liu等人，2007)、CHIR-265(Novartis)、CTT239065(Institute of Cancer Research)、达拉非尼(GSK2118436)、DP-4978(Deciphera Pharmaceuticals)、HM-95573(Hanmi)、GDC-0879(Genentech)、GW-5074(Sigma Aldrich)、ISIS 5132(Novartis)、L779450(Merck)、LBT613(Novartis)、LXH254(Novartis)、LErafAON(NeoPharm,Inc.)、LGX-818(Novartis)、帕唑帕尼(pazopanib)(GlaxoSmithKline)、PLX3202(Plexxikon)、PLX4720(Plexxikon)、PLX5568(Plexxikon)、PLX3603(Daiichi Sankyo)、PLX8394(Daiichi Sankyo)、RAF-265(Novartis)、RAF-365(Novartis)、REDX0535(RedX Pharma Plc)、瑞戈非尼(regorafenib)(Bayer HealthcarePharmaceuticals,Inc.)、RO 5126766(Hoffmann-La Roche)、SB-590885(GlaxoSmithKline)、SB699393(GlaxoSmithKline)、索拉非尼(sorafenib)(OnyxPharmaceuticals)、TAK 632(Takeda)、TL-241(Teligene)、维拉非尼(vemurafenib)(RG7204或PLX4032)(Daiichi Sankyo)、XL-281(Exelixis)、ZM-336372(AstraZeneca)、其药学上可接受的盐及其组合。
根据一些实施方案，HDAC抑制剂选自艾贝司他(Abexinostat)(PCI-24781)、吉诺司他(Givinostat)、恩替司他(Entinostat)、扶林司他(Vorinostat)、CI-994、CUDC-101、恩替司他(Entinostat)、BML-210、M344、NVP-LAQ824、帕比司他(Panobinostat)、Pracinosat(SB939)、Mocetinostat、Resminostat、罗米地辛(Romidepsin)、贝利诺司他(Belinostat)、其药学上可接受的盐及其组合。
根据一些实施方案，该方法进一步包括向受试者施用选自抗体、抗体片段、抗体缀合物、细胞毒性剂、毒素、放射性核素、免疫调控剂、光活化治疗剂、放射增敏剂、激素、抗血管生成剂及其组合的至少一种另外的治疗剂。
根据一些实施方案，抗体、其片段或其缀合物选自利妥昔单抗(Rituxan)、布伦妥昔单抗维多汀(Brentuximab Vedotin)(Adcetriz)、阿多曲妥珠单抗艾坦肽(Ado-trastuzumab emtansine)(Kadcyla)西妥昔单抗(Erbitux)、贝伐单抗(bevacizumab)(Avastin)、替伊莫单抗(Ibritumomab)(Zevalin)、维多珠单抗(vedolizumab)(Entyvio)、伊匹单抗(Ipilimumab)(Yervoy)、纳武单抗(Nivolumab)(Opdivo)、派姆单抗(pembrolizumab)(Keytruda)、阿伦单抗(Alemtuzamab)阿特朱单抗(atezolizumab)(Tecentriq)、阿维鲁单抗(avelumab)(Bavencio)、德鲁瓦单抗(durvalumab)(Imfinzi)、B-701、奥法木单抗(Ofatumumab)、阿托珠单抗(Obinutuzumab)(Gazyva)帕尼单抗(Panitumumab)、plozalizumab、BI-754091、OREG-103、COM-701、BI-754111及其组合。
根据一些实施方案，细胞毒性剂选自环磷酰胺、甲氯乙胺、尿嘧啶氮芥、美法仑、苯丁酸甲氯乙胺、异环磷酰胺、卡莫司汀、洛莫司汀、链脲霉素、白消安、替莫唑胺、顺铂、卡铂、奥沙利铂、奈达铂、沙铂、三硝酸四铂、阿霉素、柔红霉素、伊达比星、米托蒽醌、甲氨蝶呤、培美曲塞、6-巯基嘌呤、达卡巴嗪、氟达拉滨、5-氟尿嘧啶、阿拉伯糖胞嘧啶、卡培他滨、吉西他滨、地西他滨、长春花生物碱、紫杉醇(Taxol)、多西他赛(Taxotere)、依沙贝比隆(Ixempra)、放线菌素、蒽环类、缬沙星、表柔比星、博来霉素、普卡霉素、丝裂霉素、其药学上可接受的盐、前药及其组合。
根据一些实施方案，毒素是白喉毒素或其部分。
根据一些实施方案，放射性核素选自I-125、At-211、Lu-177、Cu-67、I-131、Sm-153、Re-186、P-32、Re-188、In-114m、Y-90及其组合。
根据一些实施方案，免疫调控剂选自粒细胞集落刺激因子(G-CSF)、LAG-3、IMP-321、JCAR-014、ASLAN-002(BMS-777607)、干扰素、咪喹莫特和来自细菌的细胞膜组分、IL-2、IL-7、IL-12、CCL3、CCL26、CXCL7、合成的胞嘧啶磷酸鸟苷(CpG)、免疫检查点抑制剂及其组合。
根据一些实施方案，放射增敏剂选自米索硝唑、甲硝唑、替拉帕明、反式丁香酸钠及其组合。
根据一些实施方案，激素选自前列腺素、白三烯、前列环素、血栓烷、淀粉纤维素、抗苗勒管激素、脂联素、促肾上腺皮质激素、血管紧张素原、血管紧张素、血管加压素、心房肽(atriopeptin)、脑钠尿肽、降血钙素、胆囊收缩素、促肾上腺皮质激素释放激素、脑啡肽、内皮素、促红细胞生成素、促卵泡激素、甘丙肽、胃泌素、生长激素释放肽、胰高血糖素、促性腺激素释放激素、生长激素释放激素、人绒毛膜促性腺激素、人胎盘促泌素、生长激素、抑制素、胰岛素、生长调节素(somatomedin)、瘦素、促脂素、促黄体生成素、黑素细胞刺激激素、胃动素、食欲素、催产素、胰多肽、甲状旁腺激素、催乳素、催乳素释放激素、松弛素、肾素、分泌素、生长抑素(somatostain)、血小板生成素、促甲状腺激素、睾丸酮、脱氢表雄酮、雄烯二酮、二氢睾丸酮、醛固酮、雌二醇、雌酮、雌三醇、皮质醇、孕酮、骨化三醇、骨化二醇、他莫昔芬(Nolvadex)、阿那曲唑(Arimidex)、来曲唑(Femara)、氟司韦特(Faslodex)及其组合。
根据一些实施方案，抗血管生成剂选自2-甲氧基雌二醇、血管抑制素、贝伐单抗、软骨衍生的血管生成抑制因子、内皮抑素、IFN-α、IL-12、伊曲康唑、利诺米特、血小板因子4、催乳素、SU5416、苏拉明、他克莫尼、替加仑、四硫代钼酸盐、沙利度胺、血小板反应蛋白、血小板反应蛋白、TNP-470、齐夫-阿柏西普、其药学上可接受的盐、前药及其组合。
根据一些实施方案，另外的治疗剂是PI3K/Akt途径的抑制剂。
根据一些实施方案，PI3K/Akt途径的抑制剂选自A-674563(CAS#552325-73-2)、AGL 2263、AMG-319(Amgen,Thousand Oaks,CA)、AS-041164(5-苯并[1,3]二恶唑-5-基亚甲基-噻唑烷-2,4-二酮)、AS-604850(5-(2,2-二氟-苯并[1,3]二恶唑-5-基亚甲基)-噻唑烷-2,4-二酮)、AS-605240(5-喹喔啉-6-亚甲基-1,3-噻唑烷-2,4-二酮)、AT7867(CAS#857531-00-1)、苯并咪唑系列，Genentech(Roche Holdings Inc.,South San Francisco,CA)、BML-257(CAS#32387-96-5)、BVD-723、CAL-120(Gilead Sciences,Foster City,CA)、CAL-129(Gilead Sciences)、CAL-130(Gilead Sciences)、CAL-253(Gilead Sciences)、CAL-263(Gilead Sciences)、CAS#612847-09-3、CAS#681281-88-9、CAS#75747-14-7、CAS#925681-41-0、CAS#98510-80-6、CCT128930(CAS#885499-61-6)、CH5132799(CAS#1007207-67-1)、CHR-4432(Chroma Therapeutics,Ltd.,Abingdon,UK)、FPA 124(CAS#902779-59-3)、GS-1101(CAL-101)(Gilead Sciences)、GSK 690693(CAS#937174-76-0)、H-89(CAS#127243-85-0)、Honokiol、IC87114(Gilead Science)、IPI-145(Intellikine Inc.)、KAR-4139(Karus Therapeutics,Chilworth,UK)、KAR-4141(Karus Therapeutics)、KIN-1(KarusTherapeutics)、KT 5720(CAS#108068-98-0)、米替福新(Miltefosine)、MK-2206二盐酸化物(CAS#1032350-13-2)、ML-9(CAS#105637-50-1)、盐酸纳曲通、OXY-111A(NormOxys Inc.,Brighton,MA)、perifosine、PHT-427(CAS#1191951-57-1)、PI3激酶δ抑制剂，Merck KGaA(Merck&Co.,Whitehouse Station,NJ)、PI3激酶δ抑制剂，Genentech(Roche HoldingsInc.)、PI3激酶δ抑制剂，Incozen(Incozen Therapeutics,Pvt.Ltd.,Hydrabad,India)、PI3激酶δ抑制剂2，Incozen(Incozen Therapeutics)、PI3激酶抑制剂，Roche-4(RocheHoldings Inc.)、PI3激酶抑制剂，Roche(Roche Holdings Inc.)、PI3激酶抑制剂，Roche-5(Roche Holdings Inc.)、PI3-α/δ抑制剂，Pathway Therapeutics(Pathway TherapeuticsLtd.,South San Francisco,CA)、PI3-δ抑制剂，Cellzome(Cellzome AG,Heidelberg,Germany)、PI3-δ抑制剂，Intellikine(Intellikine Inc.,La Jolla,CA)、PI3-δ抑制剂，Pathway Therapeutics-1(Pathway Therapeutics Ltd.)、PI3-δ抑制剂，PathwayTherapeutics-2(Pathway Therapeutics Ltd.)、PI3-δ/γ抑制剂，Cellzome(CellzomeAG)、PI3-δ/γ抑制剂，Cellzome(Cellzome AG)、PI3-δ/γ抑制剂，Intellikine(Intellikine Inc.)、PI3-δ/γ抑制剂，Intellikine(Intellikine Inc.)、PI3-δ/γ抑制剂，Pathway Therapeutics(Pathway Therapeutics Ltd.)、PI3-δ/γ抑制剂，PathwayTherapeutics(Pathway Therapeutics Ltd.)、PI3-γ抑制剂，Evotec(Evotec)、PI3-γ抑制剂，Cellzome(Cellzome AG)、PI3-γ抑制剂，Pathway Therapeutics(PathwayTherapeutics Ltd.)、PI3Kδ/γ抑制剂，Intellikine-1(Intellikine Inc.)、PI3Kδ/γ抑制剂，Intellikine-1(Intellikine Inc.)、pictilisib(Roche Holdings Inc.)、PIK-90(CAS#677338-12-4)、SC-103980(Pfizer,New York,NY)、SF-1126(SemaforePharmaceuticals,Indianapolis,IN)、SH-5、SH-6、四氢姜黄素、TG100-115(TargegenInc.,San Diego,CA)、曲西瑞宾(Triciribine)、X-339(Xcovery,West Palm Beach,FL)、XL-499(Evotech,Hamburg,Germany)、其药学上可接受的盐及其组合。
根据一个方面，本公开内容提供了用于在受试者中治疗或缓解癌症的影响的方法，包括：(a)鉴定携带非V600E/K BRAF突变的患有癌症的受试者；和(b)对受试者施用有效量的ERK抑制剂或其药学上可接受的盐。
根据一些实施方案，ERK抑制剂选自BVD-523、SCH-722984(Merck&Co.)、SCH-772984(Merck&Co.)、SCH-900353(MK-8353)(Merck&Co.)、LY3214996(Lilly)、AEZS-140(Aeterna Zentaris)、AEZS-131(Aeterna Zentaris)、AEZS-136(Aeterna Zentaris)、LTT-462(Novartis)、RG-7842(Genentech)、CC-90003(Celgene)、KIN-4050(Kinentia)及其组合。
根据一些实施方案，ERK抑制剂是BVD-523。
根据一些实施方案，非V600E/K BRAF突变是激酶活化的突变、激酶受损的突变或激酶未知的突变及其组合。
根据一些实施方案，激酶活化的突变选自R462I、I463S、G464E、G464R、G464V、G466A、G469A、N581S、E586K、F595L、L597Q、L597R、L597S、L597V、A598V、T599E、V600R、K601E、S602D、A728V及其组合。
根据一些实施方案，激酶受损的突变选自G466E、G466R、G466V、Y472C、K483M、D594A、D594E、D594G、D594H、D594N、D594V、G596R、T599A、S602A及其组合。
根据一些实施方案，激酶未知的突变选自T440I、S467L、G469E、G469R、G469S、G469V、L584F、L588F、V600_K601delinsE、S605I、Q609L、E611Q及其组合。
根据一些实施方案，受试者是哺乳动物。
根据一些实施方案，哺乳动物选自人、灵长类动物、农场动物和家养动物。
根据一些实施方案，哺乳动物是人。
根据一些实施方案，癌症是实体瘤癌症或血液癌症。
根据一些实施方案，癌症选自胶质母细胞瘤、黑素瘤、胆管癌、小细胞肺癌、结肠直肠癌、前列腺癌、阴道癌、血管肉瘤、非小细胞肺癌、阑尾癌、鳞状细胞癌、唾液管癌、腺样囊性癌、小肠癌和胆囊癌。
根据一些实施方案，癌症选自小肠癌、非小细胞肺癌、胆囊癌和鳞状细胞癌。
根据一些实施方案，该方法进一步包括：(i)从受试者获得生物样品；和(ii)筛选样品以确定受试者是否具有非V600E/K BRAF突变。
根据一些实施方案，该方法进一步包括向受试者施用选自MEK抑制剂、RAF抑制剂、HDAC抑制剂及其组合的至少一种另外的治疗剂。
根据一些实施方案，MEK抑制剂选自炭疽毒素、蒽醌(Golden Biotechnology)、ARRY-142886(6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺)(Array BioPharma)、ARRY-438162(Array BioPharma)贝美替尼(MEK162，ARRY-1662)、AS-1940477(Astellas)、AS-703988(Merck KGaA)、bentamapimod(Merck KGaA)、BI-847325(Boehringer Ingelheim)、E-6201(Eisai)、GDC-0623(Hoffmann-La Roche)、GDC-0973(考比替尼)(Hoffmann-La Roche)、L783277(Merck)、炭疽毒素的致死因子部分、MEK162(Array BioPharma)、PD 098059(2-(2'-氨基-3'-甲氧苯基)-氧萘-4-酮)(Pfizer)、PD 184352(CI-1040)(Pfizer)、PD-0325901(Pfizer)、PD318088(Pfizer)、PD334581(Pfizer)、6-甲氧基-7-(3-吗啉-4-基-丙氧基)-4-(4-苯氧基-苯基氨基)-喹啉-3-甲腈、4-[3-氯-4-(1-甲基-1H-咪唑-2-基硫烷基)-苯基氨基]-6-甲氧基-7-(3-吗啉-4-基-丙氧基)-喹啉-3-甲腈、pimasertib(Santhera Pharmaceuticals)、RDEA119(ArdeaBiosciences/Bayer)、瑞美替尼(refametinib)(AstraZeneca)、RG422(ChugaiPharmaceutical Co.)、R0092210(Roche)、R04987655(Hoffmann-La Roche)、R05126766(Hoffmann-La Roche)、司美替尼(selumetinib)(AZD6244)(AstraZeneca)、SL327(Sigma)、TAK-733(Takeda)、曲美替尼(trametinib)(Japan Tobacco)、U0126(1,4-二氨基-2,3-二氰基-1,4-双(2-氨基苯硫基)丁二烯)(Sigma)、WX-554(Wilex)、YopJ多肽(Mittal等人，2010)、其药学上可接受的盐及其组合。
根据一些实施方案，RAF抑制剂选自AAL881(Novartis)、AB-024(AmbitBiosciences)、ARQ-736(ArQule)、ARQ-761(ArQule)、AZ628(Axon Medchem BV)、BAY 43-9006索拉非尼、BeiGene-283(BeiGene)、BUB-024(MLN 2480)(Sunesis&Takeda)、b-raf抑制剂(Sareum)、BRAF激酶抑制剂(Selexagen Therapeutics)、BRAF siRNA 313(tacaccagcaagctagatgca)和523(cctatcgttagagtcttcctg)(Liu等人，2007)、CHIR-265(Novartis)、CTT239065(Institute of Cancer Research)、达拉非尼(GSK2118436)、DP-4978(Deciphera Pharmaceuticals)、HM-95573(Hanmi)、GDC-0879(Genentech)、GW-5074(Sigma Aldrich)、ISIS 5132(Novartis)、L779450(Merck)、LBT613(Novartis)、LXH254(Novartis)、LErafAON(NeoPharm,Inc.)、LGX-818(Novartis)、帕唑帕尼(GlaxoSmithKline)、PLX3202(Plexxikon)、PLX4720(Plexxikon)、PLX5568(Plexxikon)、PLX3603(Daiichi Sankyo)、PLX8394(Daiichi Sankyo)、RAF-265(Novartis)、RAF-365(Novartis)、REDX0535(RedX Pharma Plc)、瑞戈非尼(Bayer HealthcarePharmaceuticals,Inc.)、RO 5126766(Hoffmann-La Roche)、SB-590885(GlaxoSmithKline)、SB699393(GlaxoSmithKline)、索拉非尼(Onyx Pharmaceuticals)、TAK 632(Takeda)、TL-241(Teligene)、维拉非尼(RG7204或PLX4032)(Daiichi Sankyo)、XL-281(Exelixis)、ZM-336372(AstraZeneca)、其药学上可接受的盐及其组合。
根据一些实施方案，HDAC抑制剂选自艾贝司他(PCI-24781)、吉诺司他、恩替司他、扶林司他、CI-994、CUDC-101、恩替司他、BML-210、M344、NVP-LAQ824、帕比司他、Pracinosat(SB939)、Mocetinostat、Resminostat、罗米地辛、贝利诺司他、其药学上可接受的盐及其组合。
根据一些实施方案，该方法进一步包括向受试者施用选自抗体或其片段、细胞毒性剂、毒素、放射性核素、免疫调控剂、光活化治疗剂、放射增敏剂、激素、抗血管生成剂及其组合的至少一种另外的治疗剂。
根据一些实施方案，抗体、其片段或其缀合物选自利妥昔单抗(Rituxan)、布伦妥昔单抗维多汀(Adcetriz)、阿多曲妥珠单抗艾坦肽(Kadcyla)西妥昔单抗(Erbitux)、贝伐单抗(Avastin)、替伊莫单抗(Zevalin)、维多珠单抗(Entyvio)、伊匹单抗(Yervoy)、纳武单抗(Opdivo)、派姆单抗(Keytruda)、阿伦单抗阿特朱单抗(Tecentriq)、阿维鲁单抗(Bavencio)、德鲁瓦单抗(Imfinzi)、B-701、奥法木单抗、阿托珠单抗(Gazyva)帕尼单抗、plozalizumab、BI-754091、OREG-103、COM-701、BI-754111及其组合。
根据一些实施方案，细胞毒性剂选自环磷酰胺、甲氯乙胺、尿嘧啶氮芥、美法仑、苯丁酸甲氯乙胺、异环磷酰胺、卡莫司汀、洛莫司汀、链脲霉素、白消安、替莫唑胺、顺铂、卡铂、奥沙利铂、奈达铂、沙铂、三硝酸四铂、阿霉素、柔红霉素、伊达比星、米托蒽醌、甲氨蝶呤、培美曲塞、6-巯基嘌呤、达卡巴嗪、氟达拉滨、5-氟尿嘧啶、阿拉伯糖胞嘧啶、卡培他滨、吉西他滨、地西他滨、长春花生物碱、紫杉醇(Taxol)、多西他赛(Taxotere)、依沙贝比隆(Ixempra)、放线菌素、蒽环类、缬沙星、表柔比星、博来霉素、普卡霉素、丝裂霉素、其药学上可接受的盐、前药及其组合。
根据一些实施方案，毒素是白喉毒素或其部分。
根据一些实施方案，放射性核素选自I-125、At-211、Lu-177、Cu-67、I-131、Sm-153、Re-186、P-32、Re-188、In-114m、Y-90及其组合。
根据一些实施方案，免疫调控剂选自粒细胞集落刺激因子(G-CSF)、LAG-3、IMP-321、JCAR-014、ASLAN-002(BMS-777607)、干扰素、咪喹莫特和来自细菌的细胞膜组分、IL-2、IL-7、IL-12、CCL3、CCL26、CXCL7、合成的胞嘧啶磷酸鸟苷(CpG)、免疫检查点抑制剂及其组合。
根据一些实施方案，放射增敏剂选自米索硝唑、甲硝唑、替拉帕明、反式丁香酸钠及其组合。
根据一些实施方案，激素选自前列腺素、白三烯、前列环素、血栓烷、淀粉纤维素、抗苗勒管激素、脂联素、促肾上腺皮质激素、血管紧张素原、血管紧张素、血管加压素、心房肽、脑钠尿肽、降血钙素、胆囊收缩素、促肾上腺皮质激素释放激素、脑啡肽、内皮素、促红细胞生成素、促卵泡激素、甘丙肽、胃泌素、生长激素释放肽、胰高血糖素、促性腺激素释放激素、生长激素释放激素、人绒毛膜促性腺激素、人胎盘促泌素、生长激素、抑制素、胰岛素、生长调节素、瘦素、促脂素、促黄体生成素、黑素细胞刺激激素、胃动素、食欲素、催产素、胰多肽、甲状旁腺激素、催乳素、催乳素释放激素、松弛素、肾素、分泌素、生长抑素、血小板生成素、促甲状腺激素、睾丸酮、脱氢表雄酮、雄烯二酮、二氢睾丸酮、醛固酮、雌二醇、雌酮、雌三醇、皮质醇、孕酮、骨化三醇、骨化二醇、他莫昔芬(Nolvadex)、阿那曲唑(Arimidex)、来曲唑(Femara)、氟司韦特(Faslodex)及其组合。
根据一些实施方案，抗血管生成剂选自2-甲氧基雌二醇、血管抑制素、贝伐单抗、软骨衍生的血管生成抑制因子、内皮抑素、IFN-α、IL-12、伊曲康唑、利诺米特、血小板因子4、催乳素、SU5416、苏拉明、他克莫尼、替加仑、四硫代钼酸盐、沙利度胺、血小板反应蛋白、血小板反应蛋白、TNP-470、齐夫-阿柏西普、其药学上可接受的盐、前药及其组合。
根据一些实施方案，另外的治疗剂是PI3K/Akt途径的抑制剂。
根据一些实施方案，PI3K/Akt途径的抑制剂选自A-674563(CAS#552325-73-2)、AGL 2263、AMG-319(Amgen,Thousand Oaks,CA)、AS-041164(5-苯并[1,3]二恶唑-5-基亚甲基-噻唑烷-2,4-二酮)、AS-604850(5-(2,2-二氟-苯并[1,3]二恶唑-5-基亚甲基)-噻唑烷-2,4-二酮)、AS-605240(5-喹喔啉-6-亚甲基-1,3-噻唑烷-2,4-二酮)、AT7867(CAS#857531-00-1)、苯并咪唑系列，Genentech(Roche Holdings Inc.,South San Francisco,CA)、BML-257(CAS#32387-96-5)、BVD-723、CAL-120(Gilead Sciences,Foster City,CA)、CAL-129(Gilead Sciences)、CAL-130(Gilead Sciences)、CAL-253(Gilead Sciences)、CAL-263(Gilead Sciences)、CAS#612847-09-3、CAS#681281-88-9、CAS#75747-14-7、CAS#925681-41-0、CAS#98510-80-6、CCT128930(CAS#885499-61-6)、CH5132799(CAS#1007207-67-1)、CHR-4432(Chroma Therapeutics,Ltd.,Abingdon,UK)、FPA 124(CAS#902779-59-3)、GS-1101(CAL-101)(Gilead Sciences)、GSK 690693(CAS#937174-76-0)、H-89(CAS#127243-85-0)、Honokiol、IC87114(Gilead Science)、IPI-145(Intellikine Inc.)、KAR-4139(Karus Therapeutics,Chilworth,UK)、KAR-4141(Karus Therapeutics)、KIN-1(KarusTherapeutics)、KT 5720(CAS#108068-98-0)、米替福新、MK-2206二盐酸化物(CAS#1032350-13-2)、ML-9(CAS#105637-50-1)、盐酸纳曲通、OXY-111A(NormOxys Inc.,Brighton,MA)、perifosine、PHT-427(CAS#1191951-57-1)、PI3激酶δ抑制剂，Merck KGaA(Merck&Co.,Whitehouse Station,NJ)、PI3激酶δ抑制剂，Genentech(Roche HoldingsInc.)、PI3激酶δ抑制剂，Incozen(Incozen Therapeutics,Pvt.Ltd.,Hydrabad,India)、PI3激酶δ抑制剂2，Incozen(Incozen Therapeutics)、PI3激酶抑制剂，Roche-4(RocheHoldings Inc.)、PI3激酶抑制剂，Roche(Roche Holdings Inc.)、PI3激酶抑制剂，Roche-5(Roche Holdings Inc.)、PI3-α/δ抑制剂，Pathway Therapeutics(Pathway TherapeuticsLtd.,South San Francisco,CA)、PI3-δ抑制剂，Cellzome(Cellzome AG,Heidelberg,Germany)、PI3-δ抑制剂，Intellikine(Intellikine Inc.,La Jolla,CA)、PI3-δ抑制剂，Pathway Therapeutics-1(Pathway Therapeutics Ltd.)、PI3-δ抑制剂，PathwayTherapeutics-2(Pathway Therapeutics Ltd.)、PI3-δ/γ抑制剂，Cellzome(CellzomeAG)、PI3-δ/γ抑制剂，Cellzome(Cellzome AG)、PI3-δ/γ抑制剂，Intellikine(Intellikine Inc.)、PI3-δ/γ抑制剂，Intellikine(Intellikine Inc.)、PI3-δ/γ抑制剂，Pathway Therapeutics(Pathway Therapeutics Ltd.)、PI3-δ/γ抑制剂，PathwayTherapeutics(Pathway Therapeutics Ltd.)、PI3-γ抑制剂，Evotec(Evotec)、PI3-γ抑制剂，Cellzome(Cellzome AG)、PI3-γ抑制剂，Pathway Therapeutics(PathwayTherapeutics Ltd.)、PI3Kδ/γ抑制剂，Intellikine-1(Intellikine Inc.)、PI3Kδ/γ抑制剂，Intellikine-1(Intellikine Inc.)、pictilisib(Roche Holdings Inc.)、PIK-90(CAS#677338-12-4)、SC-103980(Pfizer,New York,NY)、SF-1126(SemaforePharmaceuticals,Indianapolis,IN)、SH-5、SH-6、四氢姜黄素、TG100-115(TargegenInc.,San Diego,CA)、曲西瑞宾、X-339(Xcovery,West Palm Beach,FL)、XL-499(Evotech,Hamburg,Germany)、其药学上可接受的盐及其组合。
根据一个方面，本公开内容提供了鉴定将从ERK抑制剂或其药学上可接受的盐的疗法中受益的患有癌症的受试者的方法，该方法包括：(a)从受试者获得生物样品；和(b)筛选样品以确定受试者是否具有非V600E/K BRAF突变，
其中非V600E/K BRAF突变的存在证实受试者将从ERK抑制剂或其药学上可接受的盐的疗法中受益。
根据一些实施方案，ERK抑制剂选自BVD-523、SCH-722984
(Merck&Co.)、SCH-772984(Merck&Co.)、SCH-900353(MK-8353)
(Merck&Co.)、LY3214996(Lilly)、AEZS-140(Aeterna Zentaris)、AEZS-131
(Aeterna Zentaris)、AEZS-136(Aeterna Zentaris)、LTT-462(Novartis)、RG-7842(Genentech)、CC-90003(Celgene)、KIN-4050(Kinentia)及其组合。
根据一些实施方案，ERK抑制剂是BVD-523。
根据一些实施方案，非V600E/K BRAF突变是激酶活化的突变、激酶受损的突变或激酶未知的突变及其组合。
根据一些实施方案，激酶活化的突变选自R462I、I463S、G464E、G464R、G464V、G466A、G469A、N581S、E586K、F595L、L597Q、L597R、L597S、L597V、A598V、T599E、V600R、K601E、S602D、A728V及其组合。
根据一些实施方案，激酶受损的突变选自G466E、G466R、G466V、Y472C、K483M、D594A、D594E、D594G、D594H、D594N、D594V、G596R、T599A、S602A及其组合。
根据一些实施方案，激酶未知的突变选自T440I、S467L、G469E、G469R、G469S、G469V、L584F、L588F、V600_K601delinsE、S605I、Q609L、E611Q及其组合。
根据一些实施方案，受试者是哺乳动物。
根据一些实施方案，哺乳动物选自人、灵长类动物、农场动物和家养动物。
根据一些实施方案，哺乳动物是人。
根据一些实施方案，癌症是实体瘤癌症或血液癌症。
根据一些实施方案，癌症选自胶质母细胞瘤、黑素瘤、胆管癌、小细胞肺癌、结肠直肠癌、前列腺癌、阴道癌、血管肉瘤、非小细胞肺癌、阑尾癌、鳞状细胞癌、唾液管癌、腺样囊性癌、小肠癌和胆囊癌。
根据一些实施方案，癌症选自小肠癌、非小细胞肺癌、胆囊癌和鳞状细胞癌。
根据一些实施方案，该方法进一步包括将ERK抑制剂或其药学上可接受的盐施用给具有非V600E/K BRAF突变的受试者。
根据一些实施方案，该方法进一步包括向受试者施用选自MEK抑制剂、RAF抑制剂、HDAC抑制剂及其组合的至少一种另外的治疗剂。
根据一些实施方案，MEK抑制剂选自炭疽毒素、蒽醌(Golden Biotechnology)、ARRY-142886(6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺)(Array BioPharma)、ARRY-438162(Array BioPharma)贝美替尼(MEK162，ARRY-1662)、AS-1940477(Astellas)、AS-703988(Merck KGaA)、bentamapimod(Merck KGaA)、BI-847325(Boehringer Ingelheim)、E-6201(Eisai)、GDC-0623(Hoffmann-La Roche)、GDC-0973(考比替尼)(Hoffmann-La Roche)、L783277(Merck)、炭疽毒素的致死因子部分、MEK162(Array BioPharma)、PD 098059(2-(2'-氨基-3'-甲氧苯基)-氧萘-4-酮)(Pfizer)、PD 184352(CI-1040)(Pfizer)、PD-0325901(Pfizer)、PD318088(Pfizer)、PD334581(Pfizer)、6-甲氧基-7-(3-吗啉-4-基-丙氧基)-4-(4-苯氧基-苯基氨基)-喹啉-3-甲腈、4-[3-氯-4-(1-甲基-1H-咪唑-2-基硫烷基)-苯基氨基]-6-甲氧基-7-(3-吗啉-4-基-丙氧基)-喹啉-3-甲腈、pimasertib(Santhera Pharmaceuticals)、RDEA119(ArdeaBiosciences/Bayer)、瑞美替尼(AstraZeneca)、RG422(Chugai Pharmaceutical Co.)、R0092210(Roche)、R04987655(Hoffmann-La Roche)、R05126766(Hoffmann-La Roche)、司美替尼(AZD6244)(AstraZeneca)、SL327(Sigma)、TAK-733(Takeda)、曲美替尼(JapanTobacco)、U0126(1,4-二氨基-2,3-二氰基-1,4-双(2-氨基苯硫基)丁二烯)(Sigma)、WX-554(Wilex)、YopJ多肽(Mittal等人，2010)、其药学上可接受的盐及其组合。
根据一些实施方案，RAF抑制剂选自AAL881(Novartis)、AB-024(AmbitBiosciences)、ARQ-736(ArQule)、ARQ-761(ArQule)、AZ628(Axon Medchem BV)、BAY 43-9006索拉非尼、BeiGene-283(BeiGene)、BUB-024(MLN 2480)(Sunesis&Takeda)、b-raf抑制剂(Sareum)、BRAF激酶抑制剂(Selexagen Therapeutics)、BRAF siRNA 313(tacaccagcaagctagatgca)和523(cctatcgttagagtcttcctg)(Liu等人，2007)、CHIR-265(Novartis)、CTT239065(Institute of Cancer Research)、达拉非尼(GSK2118436)、DP-4978(Deciphera Pharmaceuticals)、HM-95573(Hanmi)、GDC-0879(Genentech)、GW-5074(Sigma Aldrich)、ISIS 5132(Novartis)、L779450(Merck)、LBT613(Novartis)、LXH254(Novartis)、LErafAON(NeoPharm,Inc.)、LGX-818(Novartis)、帕唑帕尼(GlaxoSmithKline)、PLX3202(Plexxikon)、PLX4720(Plexxikon)、PLX5568(Plexxikon)、PLX3603(Daiichi Sankyo)、PLX8394(Daiichi Sankyo)、RAF-265(Novartis)、RAF-365(Novartis)、REDX0535(RedX Pharma Plc)、瑞戈非尼(Bayer HealthcarePharmaceuticals,Inc.)、RO 5126766(Hoffmann-La Roche)、SB-590885(GlaxoSmithKline)、SB699393(GlaxoSmithKline)、索拉非尼(Onyx Pharmaceuticals)、TAK 632(Takeda)、TL-241(Teligene)、维拉非尼(RG7204或PLX4032)(Daiichi Sankyo)、XL-281(Exelixis)、ZM-336372(AstraZeneca)、其药学上可接受的盐及其组合。
根据一些实施方案，HDAC抑制剂选自艾贝司他(PCI-24781)、吉诺司他、恩替司他、扶林司他、CI-994、CUDC-101、恩替司他、BML-210、M344、NVP-LAQ824、帕比司他、Pracinosat(SB939)、Mocetinostat、Resminostat、罗米地辛、贝利诺司他、其药学上可接受的盐及其组合。
根据一些实施方案，该方法进一步包括向具有非V600E/K BRAF突变的受试者施用选自抗体、抗体片段、抗体缀合物、细胞毒性剂、毒素、放射性核素、免疫调控剂、光活化治疗剂、放射增敏剂、激素、抗血管生成剂及其组合的至少一种另外的治疗剂。
根据一些实施方案，抗体或其片段选自利妥昔单抗(Rituxan)、布伦妥昔单抗维多汀(Adcetriz)、阿多曲妥珠单抗艾坦肽(Kadcyla)西妥昔单抗(Erbitux)、贝伐单抗(Avastin)、替伊莫单抗(Zevalin)、维多珠单抗(Entyvio)、伊匹单抗(Yervoy)、纳武单抗(Opdivo)、派姆单抗(Keytruda)、阿伦单抗阿特朱单抗(Tecentriq)、阿维鲁单抗(Bavencio)、德鲁瓦单抗(Imfinzi)、B-701、奥法木单抗、阿托珠单抗(Obinutuzumab)(Gazyva)帕尼单抗、plozalizumab、BI-754091、OREG-103、COM-701、BI-754111及其组合。
根据一些实施方案，细胞毒性剂选自环磷酰胺、甲氯乙胺、尿嘧啶氮芥、美法仑、苯丁酸甲氯乙胺、异环磷酰胺、卡莫司汀、洛莫司汀、链脲霉素、白消安、替莫唑胺、顺铂、卡铂、奥沙利铂、奈达铂、沙铂、三硝酸四铂、阿霉素、柔红霉素、伊达比星、米托蒽醌、甲氨蝶呤、培美曲塞、6-巯基嘌呤、达卡巴嗪、氟达拉滨、5-氟尿嘧啶、阿拉伯糖胞嘧啶、卡培他滨、吉西他滨、地西他滨、长春花生物碱、紫杉醇(Taxol)、多西他赛(Taxotere)、依沙贝比隆(Ixempra)、放线菌素、蒽环类、缬沙星、表柔比星、博来霉素、普卡霉素、丝裂霉素、其药学上可接受的盐、前药及其组合。
根据一些实施方案，毒素是白喉毒素或其部分。
根据一些实施方案，放射性核素选自I-125、At-211、Lu-177、Cu-67、I-131、Sm-153、Re-186、P-32、Re-188、In-114m、Y-90及其组合。
根据一些实施方案，免疫调控剂选自粒细胞集落刺激因子(G-CSF)、LAG-3、IMP-321、JCAR-014、ASLAN-002(BMS-777607)、干扰素、咪喹莫特和来自细菌的细胞膜组分、IL-2、IL-7、IL-12、CCL3、CCL26、CXCL7、合成的胞嘧啶磷酸鸟苷(CpG)、免疫检查点抑制剂及其组合。
根据一些实施方案，放射增敏剂选自米索硝唑、甲硝唑、替拉帕明、反式丁香酸钠及其组合。
根据一些实施方案，激素选自前列腺素、白三烯、前列环素、血栓烷、淀粉纤维素、抗苗勒管激素、脂联素、促肾上腺皮质激素、血管紧张素原、血管紧张素、血管加压素、心房肽、脑钠尿肽、降血钙素、胆囊收缩素、促肾上腺皮质激素释放激素、脑啡肽、内皮素、促红细胞生成素、促卵泡激素、甘丙肽、胃泌素、生长激素释放肽、胰高血糖素、促性腺激素释放激素、生长激素释放激素、人绒毛膜促性腺激素、人胎盘促泌素、生长激素、抑制素、胰岛素、生长调节素、瘦素、促脂素、促黄体生成素、黑素细胞刺激激素、胃动素、食欲素、催产素、胰多肽、甲状旁腺激素、催乳素、催乳素释放激素、松弛素、肾素、分泌素、生长抑素、血小板生成素、促甲状腺激素、睾丸酮、脱氢表雄酮、雄烯二酮、二氢睾丸酮、醛固酮、雌二醇、雌酮、雌三醇、皮质醇、孕酮、骨化三醇、骨化二醇、他莫昔芬(Nolvadex)、阿那曲唑(Arimidex)、来曲唑(Femara)、氟司韦特(Faslodex)及其组合。
根据一些实施方案，抗血管生成剂选自2-甲氧基雌二醇、血管抑制素、贝伐单抗、软骨衍生的血管生成抑制因子、内皮抑素、IFN-α、IL-12、伊曲康唑、利诺米特、血小板因子4、催乳素、SU5416、苏拉明、他克莫尼、替加仑、四硫代钼酸盐、沙利度胺、血小板反应蛋白、血小板反应蛋白、TNP-470、齐夫-阿柏西普、其药学上可接受的盐、前药及其组合。
根据一些实施方案，另外的治疗剂是PI3K/Akt途径的抑制剂。
根据一些实施方案，PI3K/Akt途径的抑制剂选自A-674563(CAS#552325-73-2)、AGL 2263、AMG-319(Amgen,Thousand Oaks,CA)、AS-041164(5-苯并[1,3]二恶唑-5-基亚甲基-噻唑烷-2,4-二酮)、AS-604850(5-(2,2-二氟-苯并[1,3]二恶唑-5-基亚甲基)-噻唑烷-2,4-二酮)、AS-605240(5-喹喔啉-6-亚甲基-1,3-噻唑烷-2,4-二酮)、AT7867(CAS#857531-00-1)、苯并咪唑系列，Genentech(Roche Holdings Inc.,South San Francisco,CA)、BML-257(CAS#32387-96-5)、BVD-723、CAL-120(Gilead Sciences,Foster City,CA)、CAL-129(Gilead Sciences)、CAL-130(Gilead Sciences)、CAL-253(Gilead Sciences)、CAL-263(Gilead Sciences)、CAS#612847-09-3、CAS#681281-88-9、CAS#75747-14-7、CAS#925681-41-0、CAS#98510-80-6、CCT128930(CAS#885499-61-6)、CH5132799(CAS#1007207-67-1)、CHR-4432(Chroma Therapeutics,Ltd.,Abingdon,UK)、FPA 124(CAS#902779-59-3)、GS-1101(CAL-101)(Gilead Sciences)、GSK 690693(CAS#937174-76-0)、H-89(CAS#127243-85-0)、Honokiol、IC87114(Gilead Science)、IPI-145(Intellikine Inc.)、KAR-4139(Karus Therapeutics,Chilworth,UK)、KAR-4141(Karus Therapeutics)、KIN-1(KarusTherapeutics)、KT 5720(CAS#108068-98-0)、米替福新、MK-2206二盐酸化物(CAS#1032350-13-2)、ML-9(CAS#105637-50-1)、盐酸纳曲通、OXY-111A(NormOxys Inc.,Brighton,MA)、perifosine、PHT-427(CAS#1191951-57-1)、PI3激酶δ抑制剂，Merck KGaA(Merck&Co.,Whitehouse Station,NJ)、PI3激酶δ抑制剂，Genentech(Roche HoldingsInc.)、PI3激酶δ抑制剂，Incozen(Incozen Therapeutics,Pvt.Ltd.,Hydrabad,India)、PI3激酶δ抑制剂2，Incozen(Incozen Therapeutics)、PI3激酶抑制剂，Roche-4(RocheHoldings Inc.)、PI3激酶抑制剂，Roche(Roche Holdings Inc.)、PI3激酶抑制剂，Roche-5(Roche Holdings Inc.)、PI3-α/δ抑制剂，Pathway Therapeutics(Pathway TherapeuticsLtd.,South San Francisco,CA)、PI3-δ抑制剂，Cellzome(Cellzome AG,Heidelberg,Germany)、PI3-δ抑制剂，Intellikine(Intellikine Inc.,La Jolla,CA)、PI3-δ抑制剂，Pathway Therapeutics-1(Pathway Therapeutics Ltd.)、PI3-δ抑制剂，PathwayTherapeutics-2(Pathway Therapeutics Ltd.)、PI3-δ/γ抑制剂，Cellzome(CellzomeAG)、PI3-δ/γ抑制剂，Cellzome(Cellzome AG)、PI3-δ/γ抑制剂，Intellikine(Intellikine Inc.)、PI3-δ/γ抑制剂，Intellikine(Intellikine Inc.)、PI3-δ/γ抑制剂，Pathway Therapeutics(Pathway Therapeutics Ltd.)、PI3-δ/γ抑制剂，PathwayTherapeutics(Pathway Therapeutics Ltd.)、PI3-γ抑制剂，Evotec(Evotec)、PI3-γ抑制剂，Cellzome(Cellzome AG)、PI3-γ抑制剂，Pathway Therapeutics(PathwayTherapeutics Ltd.)、PI3Kδ/γ抑制剂，Intellikine-1(Intellikine Inc.)、PI3Kδ/γ抑制剂，Intellikine-1(Intellikine Inc.)、pictilisib(Roche Holdings Inc.)、PIK-90(CAS#677338-12-4)、SC-103980(Pfizer,New York,NY)、SF-1126(SemaforePharmaceuticals,Indianapolis,IN)、SH-5、SH-6、四氢姜黄素、TG100-115(TargegenInc.,San Diego,CA)、曲西瑞宾、X-339(Xcovery,West Palm Beach,FL)、XL-499(Evotech,Hamburg,Germany)、其药学上可接受的盐及其组合。
根据一方面，本公开内容提供了用于在携带非V600E/K BRAF突变的受试者中治疗或缓解癌症的影响的药物组合物，该组合物包含药学上可接受的载体或稀释剂和有效量的ERK抑制剂或其药学上可接受的盐。
根据一些实施方案，ERK抑制剂选自BVD-523、SCH-722984(Merck&Co.)、SCH-772984(Merck&Co.)、SCH-900353(MK-8353)(Merck&Co.)、LY3214996(Lilly)、LY3214996(Lilly)、AEZS-140(Aeterna Zentaris)、AEZS-131(Aeterna Zentaris)、AEZS-136(Aeterna Zentaris)、LTT-462(Novartis)、RG-7842(Genentech)、CC-90003(Celgene)、KIN-4050(Kinentia)及其组合。
根据一些实施方案，ERK抑制剂是BVD-523。
根据一些实施方案，非V600E/K BRAF突变是激酶活化的突变、激酶受损的突变或激酶未知的突变及其组合。
根据一些实施方案，激酶活化的突变选自R462I、I463S、G464E、G464R、G464V、G466A、G469A、N581S、E586K、F595L、L597Q、L597R、L597S、L597V、A598V、T599E、V600R、K601E、S602D、A728V及其组合。
根据一些实施方案，激酶受损的突变选自G466E、G466R、G466V、Y472C、K483M、D594A、D594E、D594G、D594H、D594N、D594V、G596R、T599A、S602A及其组合。
根据一些实施方案，激酶未知的突变选自T440I、S467L、G469E、G469R、G469S、G469V、L584F、L588F、V600_K601delinsE、S605I、Q609L、E611Q及其组合。
根据一些实施方案，受试者是哺乳动物。
根据一些实施方案，哺乳动物选自人、灵长类动物、农场动物和家养动物。
根据一些实施方案，哺乳动物是人。
根据一些实施方案，癌症是实体瘤癌症或血液癌症。
根据一些实施方案，癌症选自胶质母细胞瘤、黑素瘤、胆管癌、小细胞肺癌、结肠直肠癌、前列腺癌、阴道癌、血管肉瘤、非小细胞肺癌、阑尾癌、鳞状细胞癌、唾液管癌、腺样囊性癌、小肠癌和胆囊癌。
根据一些实施方案，癌症选自小肠癌、非小细胞肺癌、胆囊癌和鳞状细胞癌。
根据一些实施方案，组合物口服或通过注射施用给受试者。
根据一些实施方案，组合物以片剂施用给受试者。
根据一些实施方案，药物组合选自MEK抑制剂、RAF抑制剂、HDAC抑制剂及其组合的至少一种另外的治疗剂。
根据一些实施方案，MEK抑制剂选自炭疽毒素、蒽醌(Golden Biotechnology)、ARRY-142886(6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺)(Array BioPharma)、ARRY-438162(Array BioPharma)贝美替尼(MEK162，ARRY-1662)、AS-1940477(Astellas)、AS-703988(Merck KGaA)、bentamapimod(Merck KGaA)、BI-847325(Boehringer Ingelheim)、E-6201(Eisai)、GDC-0623(Hoffmann-La Roche)、GDC-0973(考比替尼)(Hoffmann-La Roche)、L783277(Merck)、炭疽毒素的致死因子部分、MEK162(Array BioPharma)、PD 098059(2-(2'-氨基-3'-甲氧苯基)-氧萘-4-酮)(Pfizer)、PD 184352(CI-1040)(Pfizer)、PD-0325901(Pfizer)、PD318088(Pfizer)、PD334581(Pfizer)、6-甲氧基-7-(3-吗啉-4-基-丙氧基)-4-(4-苯氧基-苯基氨基)-喹啉-3-甲腈、4-[3-氯-4-(1-甲基-1H-咪唑-2-基硫烷基)-苯基氨基]-6-甲氧基-7-(3-吗啉-4-基-丙氧基)-喹啉-3-甲腈、pimasertib(Santhera Pharmaceuticals)、RDEA119(ArdeaBiosciences/Bayer)、瑞美替尼(AstraZeneca)、RG422(Chugai Pharmaceutical Co.)、R0092210(Roche)、R04987655(Hoffmann-La Roche)、R05126766(Hoffmann-La Roche)、司美替尼(AZD6244)(AstraZeneca)、SL327(Sigma)、TAK-733(Takeda)、曲美替尼(JapanTobacco)、U0126(1,4-二氨基-2,3-二氰基-1,4-双(2-氨基苯硫基)丁二烯)(Sigma)、WX-554(Wilex)、YopJ多肽(Mittal等人，2010)、其药学上可接受的盐及其组合。
根据一些实施方案，RAF抑制剂选自AAL881(Novartis)、AB-024(AmbitBiosciences)、ARQ-736(ArQule)、ARQ-761(ArQule)、AZ628(Axon Medchem BV)、BAY 43-9006索拉非尼、BeiGene-283(BeiGene)、BUB-024(MLN 2480)(Sunesis&Takeda)、b-raf抑制剂(Sareum)、BRAF激酶抑制剂(Selexagen Therapeutics)、BRAF siRNA 313(tacaccagcaagctagatgca)和523(cctatcgttagagtcttcctg)(Liu等人，2007)、CHIR-265(Novartis)、CTT239065(Institute of Cancer Research)、达拉非尼(GSK2118436)、DP-4978(Deciphera Pharmaceuticals)、HM-95573(Hanmi)、GDC-0879(Genentech)、GW-5074(Sigma Aldrich)、ISIS 5132(Novartis)、L779450(Merck)、LBT613(Novartis)、LXH254(Novartis)、LErafAON(NeoPharm,Inc.)、LGX-818(Novartis)、帕唑帕尼(GlaxoSmithKline)、PLX3202(Plexxikon)、PLX4720(Plexxikon)、PLX5568(Plexxikon)、PLX3603(Daiichi Sankyo)、PLX8394(Daiichi Sankyo)、RAF-265(Novartis)、RAF-365(Novartis)、REDX0535(RedX Pharma Plc)、瑞戈非尼(Bayer HealthcarePharmaceuticals,Inc.)、RO 5126766(Hoffmann-La Roche)、SB-590885(GlaxoSmithKline)、SB699393(GlaxoSmithKline)、索拉非尼(Onyx Pharmaceuticals)、TAK 632(Takeda)、TL-241(Teligene)、维拉非尼(RG7204或PLX4032)(Daiichi Sankyo)、XL-281(Exelixis)、ZM-336372(AstraZeneca)、其药学上可接受的盐及其组合。
根据一些实施方案，HDAC抑制剂选自艾贝司他(PCI-24781)、吉诺司他、恩替司他、扶林司他、CI-994、CUDC-101、恩替司他、BML-210、M344、NVP-LAQ824、帕比司他、Pracinosat(SB939)、Mocetinostat、Resminostat、罗米地辛、贝利诺司他、其药学上可接受的盐及其组合。
根据一些实施方案，药物组合物进一步包含选自抗体或其片段、细胞毒性剂、毒素、放射性核素、免疫调控剂、光活化治疗剂、放射增敏剂、激素、抗血管生成剂及其组合的至少一种另外的治疗剂。
根据一些实施方案，抗体、其片段或其缀合物选自利妥昔单抗(Rituxan)、布伦妥昔单抗维多汀(Adcetriz)、阿多曲妥珠单抗艾坦肽(Kadcyla)西妥昔单抗(Erbitux)、贝伐单抗(Avastin)、替伊莫单抗(Zevalin)、维多珠单抗(Entyvio)、伊匹单抗(Yervoy)、纳武单抗(Opdivo)、派姆单抗(Keytruda)、阿伦单抗阿特朱单抗(Tecentriq)、阿维鲁单抗(Bavencio)、德鲁瓦单抗(Imfinzi)、B-701、奥法木单抗、阿托珠单抗(Gazyva)帕尼单抗、plozalizumab、BI-754091、OREG-103、COM-701、BI-754111及其组合。
根据一些实施方案，细胞毒性剂选自环磷酰胺、甲氯乙胺、尿嘧啶氮芥、美法仑、苯丁酸甲氯乙胺、异环磷酰胺、卡莫司汀、洛莫司汀、链脲霉素、白消安、替莫唑胺、顺铂、卡铂、奥沙利铂、奈达铂、沙铂、三硝酸四铂、阿霉素、柔红霉素、伊达比星、米托蒽醌、甲氨蝶呤、培美曲塞、6-巯基嘌呤、达卡巴嗪、氟达拉滨、5-氟尿嘧啶、阿拉伯糖胞嘧啶、卡培他滨、吉西他滨、地西他滨、长春花生物碱、紫杉醇(Taxol)、多西他赛(Taxotere)、依沙贝比隆(Ixempra)、放线菌素、蒽环类、缬沙星、表柔比星、博来霉素、普卡霉素、丝裂霉素、其药学上可接受的盐、前药及其组合。
根据一些实施方案，毒素是白喉毒素或其部分。
根据一些实施方案，放射性核素选自I-125、At-211、Lu-177、Cu-67、I-131、Sm-153、Re-186、P-32、Re-188、In-114m、Y-90及其组合。
根据一些实施方案，免疫调控剂选自粒细胞集落刺激因子(G-CSF)、LAG-3、IMP-321、JCAR-014、ASLAN-002(BMS-777607)、干扰素、咪喹莫特和来自细菌的细胞膜组分、IL-2、IL-7、IL-12、CCL3、CCL26、CXCL7、合成的胞嘧啶磷酸鸟苷(CpG)、免疫检查点抑制剂及其组合。
根据一些实施方案，放射增敏剂选自米索硝唑、甲硝唑、替拉帕明、反式丁香酸钠及其组合。
根据一些实施方案，激素选自前列腺素、白三烯、前列环素、血栓烷、淀粉纤维素、抗苗勒管激素、脂联素、促肾上腺皮质激素、血管紧张素原、血管紧张素、血管加压素、心房肽、脑钠尿肽、降血钙素、胆囊收缩素、促肾上腺皮质激素释放激素、脑啡肽、内皮素、促红细胞生成素、促卵泡激素、甘丙肽、胃泌素、生长激素释放肽、胰高血糖素、促性腺激素释放激素、生长激素释放激素、人绒毛膜促性腺激素、人胎盘促泌素、生长激素、抑制素、胰岛素、生长调节素、瘦素、促脂素、促黄体生成素、黑素细胞刺激激素、胃动素、食欲素、催产素、胰多肽、甲状旁腺激素、催乳素、催乳素释放激素、松弛素、肾素、分泌素、生长抑素、血小板生成素、促甲状腺激素、睾丸酮、脱氢表雄酮、雄烯二酮、二氢睾丸酮、醛固酮、雌二醇、雌酮、雌三醇、皮质醇、孕酮、骨化三醇、骨化二醇、他莫昔芬(Nolvadex)、阿那曲唑(Arimidex)、来曲唑(Femara)、氟司韦特(Faslodex)及其组合。
根据一些实施方案，抗血管生成剂选自2-甲氧基雌二醇、血管抑制素、贝伐单抗、软骨衍生的血管生成抑制因子、内皮抑素、IFN-α、IL-12、伊曲康唑、利诺米特、血小板因子4、催乳素、SU5416、苏拉明、他克莫尼、替加仑、四硫代钼酸盐、沙利度胺、血小板反应蛋白、血小板反应蛋白、TNP-470、齐夫-阿柏西普、其药学上可接受的盐、前药及其组合。
根据一些实施方案，另外的治疗剂是PI3K/Akt途径的抑制剂。
根据一些实施方案，PI3K/Akt途径的抑制剂选自A-674563(CAS#552325-73-2)、AGL 2263、AMG-319(Amgen,Thousand Oaks,CA)、AS-041164(5-苯并[1,3]二恶唑-5-基亚甲基-噻唑烷-2,4-二酮)、AS-604850(5-(2,2-二氟-苯并[1,3]二恶唑-5-基亚甲基)-噻唑烷-2,4-二酮)、AS-605240(5-喹喔啉-6-亚甲基-1,3-噻唑烷-2,4-二酮)、AT7867(CAS#857531-00-1)、苯并咪唑系列，Genentech(Roche Holdings Inc.,South San Francisco,CA)、BML-257(CAS#32387-96-5)、BVD-723、CAL-120(Gilead Sciences,Foster City,CA)、CAL-129(Gilead Sciences)、CAL-130(Gilead Sciences)、CAL-253(Gilead Sciences)、CAL-263(Gilead Sciences)、CAS#612847-09-3、CAS#681281-88-9、CAS#75747-14-7、CAS#925681-41-0、CAS#98510-80-6、CCT128930(CAS#885499-61-6)、CH5132799(CAS#1007207-67-1)、CHR-4432(Chroma Therapeutics,Ltd.,Abingdon,UK)、FPA 124(CAS#902779-59-3)、GS-1101(CAL-101)(Gilead Sciences)、GSK 690693(CAS#937174-76-0)、H-89(CAS#127243-85-0)、Honokiol、IC87114(Gilead Science)、IPI-145(Intellikine Inc.)、KAR-4139(Karus Therapeutics,Chilworth,UK)、KAR-4141(Karus Therapeutics)、KIN-1(KarusTherapeutics)、KT 5720(CAS#108068-98-0)、米替福新、MK-2206二盐酸化物(CAS#1032350-13-2)、ML-9(CAS#105637-50-1)、盐酸纳曲通、OXY-111A(NormOxys Inc.,Brighton,MA)、perifosine、PHT-427(CAS#1191951-57-1)、PI3激酶δ抑制剂，Merck KGaA(Merck&Co.,Whitehouse Station,NJ)、PI3激酶δ抑制剂，Genentech(Roche HoldingsInc.)、PI3激酶δ抑制剂，Incozen(Incozen Therapeutics,Pvt.Ltd.,Hydrabad,India)、PI3激酶δ抑制剂2，Incozen(Incozen Therapeutics)、PI3激酶抑制剂，Roche-4(RocheHoldings Inc.)、PI3激酶抑制剂，Roche(Roche Holdings Inc.)、PI3激酶抑制剂，Roche-5(Roche Holdings Inc.)、PI3-α/δ抑制剂，Pathway Therapeutics(Pathway TherapeuticsLtd.,South San Francisco,CA)、PI3-δ抑制剂，Cellzome(Cellzome AG,Heidelberg,Germany)、PI3-δ抑制剂，Intellikine(Intellikine Inc.,La Jolla,CA)、PI3-δ抑制剂，Pathway Therapeutics-1(Pathway Therapeutics Ltd.)、PI3-δ抑制剂，PathwayTherapeutics-2(Pathway Therapeutics Ltd.)、PI3-δ/γ抑制剂，Cellzome(CellzomeAG)、PI3-δ/γ抑制剂，Cellzome(Cellzome AG)、PI3-δ/γ抑制剂，Intellikine(Intellikine Inc.)、PI3-δ/γ抑制剂，Intellikine(Intellikine Inc.)、PI3-δ/γ抑制剂，Pathway Therapeutics(Pathway Therapeutics Ltd.)、PI3-δ/γ抑制剂，PathwayTherapeutics(Pathway Therapeutics Ltd.)、PI3-γ抑制剂，Evotec(Evotec)、PI3-γ抑制剂，Cellzome(Cellzome AG)、PI3-γ抑制剂，Pathway Therapeutics(PathwayTherapeutics Ltd.)、PI3Kδ/γ抑制剂，Intellikine-1(Intellikine Inc.)、PI3Kδ/γ抑制剂，Intellikine-1(Intellikine Inc.)、pictilisib(Roche Holdings Inc.)、PIK-90(CAS#677338-12-4)、SC-103980(Pfizer,New York,NY)、SF-1126(SemaforePharmaceuticals,Indianapolis,IN)、SH-5、SH-6、四氢姜黄素、TG100-115(TargegenInc.,San Diego,CA)、曲西瑞宾、X-339(Xcovery,West Palm Beach,FL)、XL-499(Evotech,Hamburg,Germany)、其药学上可接受的盐及其组合。
根据一些实施方案，药物组合物是包含ERK抑制剂和另外的治疗剂的单位剂型。
根据一些实施方案，药物组合物ERK抑制剂为第一单位剂型和另外的治疗剂为与第一单位剂型分开的第二单位剂型。
根据一些实施方案，将ERK抑制剂和另外的治疗剂共同施用给受试者。
根据一些实施方案，将ERK抑制剂和另外的治疗剂逐次地施用给受试者。
根据一些实施方案，ERK抑制剂在另外的治疗剂的施用之前或之后施用给受试者。
根据一方面，本公开内容提供了用于在携带非V600E/K BRAF突变的受试者中治疗或缓解癌症的影响的方法，该方法包括向受试者施用有效量的BVD-523或其药学上可接受的盐。
根据一方面，本公开内容提供了用于在受试者中治疗或改善癌症的影响的方法，包括：(a)鉴定携带非V600E/K BRAF突变的患有癌症的受试者；和(b)向受试者施用有效量的BVD-523或其药学上可接受的盐。
根据一方面，本公开内容提供了用于鉴定将从BVD-523或其药学上可接受的盐的疗法中受益的患有癌症的受试者的方法，该方法包括：(a)从受试者获得生物样品；和(b)筛选样品以确定受试者是否具有非V600E/K BRAF突变，其中非V600E/K BRAF突变的存在证实受试者将从BVD-523或其药学上可接受的盐疗法中受益。
根据一方面，本公开内容提供了用于在携带非V600E/K BRAF突变的受试者中治疗或缓解癌症的影响的药物组合物，该组合物包含药学上可接受的载体或稀释剂和有效量的BVD-523或其药学上可接受的盐。
根据一方面，本公开内容提供了用于在携带非V600E/K BRAF突变的受试者中治疗或缓解癌症的影响的试剂盒，该试剂盒包括根据权利要求88、103和107中任一项的药物组合物及包装在一起的其使用说明书。
根据一些实施方案，RAF抑制剂选自厄洛替尼(Tarceva)、吉非替尼
(Iressa)、甲磺酸伊马替尼(Gleevec)、拉帕替尼(Tyverb)、苹果酸舒尼替尼(Sutent)、其药学上可接受的盐及其组合。
根据一些实施方案，RAF抑制剂选自LXH254(Novartis)、PLX3603(DaiichiSankyo)、PLX8394(Daiichi Sankyo)、REDX0535(RedX Pharma Plc)、其药学上可接受的盐及其组合。
根据一些实施方案，HDAC抑制剂选自扶林司他、帕诺比司他、罗米地辛、贝利司他、其药学上可接受的盐及其组合。
根据一些实施方案，抗体、其片段或其缀合物选自利妥昔单抗(Rituxan)、布伦妥昔单抗维多汀(Adcetriz)、阿多曲妥珠单抗艾坦肽(Kadcyla)、伊匹单抗(Yervoy)、纳武单抗(Opdivo)、派姆单抗(Keytruda)、阿伦单抗阿特朱单抗(Tecentriq)、德鲁瓦单抗(Imfinzi)、奥法木单抗、阿托珠单抗(Gazyva)、帕尼单抗及其组合。
根据一些实施方案，PI3K/Akt途径的抑制剂是BVD-723。
附图的简要说明
图1显示了丝裂原活化蛋白激酶(MAPK)途径的示意图。
图2显示了用BVD-523治疗的患者的应答。包括通过RECIST v1.1测量的所有患病患者，他们接受了一剂或更多的研究治疗以及一次以上的治疗中肿瘤评估。应答被测量为每个靶病变最长直径的总和相对于基线的变化。实线指示根据RECIST v1.1对于部分应答的阈值。缩写：GBM，胶质母细胞瘤；NSCLC，非小细胞肺癌；CRC，结肠直肠癌。指示了与每个患者的癌症相关的非典型BRAF突变。
图3显示了按组分类的游泳者图(Swimmer’s plot)中的治疗持续时间。第一组的成员是在除结肠直肠癌(CRC)和非小细胞肺癌(NSCLC)以外的任何肿瘤类型中具有任何BRAF突变，并且先前未接受过MAPK途径抑制剂的治疗的任何患者。第2组的成员是在CRC中具有任何BRAF突变，先前未接受MAPK途径抑制剂的治疗的患者。第3组的成员是患有具有BRAF V600E/K突变的肿瘤，该肿瘤对MAPK抑制剂治疗无效的患者。第6组的成员是具有在NSCLC中存在的任何BRAF突变的患者。如图3所示，包括所有28名患者通过横线表示，每个受试者一个横线。从组的顶部(最长治疗持续时间)到底部(最短治疗持续时间)说明了每个组中每个受试者的治疗持续时间。水平轴表示患者在研究中的持续时间(天)。图3还显示了根据RECIST v1.1为每个患者实现的应答应类型(菱形＝部分应答；圆圈＝稳定疾病；垂直线＝进展性疾病；三角形＝未评估)。
图4显示了因BRAF突变而破坏的游泳者图中的治疗持续时间。包括所有根据RECIST v1.1应答标准测量的28位患者，以及未通过RECIST v1.1评估的其他患者(菱形＝部分应答；圆圈＝稳定疾病；竖线＝进展性疾病；三角形＝未评估)。
发明详述
根据一个方面，本公开提供了用于在携带非V600E/K BRAF突变的受试者中治疗或缓解癌症的影响的方法，该方法包括向受试者施用有效量的ERK抑制剂或其药学上可接受的盐。
如本文所用，术语“V600E/K BRAF突变”，与受试者中的癌症有关，及其语法变化，是指在编码人BRAF(SEQ ID NO：2)的基因中包含非同义取代突变的癌细胞，所述非同义取代突变导致在BRAF的氨基酸位置600的氨基酸缬氨酸(V)被取代为谷氨酸(E)或赖氨酸(K)。如本文所用，术语“携带非V600E/K BRAF突变”，与受试者中的癌症有关，及其语法变化，是指癌细胞包含不是V600E/K BRAF突变的体细胞突变。如本文所用，所有BRAF突变均基于人野生型序列(SEQ ID NO：2)。本文也包括来自其他物种的直系同源物。
如本文所用，术语“治疗”，“在治疗”、“处理”及其语法变化是指使个体受试者接受方法、方案、过程或措施，其中希望在受试者例如患者中获得生理学应答或结果。特别地，本发明的方法和组合物可以用于减缓疾病症状的发展或延迟疾病或病况的发作，或者中止疾病发展的进程。然而，因为每个被治疗的受试者可能对特定的治疗方法、方案、过程或措施没有应答，所以治疗不需要在各个或每个受试者或受试者群体例如患者群体中实现所需的生理应答或结果。因此，给定的受试者或受试者群体，例如患者群体可能对治疗没有应答或应答不足。
如本文所用，术语“缓解”及其语法变化是指降低受试者中疾病症状的严重性。
如本文所用，“受试者”是哺乳动物，优选地地人。除了人以外，在本发明范围内的哺乳动物的类别包括例如农场动物、家养动物、实验动物等。农场动物的一些实例包括牛、猪、马、山羊等。家养动物的一些实例包括狗，猫等。实验动物的一些实例包括灵长类动物、大鼠、小鼠、兔子、豚鼠等。
如本文所用，术语本文所公开的化合物或组合物的“有效量”或“治疗有效量”是当施用给受试者时足以实现如本文所述的有益或所需结果的此类化合物或组合物的量。有效的剂型、施用方式和剂量可以凭经验确定，并且这种确定在本领域技术范围内。本领域技术人员应理解，剂量将随施用途径，排泄速率，治疗持续时间，施用的任何其他药物的特征，哺乳动物例如人类患者的年龄、大小和种类，以及医学和兽医学领域众所周知的类似因素而变化。通常，根据本发明的化合物或组合物的合适剂量将是该组合物的这样的量，其是有效产生所需作用的最低剂量。本发明化合物或组合物的有效剂量可以全天以适当的间隔分开以两个、三个、四个、五个、六个或更多个亚剂量施用。
根据一些实施方案，ERK抑制剂选自BVD-523、SCH-722984(Merck&Co.)、SCH-772984(Merck&Co.)、SCH-900353(MK-8353)(Merck&Co.)、LY3214996(Lilly)、AEZS-140(Aeterna Zentaris)、AEZS-131(Aeterna Zentaris)、AEZS-136(Aeterna Zentaris)、LTT-462(Novartis)、RG-7842(Genentech)、CC-90003(Celgene)、KIN-4050(Kinentia)及其组合。根据一些实施方案，ERK抑制剂是BVD-523。
在本发明中，BVD-523是根据式(I)的化合物：
Figure BDA0002323874170000271
及其药学上可接受的盐。BVD-523是一种高效的、选择性的、可逆的、ATP竞争性的ERK1/2抑制剂。BVD-523可以根据例如美国专利号7,354,939中公开的方法进行合成，其通过引用并入本文。BVD-523的两个对映异构体的对映异构体和外消旋混合物也包括在本发明的范围内。BVD-523是其作用机理被认为例如与某些其他ERK1/2抑制剂例如SCH772984是独特的和不同的ERK1/2抑制剂。例如，其他ERK1/2抑制剂(例如SCH772984)抑制ERK的自磷酸化(Morris等人，2013)，而BVD-523允许ERK的自磷酸化同时仍抑制ERK。
根据一些实施方案，受试者的癌症在BRAF基因中具有体细胞突变。如本文所用，“体细胞突变”是指在不注定要成为生殖细胞的任何细胞中发生的变化。突变可以是例如取代、缺失、插入或融合。下表1显示了BRAF突变的分布概况，如Sanger数据库所示。
表1
Figure BDA0002323874170000272
在大约66％黑色素瘤中发现了BRAF突变(Davies等人，2002；Brose等人，2002；Hocket等人，2007)，并且在其他癌症中相对更低的百分比，36％甲状腺肿瘤和10％结肠癌(Xu等人，2003；Fransen等人，2004)。最普遍的BRAF突变发生在人野生型蛋白激酶(SEQ IDNO：2)的氨基酸600处，通过用谷氨酸取代缬氨酸产生突变体B-RafV600E，其占BRAF突变的约80％(Davies等人，2002；Hocker等人，2007)。与野生型B-Raf的基础活性相比，B-RafV600E激酶结构域具有500倍高的激酶活性(Wan等人，2004)。在黑素瘤中鉴定出的其他BRAF突变中，V600K和V600D/R也很常见，并且分别代表所有BRAF突变的16％和3％(Long等人，2011)。除黑色素瘤外，BRAF突变在许多其他癌症中也很常见，包括甲状腺乳头状癌、卵巢癌和结肠直肠癌。(Wellbrock等人，2004)。在一项研究中，在5/24(21％)的结肠直肠癌细胞系中发现了BRAF剪接变体(剪接第14和15外显子)(Seth等人，2009)。
来自Sanger数据库的下表2显示了人肿瘤中BRAF突变的分布和频率。
表2
Figure BDA0002323874170000281
Figure BDA0002323874170000291
下表3显示了BRAF的选择的核酸和氨基酸序列。这些序列可以用于鉴定具有突变BRAF基因型的受试者的方法中(例如在以下阐述的方法中)。
表3
Figure BDA0002323874170000292
Figure BDA0002323874170000301
鉴定核酸例如上述鉴定的BRAF基因中突变的方法是本领域已知的。核酸可获自生物样品。在本发明中，生物学样品包括但不限于血液、血浆、尿液、皮肤、唾液和活检样品。通过本领域已知的常规程序和方法从受试者获得生物样品。
用于鉴定突变的方法的非限制性实例包括PCR、测序、杂交捕获、溶液内捕获、分子倒置探针、荧光原位杂交(FISH)测定法及其组合。
多种测序方法是本领域已知的。这些包括但不限于Sanger测序(也称为双脱氧测序)和例如Metzker 2005中公开的多种合成测序(SBS)方法、通过杂交测序、通过连接测序(例如WO2005021786)、通过降解测序(例如，美国专利号5,622,824和6,140,053)和纳米孔测序(其可从Oxford Nanopore Technologies,UK商购获得)。在深度测序技术中，在测序过程中多次读取序列中的给定核苷酸。深度测序技术公开在例如美国专利公开号20120264632和国际专利公开号WO2012125848中。
用于检测突变的基于PCR的方法是本领域已知的并且采用PCR扩增，其中样品中的每个靶序列具有独特的、序列特异性引物的相应对。例如，聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法允许在通过PCR扩增基因组序列后快速检测突变。该突变通过用特异性限制性核酸内切酶的消化来区分并通过电泳来鉴定。参见，例如Ota等人，2007。还可以使用实时PCR检测突变。参见，例如国际申请公开号WO2012046981。
杂交捕获方法是本领域中已知的并且在例如美国专利公开号20130203632和美国专利号8389219和8288520中公开。这些方法基于靶基因组区域对用户设计的寡核苷酸的选择性杂交。杂交可以是与固定化在高密度或低密度微阵列上的寡核苷酸(阵列捕获)，或者是与用配体(例如生物素)修饰的寡核苷酸的溶液相杂交，所述配体随后可以固定化在固体表面例如珠上(溶液中捕获)。
分子倒置探针(MIP)方法是本领域已知的并且例如在Absalan等人，2008中公开。此类方法使用MIP分子，其是特殊的“挂锁”探针(Nilsson等人，1994)用于基因分型。MIP分子是线性寡核苷酸，包含特定区域、通用序列、限制位点和Tag(索引)序列(16-22bp)。在这种方法中，MIP在目的遗传标志物/SNP的周围直接杂交。MIP方法也可以使用与基因组DNA平行杂交的许多“挂锁”探针组(Hardenbol等人，2003)。在完美匹配的情况下，通过进行构型反转(如技术名称所暗示的)并创建环状分子来连接基因组同源区域。第一次限制性酶切后，所有分子均用通用引物进行扩增。再次限制性酶切扩增子以确保用于在微阵列上杂交的短片段。标记产生的短片段，并通过Tag序列与阵列上的cTag(索引的互补链)杂交。在形成Tag-cTag双链体后，检测到信号。
根据一些实施方案，非V600E/K BRAF突变是激酶活化的突变、激酶受损的突变、激酶未知的突变及其组合。如本文所用，术语“激酶活化的突变”及其语法变化是指相对于野生型激酶，突变引起突变的激酶的激酶活性升高。如本文所用，术语“激酶受损的突变”及其语法变化是指相对于野生型激酶，突变引起突变的激酶的激酶活性降低。如本文所用，术语“激酶未知的突变”及其语法变化是指突变体激酶的活性是未知的或者突变的激酶的活性约等于野生型激酶的激酶活性。(参见Zheng，G.等人，Clinical detection andcategorization of uncommon and concomitant mutations involving BRAF,BMCCancer,(2015)15:779，通过引用整体并入本文)
根据一些实施方案，BRAF激酶活化的突变选自R462I、I463S、G464E、G464R、G464V、G466A、G469A、N581S、E586K、F595L、L597Q、L597R、L597S、L597V、A598V、T599E、V600R、K601E、S602D、A728V及其组合。根据一些实施方案，BRAF激酶受损的突变选自G466E、G466R、G466V、Y472C、K483M、D594A、D594E、D594G、D594H、D594N、D594V、G596R、T599A、S602A及其组合。根据一些实施方案，BRAF激酶未知的突变选自T440I、S467L、G469E、G469R、G469S、G469V、L584F、L588F、V600_K601delinsE、S605I、Q609L、E611Q及其组合。如本文所用，所有BRAF突变均基于人野生型序列(SEQ ID NO：2)。本文也包括来自其他物种的直系同源物。
在本发明中，用于治疗非V600E/K BRAF突变的方法和组合物对携带单个突变和一个或多个突变的疾病状态有效。实际上，本文公开的(或下文鉴定的)任何单个突变或突变的任何组合都可以用组合物或根据本发明的方法进行处理(例如，非V600E/K突变的任何组合或者非V600E/K突变和V600E/K突变的任何组合)。
根据一些实施方案，非V600E/K BRAF突变选自D594、G469、K601E、L597、T599重复、L485W、F247L、G466V、BRAF融合、BRAF-AGAP3重排、BRAF外显子15剪接变体及其组合。
如本文所用，氨基酸取代突变的注释包括以下的封闭形式：野生型氨基酸；位置；取代的氨基酸(例如K601E)。如本文所用，氨基酸取代的注释还包括以下的开放式形式：野生型氨基酸；位置(例如G469)。如本文所用，开放式注释包括任何氨基酸的取代。例如，G469突变揭示了位置469的甘氨酸被氨基酸A、R、N、D、C、Q、E、H、I、L、K、M、F、P、S、T、W、Y、V中任何一个取代。也如本文所用，封闭的注释包括被任何氨基酸取代，并且优选地被所述取代的氨基酸取代。例如，K601E突变揭示了位置601的赖氨酸被氨基酸A、R、N、D、C、Q、E、G、H、I、L、M、F、P、S、T、W、Y、V，以及更优选地被氨基酸E取代。本文所用的封闭注释的使用不应解释为将本公开内容限制为具体说明的氨基酸取代。
根据一些实施方案，包含携带非V600E/K BRAF突变的癌症的受试者是哺乳动物。根据一些实施方案，所述哺乳动物选自人、灵长类动物、农场动物和家养动物。根据一些实施方案，哺乳动物是人。
根据一些方面，本公开内容提供了实体癌和血液癌。实体癌的非限制性实例包括肾上腺皮质癌、肛门癌、膀胱癌、骨癌(例如骨肉瘤)、脑癌、乳腺癌、类癌、癌(carcinoma)、宫颈癌、结肠癌、子宫内膜癌、食道癌、肝外胆汁导管癌、尤因家族癌、颅外生殖细胞癌、眼癌、胆囊癌、胃癌、生殖细胞瘤、妊娠滋养细胞肿瘤、头颈癌、下咽癌、胰岛细胞癌、肾癌、大肠癌、喉癌、白血病、嘴唇和口腔癌、肝肿瘤/癌、肺肿瘤/癌、淋巴瘤、恶性间皮瘤、默克尔细胞癌、蕈样肉芽肿、骨髓增生异常综合征、骨髓增生性疾病、鼻咽癌、神经母细胞瘤、口腔癌、口咽癌、骨肉瘤、卵巢上皮癌、卵巢生殖细胞癌、胰腺癌、鼻旁窦和鼻腔癌、甲状旁腺癌、阴茎癌、垂体癌、浆细胞瘤、前列腺癌、横纹肌肉瘤、直肠癌、肾细胞癌、肾盂和输尿管的移行细胞癌、唾液腺癌、塞氏综合征、皮肤癌(如皮肤T细胞淋巴瘤、卡波西肉瘤、肥大细胞瘤和黑色素瘤)、小肠癌、软组织肉瘤、胃癌、睾丸癌、胸腺瘤、甲状腺癌、尿道癌、子宫癌、阴道癌、外阴癌和威尔姆斯瘤。
血液癌症的例子包括但不限于白血病，例如成人/儿童急性淋巴细胞白血病、成人/儿童急性髓细胞白血病、慢性淋巴细胞性白血病、慢性骨髓性白血病、和毛细胞白血病、淋巴瘤例如与艾滋病有关的淋巴瘤、皮肤T细胞淋巴瘤、成年/儿童霍奇金淋巴瘤、蕈样真菌病、成年/儿童非霍奇金淋巴瘤、原发性中枢神经系统淋巴瘤、塞氏综合征、皮肤T细胞淋巴瘤和Waldenstrom巨球蛋白血症、以及其他增生性病症例如慢性骨髓增生性疾病、朗格汉斯细胞组织细胞增生症、多发性骨髓瘤/浆细胞瘤、骨髓增生异常综合征和骨髓增生异常/骨髓增生性肿瘤。
根据一些实施方案，受试者的癌症选自胶质母细胞瘤、黑素瘤、胆管癌、小细胞肺癌、结肠直肠癌、前列腺癌、阴道癌、血管肉瘤、非小细胞肺癌、阑尾癌、鳞状细胞癌、唾液管癌、腺样囊性癌、小肠癌和胆囊癌。优选地，癌症选自小肠癌、非小细胞肺癌、胆囊癌和鳞状细胞癌。
根据一些方面，本公开提供了向受试者施用至少一种另外的丝裂原活化蛋白激酶(MAPK)途径抑制剂。根据一些实施方案，至少一种另外的治疗剂选自MEK抑制剂、RAF抑制剂、HDAC抑制剂、ERK抑制剂及其组合。
如本文所用，“丝裂原活化蛋白激酶(MAPK)途径抑制剂”是调控例如降低MAPK途径中蛋白质的活性、表达或磷酸化从而导致细胞生长减少或细胞死亡增加的任何物质。
哺乳动物MAPK级联的概述在图1中显示。关于MAPK途径的细节在例如Akinleye等人，2013中进行了综述。简言之，关于图1中的ERK1/2模块(浅紫色框)，MAPK 1/2信号传导级联通过配体与受体酪氨酸激酶(RTK)的结合而被活化。活化的受体募集并磷酸化衔接蛋白Grb2和SOS，后两者然后与膜结合的GTPase Ras相互作用并引起其活化。Ras以其活化的GTP结合形式募集并活化Raf激酶(A-Raf、B-Raf和C-Raf/RaF-1)。活化的Raf激酶活化MAPK 1/2(MKK1/2)，其进而催化ERK1/2的活化序列Thr-Glu-Tyr中苏氨酸和酪氨酸残基的磷酸化。对于JNK/p38模块(图1中的黄色框)，上游激酶MAP3K(例如MEKK1/4、ASK1/2和MLK1/2/3)活化MAP2K3/6(MKK3/6)、MAP2K4(MKK4)和MAP2K7(MKK7)。然后，这些MAP2K活化JNK蛋白激酶，包括JNK1、JNK2和JNK3以及p38α/β/γ/Δ。为了执行其功能，JNK活化多个转录因子，包括c-Jun、ATF-2、NF-ATc1、HSF-1和STAT3。关于ERK5模块(图1中的蓝色框)，MAP2K5(MKK5)上游的激酶是MEKK2和MEKK3。MEK5最具特征的下游靶标是ERK5，也称为大MAP激酶1(BMK1)，因为它是其他MAPK大小的两倍。
MAPK途径抑制剂的非限制性实例包括RAS抑制剂、RAF抑制剂、MEK抑制剂、ERK1/2抑制剂、其药学上可接受的盐及其组合。
如本文所用，“RAS抑制剂”是指(i)例如通过与RAS结合而与RAS直接相互作用和(ii)降低RAS的表达或活性的那些物质。非限制性的示例性RAS抑制剂包括但不限于法呢基转移酶抑制剂(例如，替吡法尼(tipifarnib)和洛那法尼(lonafarnib))、含法呢基基团的小分子(例如，salirasib和TLN-4601)、由Maurer(Maurer等人，2012)公开的DCAI、由Shima(Shima等，2013)公开的Kobe0065和Kobe2602、HBS 3(Patgiri等人，2011)和AIK-4(Allinky)。
如本文所用，“RAF抑制剂”是指(i)例如通过与RAF结合而与RAF直接相互作用和(ii)降低RAF的表达或活性的那些物质，例如A-RAF、B-RAF和C-RAF(Raf-1)。非限制性示例性RAF抑制剂包括：
化合物7
Figure BDA0002323874170000351
(Li等人)，
化合物9
Figure BDA0002323874170000352
(同上)，
化合物10
Figure BDA0002323874170000353
(同上)，
化合物13
Figure BDA0002323874170000354
(同上)，
化合物14
Figure BDA0002323874170000361
(同上)，
化合物15
Figure BDA0002323874170000362
(同上)，
化合物16
Figure BDA0002323874170000363
(同上)，
化合物18
Figure BDA0002323874170000364
(同上)，
化合物19
Figure BDA0002323874170000365
(同上)，
化合物20
Figure BDA0002323874170000366
(同上)，
化合物21
Figure BDA0002323874170000371
(同上)，
化合物22
Figure BDA0002323874170000372
(同上)，
化合物23
Figure BDA0002323874170000373
(同上)，
化合物24
Figure BDA0002323874170000374
(同上)，
化合物25
Figure BDA0002323874170000375
(同上)，
化合物26
Figure BDA0002323874170000376
(同上)，
化合物27
Figure BDA0002323874170000381
(同上)，
化合物28
Figure BDA0002323874170000382
(同上)，
化合物30
Figure BDA0002323874170000383
(同上)，
化合物31
Figure BDA0002323874170000384
(同上)，
化合物32
Figure BDA0002323874170000391
(同上)，
化合物33
Figure BDA0002323874170000392
(同上)，
化合物34
Figure BDA0002323874170000393
(同上)，
化合物35
Figure BDA0002323874170000394
(同上)，
化合物36
Figure BDA0002323874170000395
(同上)，
化合物37
Figure BDA0002323874170000401
(同上)，
化合物38
Figure BDA0002323874170000402
(同上)，
化合物39
Figure BDA0002323874170000403
(同上)，
化合物40
Figure BDA0002323874170000404
(同上)，
AAL881(Novartis)；AB-024(Ambit Biosciences)，ARQ-736(ArQule)，ARQ-761(ArQule)，AZ628(Axon Medchem BV)，BAY 43-9006索拉非尼，BaiGene-283(BeiGene)，BUB-024(MLN 2480)(Sunesis&Takeda)，b-raf抑制剂(Sareum)，BRAF激酶抑制剂(SelexagenTherapeutics)，BRAF siRNA 313(tacaccagcaagctagatgca)和523(cctatcgttagagtcttcctg)(Liu等人，2007)，CHIR-265(Novartis)，CTT239065(Instituteof Cancer Research)，达拉非尼(GSK2118436)，DP-4978(Deciphera Pharmaceuticals)，HM-95573(Hanmi)，GDC-0879(Genentech)，GW-5074(Sigma Aldrich)，ISIS 5132(Novartis)，L779450(Merck)，LBT613(Novartis)，LXH254(Novartis)，LErafAON(NeoPharm，Inc.)，LGX-818(Novartis)，帕唑帕尼(GlaxoSmithKline)，PLX3202(Plexxikon)，PLX4720(Plexxikon)，PLX5568(Plexxikon)，PLX3603(Daiichi Sankyo)，PLX8394(Daiichi Sankyo)，RAF-265(Novartis)，RAF-365(Novartis)，REDX0535(RedXPharma Plc)，瑞戈非尼(Bayer Healthcare Pharmaceuticals，Inc.)，RO 5126766(Hoffmann-La Roche)，SB-590885(GlaxoSmithKline)，SB699393(GlaxoSmith Kline)，索拉非尼(Onyx Pharmaceuticals)，TAK 632(Takeda)，TL-241(Teligene)，威罗非尼(RG7204或PLX4032)(Daiichi Sankyo)，XL-281(Exelixis)，ZM-336372(AstraZeneca)，其药学可接受的可盐及其组合。
根据一些实施方案，RAF抑制剂包括泛抑制剂；其非限制性实例包括厄洛替尼(Tarceva)、吉非替尼(Iressa)、甲磺酸伊马替尼(Gleevec)、拉帕替尼(Tyverb)、苹果酸舒尼替尼(Sutent)其药学可接受的可盐及其组合。
如本文所用，“MEK抑制剂”是指(i)例如通过与MEK结合而与MEK直接相互作用，和(ii)降低MEK的表达或活性的那些物质。因此，在MEK上游起作用的抑制剂，例如RAS抑制剂和RAF抑制剂，不是根据本发明的MEF抑制剂。MEK抑制剂的非限制性实例包括炭疽毒素、蒽醌(Golden Biotechnology)、ARRY-142886(6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺)(Array BioPharma)、ARRY-438162(ArrayBioPharma)、贝美替尼(MEK162，ARRY-1662)、AS-1940477(Astellas)、AS-703988(MerckKGaA)、bentamapimod(Merck KGaA)、BI-847325(Boehringer Ingelheim)、E-6201(Eisai)、GDC-0623(Hoffmann-La Roche)、GDC-0973(考比替尼)(Hoffmann-La Roche)、L783277(Merck)、炭疽毒素的致死因子部分、MEK162(Array BioPharma)、PD 098059(2-(2'-氨基-3'-甲氧苯基)-氧萘-4-酮)(Pfizer)、PD 184352(CI-1040)(Pfizer)、PD-0325901(Pfizer)、pimasertib(Santhera Pharmaceuticals)、RDEA119(Ardea Biosciences/Bayer)、瑞美替尼(AstraZeneca)、RG422(Chugai Pharmaceutical Co.)、R0092210(Roche)、R04987655(Hoffmann-La Roche)、R05126766(Hoffmann-La Roche)、司美替尼(AZD6244)(AstraZeneca)、SL327(Sigma)、TAK-733(Takeda)、曲美替尼(Japan Tobacco)、U0126(1,4-二氨基-2,3-二氰基-1,4-双(2-氨基苯硫基)丁二烯)(Sigma)、WX-554(Wilex)、YopJ多肽(Mittal等人，2010)、其药学上可接受的盐及其组合。
如本文所用，“ERK1/2抑制剂”是指(i)例如通过与ERK1/2结合而与ERK1和/或ERK2直接相互作用，和(ii)降低ERK1和/或ERK2蛋白激酶的表达或活性的那些物质。因此，在ERK1/2上游起作用的抑制剂，例如MEK抑制剂和RAF抑制剂，不是根据本发明的ERK1/2抑制剂。ERK1/2抑制剂的非限制性实例包括AEZS-131(Aeterna Zentaris)、AEZS-136(AeternaZentaris)，BVD-523，SCH-722984(Merck&Co.)、SCH-772984(Merck&Co.)、SCH-900353(MK-8353)(Merck&Co.)、LY3214996(Lilly)、其药学上可接受的盐及其组合。
如本文所用，“HDAC抑制剂”是指(i)例如通过与HDAC结合而与组蛋白脱乙酰基酶(HDAC)直接相互作用，和(ii)降低HDAC的表达或活性的那些物质。HDAC抑制剂的非限制性例子包括艾贝司他(PCI-24781)、吉诺司他、恩替司他、扶林司他、CI-994、CUDC-101、恩替司他、BML-210、M344、NVP-LAQ824、帕比司他、Pracinosat(SB939)、Mocetinostat、Resminostat、罗米地辛、贝利诺司他、其药学上可接受的盐及其组合。
根据一些实施方案，HDAC抑制剂选自扶林司他、帕比司他、罗米地辛、贝利诺司他、其药学上可接受的盐及其组合。
在另一方面，该方法进一步包括向受试者施用有效治疗或改善癌症的影响的至少一种另外的治疗剂。所述另外的治疗剂可以选自抗体、抗体片段、抗体缀合物、细胞毒性剂、毒素、放射性核素、免疫调控剂、光活化治疗剂、放射增敏剂、激素、抗血管生成剂及其组合。
如本文所用，“抗体”涵盖天然存在的免疫球蛋白以及非天然存在的免疫球蛋白，包括例如单链抗体、嵌合抗体(例如人源化鼠抗体)和杂缀合物抗体(例如双特异性抗体)。抗体的片段包括结合抗原的那些(例如，Fab'、F(ab')2、Fab、Fv和rIgG)。还参见，例如，Pierce Catalog and Handbook，1994-1995(Pierce Chemical Co.，Rockford，Ill)；Kuby,J.，Immunology，3rd Ed.,W.H.Freeman&Co.,New York(1998)。术语抗体还包括二价或双特异性分子、双抗体、三抗体和四抗体。术语“抗体”还包括多克隆和单克隆抗体。
可用于本发明的治疗性抗体的实例包括利妥昔单抗(Rituxan)、布伦妥昔单抗维多汀(Adcetriz)、阿多曲妥珠单抗艾坦肽(Kadcyla)、西妥昔单抗(Erbitux)、贝伐单抗(Avastin)、替伊莫单抗(Zevalin)、维多珠单抗(Entyvio)、伊匹单抗(Yervoy)、纳武单抗(Opdivo)、派姆单抗(Keytruda)、阿伦单抗(Alemtuzamab)阿特朱单抗(Tecentriq)、阿维鲁单抗(Bavencio)、德鲁瓦单抗(Imfinzi)、B-701、奥法木单抗、阿托珠单抗(Gazyva)帕尼单抗、plozalizumab、BI-754091、OREG-103、COM-701、BI-754111及其组合。
根据一些实施方案，所述抗体、其片段或其缀合物选自利妥昔单抗(Rituxan)、布伦妥昔单抗维多汀(Adcetriz)、阿多曲妥珠单抗艾坦肽(Kadcyla)、伊匹单抗(Yervoy)、纳武单抗(Opdivo)、派姆单抗(Keytruda)、阿伦单抗阿特朱单抗(Tecentriq)、德鲁瓦单抗(Imfinzi)、奥法木单抗、阿托珠单抗(Gazyva)帕尼单抗及其组合。
根据本发明的细胞毒剂包括DNA破坏剂、抗代谢物、抗微管剂、抗生素剂等。DNA破坏剂包括烷基化剂、铂基试剂、嵌入剂和DNA复制的抑制剂。DNA烷基化剂的非限制性实例包括环磷酰胺、甲氯乙胺、尿嘧啶氮芥、美法仑、苯丁酸甲氯乙胺、异环磷酰胺、卡莫司汀、洛莫司汀、链脲霉素、白消安、替莫唑胺、其药学上可接受的盐、前药及其组合。铂基试剂的非限制性实例包括顺铂、卡铂、奥沙利铂、奈达铂、沙铂、三硝酸四铂、其药学上可接受的盐、前药及其组合。插入剂的非限制性实例包括阿霉素、柔红霉素、伊达比星、米托蒽醌、其药学上可接受的盐、前药及其组合。DNA复制的抑制剂的非限制性实例包括伊立替康、托泊替康、氨水碱、依托泊苷、依托泊苷磷酸酯、替尼泊苷、其药学上可接受的盐、前药及其组合。抗代谢物包括叶酸拮抗剂，例如甲氨蝶呤和培美曲塞(premetrexed)；嘌呤拮抗剂，例如6-巯嘌呤、达卡巴嗪和氟达拉滨；和嘧啶拮抗剂，例如5-氟尿嘧啶、阿拉伯糖基胞嘧啶、卡培他滨，吉西他滨、地西他滨、其药学上可接受的盐、前药及其组合。抗微管剂包括但不限于长春花生物碱、紫杉醇
Figure BDA0002323874170000431
多西他赛
Figure BDA0002323874170000432
和依沙贝比隆
Figure BDA0002323874170000433
抗生素试剂包括但不限于放线菌素、蒽环类、缬沙星、表柔比星、博来霉素、普卡霉素、丝裂霉素、其药学上可接受的盐、前药及其组合。
根据一些实施方案，细胞毒性剂选自环磷酰胺、甲氯乙胺、尿嘧啶氮芥、美法仑、苯丁酸甲氯乙胺、异环磷酰胺、卡莫司汀、洛莫司汀、链脲霉素、白消安、替莫唑胺、顺铂、卡铂、奥沙利铂、奈达铂、沙铂、三硝酸四铂、阿霉素、柔红霉素、伊达比星、米托蒽醌、甲氨蝶呤、培美曲塞、6-巯基嘌呤、达卡巴嗪、氟达拉滨、5-氟尿嘧啶、阿拉伯糖胞嘧啶、卡培他滨、吉西他滨、地西他滨、长春花生物碱、紫杉醇(Taxol)、多西他赛(Taxotere)、依沙贝比隆(Ixempra)、放线菌素、蒽环类、缬沙星、表柔比星、博来霉素、普卡霉素、丝裂霉素、其药学上可接受的盐、前药及其组合。
根据本发明的细胞毒性剂还包括PI3K/Akt途径的抑制剂。PI3K/Akt途径的抑制剂的非限制性实例包括A-674563(CAS#552325-73-2)、AGL 2263、AMG-319(Amgen,ThousandOaks,Calif)、AS-041164(5-苯并[1,3]二恶唑-5-基亚甲基-噻唑烷-2,4-二酮)、AS-604850(5-(2,2-二氟-苯并[1,3]二恶唑-5-基亚甲基)-噻唑烷-2,4-二酮)、AS-605240(5-喹喔啉-6-亚甲基-1,3-噻唑烷-2,4-二酮)、AT7867(CAS#857531-00-1)、苯并咪唑系列，Genentech(Roche Holdings Inc.,South San Francisco,Calif)、BML-257(CAS#32387-96-5)、BVD-723、CAL-120(Gilead Sciences,Foster City,Calif)、CAL-129(Gilead Sciences)、CAL-130(Gilead Sciences)、CAL-253(Gilead Sciences)、CAL-263(Gilead Sciences)、CAS#612847-09-3、CAS#681281-88-9、CAS#75747-14-7、CAS#925681-41-0、CAS#98510-80-6、CCT128930(CAS#885499-61-6)、CH5132799(CAS#1007207-67-1)、CHR-4432(ChromaTherapeutics,Ltd.,Abingdon,UK)、FPA 124(CAS#902779-59-3)、GS-1101(CAL-101)(Gilead Sciences)、GSK690693(CAS#937174-76-0)、H-89(CAS#127243-85-0)、Honokiol、IC87114(Gilead Science)、IPI-145(Intellikine Inc.)、KAR-4139(KarusTherapeutics,Chilworth,UK)、KAR-4141(Karus Therapeutics)、KIN-1(KarusTherapeutics)、KT 5720(CAS#108068-98-0)、米替福新、MK-2206二盐酸化物(CAS#1032350-13-2)、ML-9(CAS#105637-50-1)、盐酸纳曲通、OXY-111A(NormOxys Inc.,Brighton,Mass.)、perifosine、PHT-427(CAS#1191951-57-1)、PI3激酶δ抑制剂，MerckKGaA(Merck&Co.,Whitehouse Station,NJ)、PI3激酶δ抑制剂，Genentech(Roche HoldingsInc.)、PI3激酶δ抑制剂，Incozen(Incozen Therapeutics,Pvt.Ltd.,Hydrabad,India)、PI3激酶δ抑制剂2，Incozen(Incozen Therapeutics)、PI3激酶抑制剂，Roche-4(RocheHoldings Inc.)、PI3激酶抑制剂，Roche(Roche Holdings Inc.)、PI3激酶抑制剂，Roche-5(Roche Holdings Inc.)、PI3-α/δ抑制剂，Pathway Therapeutics(Pathway TherapeuticsLtd.,South San Francisco,CA)、PI3-δ抑制剂，Cellzome(Cellzome AG,Heidelberg,Germany)、PI3-δ抑制剂，Intellikine(Intellikine Inc.,La Jolla,CA)、PI3-δ抑制剂，Pathway Therapeutics-1(Pathway Therapeutics Ltd.)、PI3-δ抑制剂，PathwayTherapeutics-2(Pathway Therapeutics Ltd.)、PI3-δ/γ抑制剂，Cellzome(CellzomeAG)、PI3-δ/γ抑制剂，Cellzome(Cellzome AG)、PI3-δ/γ抑制剂，Intellikine(Intellikine Inc.)、PI3-δ/γ抑制剂，Intellikine(Intellikine Inc.)、PI3-δ/γ抑制剂，Pathway Therapeutics(Pathway Therapeutics Ltd.)、PI3-δ/γ抑制剂，PathwayTherapeutics(Pathway Therapeutics Ltd.)、PI3-γ抑制剂，Evotec(Evotec)、PI3-γ抑制剂，Cellzome(Cellzome AG)、PI3-γ抑制剂，Pathway Therapeutics(PathwayTherapeutics Ltd.)、PI3Kδ/γ抑制剂，Intellikine-1(Intellikine Inc.)、PI3Kδ/γ抑制剂，Intellikine-1(Intellikine Inc.)、pictilisib(Roche Holdings Inc.)、PIK-90(CAS#677338-12-4)、SC-103980(Pfizer,New York,NY)、SF-1126(SemaforePharmaceuticals,Indianapolis,IN)、SH-5、SH-6、四氢姜黄素、TG100-115(TargegenInc.,San Diego,Calif)、曲西瑞宾、X-339(Xcovery,West Palm Beach,F1a)、XL-499(Evotech,Hamburg,Germany)、其药学上可接受的盐及其组合。
在本发明中，BVD-723是根据式(II)的化合物：
Figure BDA0002323874170000451
及其药学上可接受的盐。BVD-723是PI3Kγ的选择性抑制剂。BVD-723可以根据例如美国专利申请公开号2016/0214980进行合成，通过引用将其全部内容并入本文。BVD-723的两个对映异构体的对映异构体和外消旋混合物也包括在本发明的范围内。
在本发明中，术语“毒素”是指植物或动物来源的抗原性毒物或毒液。一个例子是白喉毒素或其部分。
在本发明中，术语“放射性核素”是指例如通过静脉内或口服施用给患者的放射性物质，之后其通过患者的正常代谢渗透到靶器官或组织中，在那里其递送局部辐射以短时间。放射性核素的例子包括但不限于I-125、At-211、Lu-177、Cu-67、I-131、Sm-153、Re-186、P-32、Re-188、In-114m和Y-90。
在本发明中，术语“免疫调控剂”是指通过增强或降低免疫系统产生抗体或致敏细胞的能力来改变免疫应答的物质，所述抗体或致敏细胞识别并与引发其产生的抗原反应。免疫调控剂可以是重组的、合成的或天然的制备物，并且包括细胞因子、皮质类固醇、细胞毒性剂、胸腺素和免疫球蛋白。某些免疫调控剂天然存在于体内，并且其中某些可以在药物制备物中获得。免疫调控剂的实例包括但不限于粒细胞集落刺激因子(G-CSF)、LAG-3、IMP-321、JCAR-014、ASLAN-002(BMS-777607)、干扰素、咪喹莫特和来自细菌的细胞膜级分、IL-2、IL-7、IL-12、CCL3、CCL26、CXCL7、合成的胞嘧啶磷酸鸟苷(CpG)、免疫检查点抑制剂及其组合。
在本发明中，术语“光活化治疗剂”是指在暴露于光后变得有活性的化合物和组合物。在例如美国专利申请序列号2011/0152230A1“Photoactive Metal Nitrosyls ForBlood Pressure Regulation And Cancer Therapy”中公开了光活化治疗剂的某些实例。
在本发明中，术语“放射增敏剂”是指使肿瘤细胞对放射疗法更敏感的化合物。放射增敏剂的实例包括米索硝唑、甲硝唑、替拉帕明和反式丁香酸钠及其组合。
在本发明中，术语“激素”是指由身体某一部分中的细胞释放的，影响在身体另一部分中的细胞的物质。激素的实例包括但不限于前列腺素、白三烯、前列环素、血栓烷、淀粉纤维素、抗苗勒管激素、脂联素、促肾上腺皮质激素、血管紧张素原、血管紧张素、血管加压素、心房肽、脑钠尿肽、降血钙素、胆囊收缩素、促肾上腺皮质激素释放激素、脑啡肽、内皮素、促红细胞生成素、促卵泡激素、甘丙肽、胃泌素、生长激素释放肽、胰高血糖素、促性腺激素释放激素、生长激素释放激素、人绒毛膜促性腺激素、人胎盘促泌素、生长激素、抑制素、胰岛素、生长调节素、瘦素、促脂素、促黄体生成素、黑素细胞刺激激素、胃动素、食欲素、催产素、胰多肽、甲状旁腺激素、催乳素、催乳素释放激素、松弛素、肾素、分泌素、生长抑素、血小板生成素、促甲状腺激素、睾丸酮、脱氢表雄酮、雄烯二酮、二氢睾丸酮、醛固酮、雌二醇、雌酮、雌三醇、皮质醇、孕酮、骨化三醇和骨化二醇。
一些化合物干扰某些激素的活性或停止某些激素的产生。这些激素干扰性化合物包括但不限于他莫昔芬
Figure BDA0002323874170000461
阿那曲唑
Figure BDA0002323874170000462
来曲唑
Figure BDA0002323874170000463
和氟司韦特
Figure BDA0002323874170000464
这些化合物也在本发明中激素的含义之中。
如本文所用，“抗血管生成”剂是指减少或抑制新血管生长的物质，例如，血管内皮生长因子(VEGF)的抑制剂和内皮细胞迁移的抑制剂。抗血管生成剂包括但不限于2-甲氧基雌二醇、血管抑制素、贝伐单抗、软骨衍生的血管生成抑制因子、内皮抑素、IFN-α、IL-12、伊曲康唑、利诺米特、血小板因子4、催乳素、SU5416、苏拉明、他克莫尼、替加仑、四硫代钼酸盐、沙利度胺、血小板反应蛋白、血小板反应蛋白、TNP-470、齐夫-阿柏西普、其药学上可接受的盐、前药及其组合。
根据一个方面，本公开内容提供了用于在受试者中治疗或缓解的癌症的影响的方法，包括：(a)鉴定携带非V600E/K BRAF突变的患有癌症的受试者；和(b)对受试者施用有效量的ERK抑制剂或其药学上可接受的盐。
根据一个实施方案，ERK抑制剂选自BVD-523、SCH-722984(Merck&Co.)、SCH-772984(Merck&Co.)、SCH-900353(MK-8353)(Merck&Co.)、LY3214996(Lilly)、AEZS-140(Aeterna Zentaris)、AEZS-131(Aeterna Zentaris)、AEZS-136(Aeterna Zentaris)、LTT-462(Novartis)、RG-7842(Genentech)、CC-90003(Celgene)、KIN-4050(Kinentia)及其组合。根据一个实施方案，ERK抑制剂是BVD-523。在该实施方案的一个方面中，BVD-523或其药学上可接受的盐以还包含药学上可接受的载体或稀释剂的药物组合物的形式进行施用。
根据一个方面，本公开内容提供了鉴定携带非V600E/K BRAF突变的患有癌症的受试者的方法，包括(i)从受试者获得生物学样品；和(ii)筛选样品以确定受试者是否具有非V600E/K BRAF突变。
合适和优选的主题如本文所公开。在该实施方案中，方法可以用于治疗上文公开的癌症，包括具有以上鉴定的突变背景的那些癌症。鉴定此类突变的方法也如上所述。
在本发明中，生物学样品包括但不限于血液、血浆、尿液、皮肤、唾液和活检样品。通过本领域已知的常规程序和方法从受试者获得生物样品。鉴定突变的方法的非限制性实例包括PCR、测序、杂交捕获、溶液内捕获、分子倒置探针、荧光原位杂交(FISH)测定及其组合。
根据一个实施方案，方法进一步包括向该受试者施用选自MEK抑制剂、RAF抑制剂、HDAC抑制剂及其组合的至少一种另外的治疗剂。合适和优选的主题如本文所公开。在该实施方案中，方法可用于使用一种或多种上文公开的另外的治疗剂来治疗上文公开的癌症，包括具有上文鉴定的突变背景的那些癌症。鉴定此类突变的方法也如上所述。
根据一个方面，本公开内容提供了用于鉴定将从ERK抑制剂或其药学上可接受的盐的疗法中受益的患有癌症的受试者的方法，该方法包括：(a)从受试者获得生物样品；和(b)筛选样品以确定受试者是否具有非V600E/K BRAF突变，其中非V600E/K BRAF突变的存在证实受试者将从ERK抑制剂或其药学上可接受的盐的疗法中受益。根据一些实施方案，方法进一步包括向受试者施用ERK抑制剂或其药学上可接受的盐。根据一些实施方案，方法进一步包括向受试者施用至少一种另外的治疗剂。在该实施方案中，方法可用于鉴定在上述癌症中的上文鉴定的突变背景。鉴定此类突变的方法也如上所述。在该实施方案中，所鉴定的患者将受益于其的ERK抑制剂如上所述。另外的治疗剂如上所述。合适和优选的主题如上所述。
根据一个方面，本公开内容提供了用于在受试者中治疗或缓解癌症的影响的方法，包括：(a)鉴定携带非V600E/K BRAF突变的患有癌症的受试者；和(b)向受试者施用有效量的BVD-523或其药学上可接受的盐。根据一个方面，本公开内容提供了用于鉴定将从BVD-523或其药学上可接受的盐的疗法中受益的患有癌症的受试者的方法，该方法包括：(a)从受试者获得生物样品；和(b)筛选样品以确定受试者是否具有非V600E/K BRAF突变，其中非V600E/K BRAF突变的存在证实受试者将从BVD-523或其药学上可接受的盐的疗法中受益。在这些实施方案中，方法可用于鉴定在上述癌症中的上文鉴定的突变背景。鉴定此类突变的方法也如上所述。合适和优选的主题如上所述。
本公开内容的另一方面提供了用于在携带非V600E/K BRAF突变的受试者中治疗或改善癌症的影响的试剂盒。根据一些实施方案，试剂盒包含有效量的如上所述的ERK抑制剂，和任选地如上所述的另外的治疗剂。
试剂盒还可包括用于本发明的每种抗癌剂(其可以例如以药物组合物的形式)和其他反应剂(例如，缓冲剂、平衡盐溶液等)的合适的储存容器，例如安瓿、小瓶、试管等，用于向受试者施用抗癌剂。本发明的抗癌剂和其他反应剂可以以任何方便的形式存在于试剂盒中，例如以溶液或粉末形式。试剂盒可进一步包括包装容器，任选地具有用于容纳药物组合物和其他任选试剂的一个或多个隔区。
在本发明中，本发明的抗癌剂包括包含本文所公开的该抗癌剂的药物组合物的“有效量”或“治疗有效量”是当施用于受试者时，足以实现本文所述有益的或所需的结果的这种试剂或组合物的量。有效的剂型、施用方式和剂量可以凭经验确定，并且这种确定在本领域技术范围内。本领域技术人员应理解，剂量将随施用途径，排泄速率，治疗持续时间，在施用的任何其他药物的特征，哺乳动物例如人类患者的年龄、大小和种类，以及医学和兽医学领域众所周知的类似因素而变化。通常，根据本发明的试剂或组合物的合适剂量将是试剂或组合物的这样的量，其是有效产生所需的作用的最低剂量。本发明的试剂或组合物的有效剂量可以全天以适当的间隔分开以两个、三个、四个、五个、六个或更多个亚剂量施用。
本文公开的BVD-523、RAF抑制剂、ERK抑制剂或另一种抗癌剂的剂量的非限制性实例为每天约1mg/kg至约2400mg/kg，例如每天约1mg/kg至约1200mg/kg、每天75mg/kg至约300mg/kg，包括每天约1mg/kg至约100mg/kg。此类试剂的其他代表性剂量包括约1mg/kg、5mg/kg、10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg、50mg/kg、60mg/kg、70mg/kg、75mg/kg、80mg/kg、90mg/kg、100mg/kg、125mg/kg、150mg/kg、175mg/kg、200mg/kg、250mg/kg、300mg/kg、400mg/kg、500mg/kg、600mg/kg、700mg/kg、800mg/kg、900mg/kg、1000mg/kg、1100mg/kg、1200mg/kg、1300mg/kg、1400mg/kg、1500mg/kg、1600mg/kg、1700mg/kg、1800mg/kg、1900mg/kg、2000mg/kg、2100mg/kg、2200mg/kg和2300mg/kg每天。本文公开的BVD-523、RAF抑制剂、ERK抑制剂或另外的抗癌剂的有效剂量可以全天以适当的间隔分开以两个、三个、四个、五个、六个或更多个亚剂量施用。
本发明的BVD-523、RAF抑制剂、ERK抑制剂或另外的治疗剂或者包含其的药物组合物可以以任何所需和有效的方式施用：用于口服摄取，或作为软膏或滴剂用于局部施用给眼，或以任何适当方式(例如腹膜内、肿瘤内、皮下、局部、皮内、吸入、肺内、直肠、阴道、舌下、肌肉内、静脉内、动脉内、鞘内或淋巴管内)进行肠胃外或其他施用。此外，可以将本发明的BVD-523、RAF抑制剂或另外的治疗剂或者包含其的药物组合物与其他治疗联合施用。如果需要，可以将本发明的BVD-523、RAF抑制剂或另外的治疗剂或者包含其的药物组合物包封或以其他方式保护以免受胃或其他分泌物。
本发明的药物组合物包含一种或多种活性成分，例如治疗剂，与一种或多种药学上可接受的稀释剂或载体以及任选的一种或多种其他化合物、药物、成分和/或材料混合。不管选择的施用途径如何，通过本领域技术人员已知的常规方法将本发明的试剂/化合物配制成药学上可接受的剂型。参见，例如，Remington,The Science and Practice ofPharmacy(21st Edition,Lippincott Williams and Wilkins,Philadelphia,Pa)。
药学上可接受的稀释剂或载体是本领域众所周知的(参见，例如，Remington,TheScience and Practice of Pharmacy(21st Edition,Lippincott Williams andWilkins,Philadelphia,Pa)和The National Formulary(American PharmaceuticalAssociation,Washington,D.C.))，并且包括糖(例如乳糖、蔗糖、甘露醇和山梨糖醇)，淀粉，纤维素制备物，磷酸钙(例如磷酸二钙、磷酸三钙和磷酸氢钙)，柠檬酸钠，水，水溶液(例如，盐水、氯化钠注射液、林格注射液、葡萄糖注射液、葡萄糖和氯化钠注射液、乳酸林格氏注射液)，醇类(例如乙醇、丙醇和苄醇)，多元醇(例如甘油、丙二醇和聚乙二醇)，有机酯(例如油酸乙酯和甘油三酸酯)，生物可降解的聚合物(例如聚丙交酯-聚乙交酯、聚(原酸酯)和聚(酐))，弹性基质，脂质体，微球，油(例如玉米、胚芽、橄榄、蓖麻、芝麻、棉籽和花生)，可可脂，蜡(例如栓剂蜡)，石蜡，硅酮，滑石，硅酸酯等。在与制剂的其他成分相容并且对受试者无害的意义上，用于本发明药物组合物中的每种药学可接受的稀释剂或载体必须是“可接受的”。适用于所选剂型和预期施用途径的稀释剂或载体是本领域众所周知的，并且用于所选剂型和施用方法的可接受的稀释剂或载体可以使用本领域的普通技术来确定。
本发明的药物组合物可以任选地包含药物组合物中常用的其他成分和/或材料。这些成分和材料在本领域中是众所周知的，并且包括(1)填充剂或增量剂，例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(2)粘合剂，例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、羟丙基甲基纤维素、蔗糖和阿拉伯胶；(3)保湿剂，如甘油；(4)崩解剂，例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐、淀粉羟乙酸钠、交联的羧甲基纤维素钠和碳酸钠；(5)缓溶剂，如石蜡；(6)吸收促进剂，例如季铵化合物；(7)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(8)吸收剂，例如高岭土和膨润土；(9)润滑剂，例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇和月桂基硫酸钠；(10)悬浮剂，例如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇和失水山梨醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶；(11)缓冲剂；(12)赋形剂，例如乳糖、奶糖、聚乙二醇、动植物脂肪、油、蜡、石蜡、可可脂、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石、水杨酸盐、氧化锌、氢氧化铝、硅酸钙和聚酰胺粉；(13)惰性稀释剂，例如水或其他溶剂；(14)防腐剂；(15)表面活性剂；(16)分散剂；(17)控释或吸收延迟剂，例如羟丙基甲基纤维素、其他聚合物基质、生物可降解的聚合物、脂质体、微球、单硬脂酸铝、明胶和蜡；(18)遮光剂；(19)佐剂；(20)润湿剂；(21)乳化悬浮剂；(22)增溶剂和乳化剂，例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(尤其是棉籽、花生、玉米、胚芽、橄榄、蓖麻和芝麻油)、甘油、四氢呋喃醇、聚乙二醇和失水山梨醇的脂肪酸酯；(23)推进剂，例如氯氟烃和挥发性未取代的烃，例如丁烷和丙烷；(24)抗氧化剂；(25)使制剂与预期接受者的血液等渗的试剂，例如糖和氯化钠；(26)增稠剂；(27)包衣材料，例如卵磷脂；和(28)甜味剂、调味剂、着色剂、芳香剂和防腐剂。在与制剂的其他成分相容并且对受试者无害的意义上，每种这样的成分或材料必须是“可接受的”。适用于所选剂型和预期施用途径的成分和材料是本领域众所周知的，并且可以使用本领域普通技术来确定用于所选剂型和施用方法的可接受的成分和材料。
适用于口服施用的本发明药物组合物可以是胶囊、扁囊剂、丸剂、片剂、粉末、颗粒、在水性或非水性液体中的溶液或悬浮液、水包油或油包水型液体乳剂、驰剂或糖浆、锭剂、大丸剂、舐剂或糊剂。这些制剂可以通过本领域已知的方法，例如通过常规的锅包衣、混合、制粒或冻干方法来制备。
可以例如通过将一种或多种活性成分与一种或多种药学上可接受的稀释剂或载体以及任选地一种或多种填充剂、增量剂、粘合剂、保湿剂、崩解剂、溶液阻滞剂、吸收促进剂、润湿剂、吸收剂、润滑剂和/或着色剂混合来制备用于口服施用的固体剂型(胶囊、片剂、丸剂、糖衣丸、粉末、颗粒等)。可以使用合适的赋形剂将相似类型的固体组合物用作软和硬填充明胶胶囊中的填充剂。片剂可以任选地与一种或多种辅助成分一起通过压制或模制制成。可以使用合适的粘合剂、润滑剂、惰性稀释剂、防腐剂、崩解剂、表面活性剂或分散剂来制备压制的片剂。模制片剂可以通过在合适的机器中模制来制备。片剂和其他固体剂型，例如糖衣丸、胶囊、丸剂和颗粒，可以任选地用包衣和衣壳，例如肠溶衣和药物配制领域众所周知的其他包衣进行刻痕或制备。它们也可以被配制为提供其中的活性成分的缓慢或受控释放。它们可以例如通过保留细菌的过滤器的过滤来灭菌。这些组合物还可以任选地包含遮光剂，并且可以是这样的组合物，使得它们仅或优选地在胃肠道的特定部分中任选地以延迟的方式释放活性成分。活性成分也可以是微囊形式。
用于口服施用的液体剂型包括药学上可接受的乳剂、微乳剂、溶液、悬浮剂液、糖浆和驰剂。液体剂型可包含本领域通常使用的合适的惰性稀释剂。除惰性稀释剂外，口服组合物还可包含佐剂，例如润湿剂、乳化和悬浮剂、甜味剂、调味剂、着色剂、芳香和防腐剂。悬浮液可以含有悬浮试剂。
用于直肠或阴道施用的本发明药物组合物可以以栓剂形式存在，其可以通过将一种或多种活性成分与一种或多种合适的无刺激性稀释剂或载体混合来制备，所述无刺激性稀释剂或载体在室温下为固体，但在人体温度下为液体，并且因此会在直肠或阴道腔内融化并释放活性化合物。适用于阴道施用的本发明药物组合物还包括阴道栓、棉塞、乳膏、凝胶、糊剂、泡沫或喷雾制剂，其含有本领域已知合适的药学上可接受的稀释剂或载体。
用于局部或透皮施用的剂型包括粉末、喷雾剂、软膏、糊剂、乳膏、洗剂、凝胶、溶液、贴剂、滴剂和吸入剂。活性剂/化合物可以在无菌条件下与合适的药学上可接受的稀释剂或载体混合。软膏、糊剂、乳膏和凝胶可以包含赋形剂。粉末和喷雾剂可以包含赋形剂和推进剂。
适用于肠胃外施用的本发明药物组合物可包含一种或多种试剂/化合物与以下组合：一种或多种药学上可接受的无菌等渗水性或非水性溶液、分散液、悬浮液或乳液，或者可以就在使用前重构为无菌可注射溶液或分散液的无菌粉末，其可以包含合适的抗氧化剂、缓冲液、溶质(使制剂与预期接受者的血液等渗)，或者悬浮剂或增稠剂。可以例如通过使用包衣材料，在分散液的情况下通过维持所需的粒径以及通过使用表面活性剂来维持适当的流动性。这些药物组合物还可包含合适的佐剂，例如润湿剂、乳化剂和分散剂。也可能需要包括等渗剂。另外，可通过包含延迟吸收的试剂来引起可注射药物形式的延长吸收。
在某些情况下，为了延长药物(例如，药物制剂)的作用，需要减慢其从皮下或肌肉内注射的吸收。这可以通过使用水溶性差的结晶或无定形材料的液体悬浮液来实现。
然后，活性剂/药物的吸收速率取决于其溶解速率，而溶解速率又取决于晶体尺寸和晶体形式。备选地，可以通过将活性剂/药物溶解或悬浮在油性媒介物中来实现肠胃外施用的试剂/药物的延迟吸收。可通过在生物可降解的聚合物中形成活性成分的微胶囊基质来制备可注射的贮库形式。取决于活性成分与聚合物的比例以及所使用的特定聚合物的性质，可以控制活性成分释放的速率。还可以通过将药物截留在与身体组织相容的脂质体或微乳剂中来制备可注射储库的制剂。可注射材料可以例如通过保留细菌的过滤器的过滤而进行灭菌。
制剂可以存在于单位剂量或多剂量的密封的容器中，例如安瓿和小瓶，并且可以在冻干条件下储存，仅需要在使用前立即添加无菌液体稀释剂或载体，例如注射用水。临时注射溶液和悬浮液可以由上述类型的无菌粉末、颗粒和片剂制备。
提供以下实施例以进一步示例说明本发明的方法。这些实施例仅是说明性的并无意以任何方式限制本发明的范围。
实施例1
以下实施例显示了BVD-523的实体瘤1b期试验的结果。图2中描绘的瀑布图提供了人类临床试验患者信息的图示，显示了每个个体患者对BVD-523治疗的应答，以肿瘤负担变化％进行测量。患者通常每天两次(BID)接受600mg，如果通过其他缓和医疗无法控制副作用，则某些患者接受降级剂量300mg–400mg BID。
如图2所示，使用Response Evaluation Criteria in Solid Tumors 1.1版(RECIST v1.1)，在28位可评估患者中评估对BVD-523的肿瘤应答。一名患者未同时接受两次靶病变扫描，因此未进行评估。图上的水平轴用作每个患者的基线测量。垂直轴是相对于基线的最大百分比变化的测量；即，根据RECIST v1.1通过放射学测量的肿瘤负担的生长或减少的百分比。放射学测量包括计算机断层扫描(CT)扫描并且极少数情况下包括磁共振成像(MRI)。
由图2表示的肿瘤负荷数据从图左侧的最差值(即，肿瘤负荷的最大进展)到图右侧的最佳值(即，肿瘤负荷的最大减少)来排列。先前已描述了用于测量靶病变的RECISTv1.1应答标准。(参见Eisenhauer,E.A.等人,New response evaluation criteria insolid tumours:Revised RECIST guideline(version 1.1),European J.of Cancer 45,228-247(2009)，通过引用整体并入本文)。应答标准如下：
完全应答(CR)-所有靶病变的消失；
部分应答(PR)-以基线总和直径为参考，靶病变的直径总和降低至少30％；如在图2中所示，用水平线指示部分应答的30％降低阈值。
进展性疾病(PD)-以研究中的最小和(如果是研究中的最小值，包括基线总和)作为参考，靶病变的直径总和增加至少20％。除了相对增加20％外，总和还必须显示至少5mm的绝对增加(注意：一个或多个新病变的出现也被视为进展)；
稳定疾病(SD)–以研究时最小的总直径作为参考，既没有足够的收缩符合PR，也没有足够的增长符合PD。
图2还显示了测量每位患者肿瘤负担的癌症或器官的类型，以及患者肿瘤样品中鉴定出的非典型BRAF突变的类型。在代表的28位患者中，有13位患者肿瘤包含BRAF D594突变(7位是D594G，6位是D594N)；1位患者肿瘤包含BRAF F247L突变；1位患者肿瘤包括BRAF基因与核因子IC(NFIC)基因融合(即BRAF-NFIC融合突变)；1位患者肿瘤包含BRAF G466V突变；5位患者肿瘤包含BRAF G469突变(1位是G469V，4位是G469A)；3位患者肿瘤包含BRAFK601E突变；1位患者肿瘤包含BRAF L485W突变；3位患者肿瘤包含BRAF L597突变(一位不明确，2位是L597Q)，并且2位患者肿瘤包含T599重复。对于每位患者，BRAF突变的类型通过颜色代码和癌症类型来指示(见图2)。
五位PR患者的靶病变总数相对于基线减少了35％至100％。这些患者表现出：包含L485W突变的胆囊肿瘤；包含G469A突变的头/颈部鳞状细胞瘤；包含BRAF L597Q突变或BRAFT599复制的非小细胞肺癌；以及包含BRAF G469A突变的小肠肿瘤。19位患者表现出稳定的疾病。初次评估时三位患者表现出进展性疾病。(见图2)。因此，BVD-523治疗出人意料地导致了具有非典型(即非V600E/K)BRAF突变的28位患者中24位的部分应答或稳定疾病。
图3显示了按组分类的游泳者图的治疗持续时间。第1组的成员是具有在除结肠直肠癌(CRC)和非小细胞肺癌(NSCLC)以外的任何肿瘤类型中的任何BRAF突变，并且先前未接受过MAPK途径抑制剂的治疗的任何患者。第2组的成员是具有在CRC中的任何BRAF突变，先前未接受过MAPK途径抑制剂的治疗的患者。第3组的成员是患有具有BRAF V600E/K突变的肿瘤，该肿瘤对MAPK抑制剂治疗无效的患者。第6组的成员是具有在NSCLC中存在的任何BRAF突变的患者。如图3所示，包括所有28位患者通过横线表示，每个受试者一个横线。从组的顶部(最长治疗持续时间)到底部(最短治疗持续时间)说明了每个组中每个受试者的治疗持续时间。水平轴表示患者在研究中的持续时间(天)。图3还显示了根据RECIST v1.1为每个患者实现的应答类型(菱形＝部分应答；圆圈＝稳定疾病；垂直线＝进展性疾病；三角形＝未评估)。
图4显示了在因BRAF突变破坏的瀑布图中的治疗持续时间。包括所有根据RECISTv1.1应答标准测量的28位患者，以及未通过RECIST v1.1评估的其他患者(菱形＝部分应答；圆圈＝稳定疾病；竖线＝进展性疾病；三角形＝未评估)。对于携带相同BRAF突变的肿瘤，在中断之前BVD-523治疗的平均持续时间为：D594，73.6天；G469，208.14天；K601E，50.25天；L597，73.3天；T599 Dup，63.5天。对于代表特定BRAF突变的单个患者，治疗持续时间为：L485W，304天；F247L，84天；G466V，77天；BRAF融合，65天；BRAF-AGAP3重排，43天；BRAF外显子15剪接变体，15天。通过对癌症患者进行BRAF突变的基因组筛选，并在对这些突变(作为驱动突变)进行完整的体外表征之前对其进行治疗，BVD-523被证明可用于研究和发现携带BRAF中突变的患者的有效治疗选择。患者的临床人群和功效主要不是由肿瘤类型决定，而是由ERK 1/2激酶活化上游的酶如BRAF的突变状态决定。
总之，所提供的实施例提供了来自新型ERK抑制剂BVD-523的实体瘤1b期试验的数据，用于治疗患有携带非典型BRAF突变的癌症的患者。连续的每天两次用BVD-523进行治疗在几位患者中产生抗肿瘤作用，并且不仅限于任何一种特定的癌症类型或非典型的BRAF突变。
文件资料
ABSALAN,Farnaz,Mostafa Ronaghi(2008).Molecular Inversion ProbeAssay.Methods in Molecular Biology 396.Humana Press.pp.315–330.
AHRONIAN LG,Sennott EM,Van Allen EM,Wagle N,Kwak EL,Faris JE,etal.Clinical acquired resistance to RAF inhibitor combinations in BRAF-mutantcolorectal cancer through MAPK pathway alterations.Cancer Discov 2015；5:358–67.
ARCILA ME,Drilon A,Sylvester BE,Lovly CM,Borsu L,Reva B,et al.MAP2K1(MEK1)mutations define a distinct subset of lung adenocarcinoma associatedwith smoking.Clin Cancer Res 2015；21:1935-43.
ARONOV AM,Baker C,Bemis GW,Cao J,Chen G,Ford PJ,et al.Flipped out:structure-guided design of selective pyrazolylpyrrole ERK inhibitors.J MedChem2007；50:1280-7.
ARONOV AM,Tang Q,Martinez-Botella G,Bemis GW,Cao J,Chen G,etal.Structure-guided design of potent and selective pyrimidylpyrroleinhibitors of extracellular signal-regulated kinase(ERK)using conformationalcontrol.J Med Chem 2009；52:6362-8.
ARRINGTON AK,Heinrich EL,Lee W,Duldulao M,Patel S,Sanchez J,etal.Prognostic and predictive roles of KRAS mutation in colorectal cancer.IntJ Mol Sci 2012；13:12153-68.
CARGNELLO M,Roux PP.Activation and function of the MAPKs and theirsubstrates,the MAPK-activated protein kinases.Microbiol Mol Biol Rev 2011；75:50-83.
CARLINO MS,Fung C,Shahheydari H,Todd JR,Boyd SC,Irvine M,etal.Preexisting MEK1P124 mutations diminish response to BRAF inhibitors inmetastatic melanoma patients.Clin Cancer Res 2015；21:98-105.
CHAPMAN PB,Hauschild A,Robert C,Haanen JB,Ascierto P,Larkin J,etal.Improved survival with vemurafenib in melanoma with BRAF V600E mutation.NEngl J Med2011；364:2507-16.
CORCORAN,R.B.,et al.BRAF gene amplification can promote acquiredresistance to MEK inhibitors in cancer cells harboring the BRAF V600Emutation.Sci Signal(2010)；3(149):ra84.
DAI,B.,et al.STAT3 mediates resistance to MEK inhibitor throughmicroRNA miR-17.Cancer Res(2011)；71:3658-3668.
DAVIES H,Bignell GR,Cox C,Stephens P,Edkins S,Clegg S,et al.Mutationsof the BRAF gene in human cancer.Nature 2002；417:949–54.
DESCHENES-SIMARD X,Kottakis F,Meloche S,Ferbeyre G.ERKs in cancer:friends or foes？Cancer Res 2014；74:412–9.
DOBRZYCKA B,Terlikowski SJ,Kowalczuk O,Niklinska W,Chyczewski L,Kulikowski M.Mutations in the KRAS gene in ovarian tumors.Folia HistochemCytobiol 2009；47:221–4.
EMERY,C.M.,et al.MEK1 mutations confer resistance to MEK and B-RAFinhibition.PNAS(2009)；106(48):20411-6.
FEDOROV O,Niesen FH,Knapp S.Kinase inhibitor selectivity profilingusing differential scanning fluorimetry.Methods Mol Biol 2012；795:109-18.
Figure BDA0002323874170000571
-MEDARDE A,Santos E.Ras in cancer and developmentaldiseases.Genes Cancer 2011；2:344–58.
FLAHERTY KT,Infante JR,Daud A,Gonzalez R,Kefford RF,Sosman J,etal.Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.NEngl J Med2012；367:1694-703.
GOETZ EM,Ghandi M,Treacy DJ,Wagle N,Garraway LA.ERK mutations conferresistance to mitogen-activated protein kinase pathway inhibitors.CancerRes2014；74:7079-89.
GOLLOB JA,Wilhelm S,Carter C,Kelley SL.Role of Raf kinase in cancer:therapeutic potential of targeting the Raf/MEK/ERK signal transductionpathway.Semin Oncol2006；33:392-406.
GREGER,James G.,et al."Combinations of BRAF,MEK,and PI3K/mTORinhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436dabrafenib,mediated by NRAS or MEK mutations."Molecular cancer therapeutics11.4(2012):909-920.
GROENENDIJK FH,Bernards R.Drug resistance to targeted therapies:dejavu all over again.Mol Oncol 2014；8:1067-83.
HALL RD,Kudchadkar RR.BRAF mutations:signaling,epidemiology,andclinical experience in multiple malignancies.Cancer Control 2014；21:221-30.
HARDENBOL,P.,et al.Multiplexed genotyping with sequence-taggedmolecular inversion probes.Nat.Biotechnol.2003,no.21,p.673-678.
HATZIVASSILIOU,Georgia,et al."RAF inhibitors prime wild-type RAF toactivate the MAPK pathway and enhance growth."Nature 464.7287(2010):431-435.
HATZIVASSILIOU G,Liu B,O'Brien C,Spoerke JM,Hoeflich KP,Haverty PM,etal.ERK inhibition overcomes acquired resistance to MEK inhibitors.Mol CancerTher2012；11:1143-54.
HAUSCHILD A,Grob J-J,Demidov LV,Jouary T,Gutzmer R,Millward M,etal.Dabrafenib in BRAF-mutated metastatic melanoma:a multicentre,open-label,phase 3randomised controlled trial.Lancet 2012；380:358-65.
HAYES TK,Neel NF,Hu C,Gautam P,Chenard M,Long B,et al.Long-Term ERKInhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYCDegradation and Senescence-like Growth Suppression.Cancer Cell 2016；29:75-89.
HEZEL AF,Noel MS,Allen JN,Abrams TA,Yurgelun M,Faris JE,et al.PhaseII study of gemcitabine,oxaliplatin in combination with panitumumab in KRASwild-type unresectable or metastatic biliary tract and gallbladder cancer.BrJ Cancer 2014；111:430–6.
JHA S,Morris EJ,Hruza A,Mansueto MS,Schroeder G,Arbanas J,etal.Dissecting therapeutic resistance to ERK inhibition.Mol Cancer Ther 2016；15:548-59.
JOHANNESSEN,C.M.,et al.COT/MAP3K8 drives resistance to RAF inhibitionthrough MAP kinase pathway reactivation.Nature(2010)；468(7326):968-972.
JOHNSON DB,Menzies AM,Zimmer L,Eroglu Z,Ye F,Zhao S,et al.AcquiredBRAF inhibitor resistance:A multicenter meta-analysis of the spectrum andfrequencies,clinical behaviour,and phenotypic associations of resistancemechanisms.Eur J Cancer2015；51:2792-9.
KANDA M,Matthaei H,Wu J,Hong SM,Yu J,Borges M,et al.Presence ofsomatic Mutations in most early-stage pancreatic intraepithelialneoplasia.Gastroenterology2012；142:730-733.
KHATTAK M,Fisher R,Turajlic S,Larkin J.Targeted therapy andimmunotherapy in advanced melanoma:an evolving paradigm.Ther Adv Med Oncol2013；5:105–18.
KING,Alastair J.,et al."Dabrafenib；preclinical characterization,increased efficacy when combined with trametinib,while BRAF/MEK toolcombination reduced skin lesions."PloS one8.7(2013):e67583.
LARKIN J,Ascierto PA,Dréno B,Atkinson V,Liszkay G,Maio M,etal.Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.N Engl J Med2014；371:1867-76.
LITTLE,A.S.,et al.,Amplification of the Driving Oncogene,KRAS orBRAF,Underpins Acquired Resistance to MEK1/2 Inhibitors in Colorectal CancerCells.Sci.Signal.4,ra17(2011).
LIU,Dingxie,et al."BRAF V600E maintains proliferation,transformation,and tumorigenicity of BRAF-mutant papillary thyroid cancer cells."Journal ofClinical Endocrinology&Metabolism 92.6(2007):2264-2271.
LIU B,Fu L,Zhang C,Zhang L,Zhang Y,Ouyang L,et al.Computationaldesign,chemical synthesis,and biological evaluation of a novel ERK inhibitor(BL-EI001)with apoptosis-inducing mechanisms in breast cancer.Oncotarget2015；6:6762-75.
LONG GV,Fung C,Menzies AM,Pupo GM,Carlino MS,Hyman J,et al.IncreasedMAPK reactivation in early resistance to dabrafenib/trametinib combinationtherapy of BRAF-mutant metastatic melanoma.Nat Commun 2014；5:5694.
LONG GV,Stroyakovskiy D,Gogas H,Levchenko E,de Braud F,Larkin J,etal.Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma:a multicentre,double-blind,phase 3 randomised controlledtrial.Lancet 2015；386:444-51.
MANANDHAR SP,Hildebrandt ER,Schmidt WK.Small-molecule inhibitors ofthe Rce1p CaaX protease.J Biomol Screen.2007；12(7):983–993.
MASSEY PR,Prasad V,Figg WD,Fojo T.Multiplying therapies and reducingtoxicity in metastatic melanoma.Cancer Biol Ther 2015；16:1014-8.
MAURER,T,Garrenton,LS,Oh,A,Pitts,K,Anderson,DJ,Skelton,NJ,Fauber,BP,Pan,B,Malek,S,Stokoe,D,Ludlam,MJC,Bowman,KK,Wu,J,Giannetti,AM,Starovasnik,MA,Mellman,I,Jackson,PK,Rudolph,J,Wang,W,Fang,G.Small-molecule ligands bind to adistinct pocket in Ras and inhibit SOS-mediated nucleotide exchangeactivity.PNAS.2012；109(14):5299-304.
MCARTHUR GA,Chapman PB,Robert C,Larkin J,Haanen JB,Dummer R,etal.Safety and efficacy of vemurafenib in BRAFv600E and BRAFv600K mutation-positive melanoma(BRIM-3):extended follow-up of a phase 3,randomised,open-label study.Lancet Oncol2014；15:323–32.
MEKINIST[package insert].Research Triangle Park,NC:GlaxoSmithKline；2014.
METZKER,Emerging technologies in DNA sequencing Genome Res.2005.15:1767-1776.
MITTAL,Rohit et al."The acetyltransferase activity of the bacterialtoxin YopJ of Yersinia is activated by eukaryotic host cell inositolhexakisphosphate."Journal of Biological Chemistry 285.26(2010):19927-19934.
MORRIS EJ,Jha S,Restaino CR,Dayananth P,Zhu H,Cooper A,etal.Discovery of a novel ERK inhibitor with activity in models of acquiredresistance to BRAF and MEK inhibitors.Cancer Discov 2013；3:742-50.
NAZARIAN,R.,et al.Melanomas acquire resistance to B-RAF(V600E)inhibition by RTK or N-RAS upregulation.Nature.2010；468(7326):973-977.
NIKOLAEV SI,Rimoldi D,Iseli C,Valsesia A,Robyr D,Gehrig C,et al.Exomesequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations inmelanoma.Nat Genet 2012；44:133–9.
NILSSON,M.,et al.Padlock probes:circularizing oligonucleotides forlocalized DNA detection.Science.1994,no.265,p.2085-2088.
O'HARA AJ,Bell DW.The genomics and genetics of endometrial cancer.AdvGenomics Genet 2012；2012:33–47.
OJESINA AI,Lichtenstein L,Freeman SS,Pedamallu CS,Imaz-Rosshandler I,Pugh TJ,et al.Landscape of genomic alterations in cervical carcinomas.Nature2014；506:371-5.
OTA et al.,Single nucleotide polymorphism detection by polymerasechain reaction-restriction fragment length polymorphism.Nat Protoc.2007；2(11):2857-64.
PARAISO KHT,Fedorenko IV,Cantini LP,Munko AC,Hall M,Sondak VK,etal.Recovery of phospho-ERK activity allows melanoma cells to escape from BRAFinhibitor therapy.Br J Cancer 2010；102:1724–30.
PATGIRI A,Yadav,KK,Arora,PS,Bar-Sagi,D.An orthosteric inhibitor ofthe Ras-Sos interaction.Nat Chem Biol.2011；7:585-587.
PENNYCUICK A,Simpson T,Crawley D,Lal R,Santis G,Cane P,et al.RoutineEGFR and KRAS mutation analysis using COLD-PCR in non-small cell lungcancer.Int J Clin Pract2012；66:748–52.
PORTER SB,Hildebrandt ER,Breevoort SR,Mokry DZ,Dore TM,SchmidtWK.Inhibition of the CaaX proteases Rce1p and Ste24p by peptidyl(acyloxy)methyl ketones.Biochim Biophys Acta.2007；1773(6):853–862.
POULIKAKOS PI,Persaud Y,Janakiraman M,Kong X,Ng C,Moriceau G,etal.RAF inhibitor resistance is mediated by dimerization of aberrantly splicedBRAF(V600E).Nature2011；480:387-90.
QUEIROLO P,Picasso V,Spagnolo F.Combined BRAF and MEK inhibition forthe treatment of BRAF-mutated metastatic melanoma.Cancer Treat Rev 2015；41:519-26.
RASOLA A,Sciacovelli M,Chiara F,Pantic B,Brusilow WS,BernardiP.Activation of mitochondrial ERK protects cancer cells from death throughinhibition of the permeability transition.Proc Natl Acad Sci U S A 2010；107:726–31.
RIZOS H,Menzies AM,Pupo GM,Carlino MS,Fung C,Hyman J,et al.BRAFinhibitor resistance mechanisms in metastatic melanoma:spectrum and clinicalimpact.Clin Cancer Res2014；20:1965-77.
ROBERT C,Karaszewska B,Schachter J,Rutkowski P,Mackiewicz A,Stroiakovski D,et al.Improved overall survival in melanoma with combineddabrafenib and trametinib.N Engl J Med 2015；372:30-9.
ROMEO Y,Zhang X,Roux PP.Regulation and function of the RSK family ofprotein kinases.Biochem J 2012；441:553–69.
RUDOLPH J,Xiao Y,Pardi A,Ahn NG.Slow inhibition and conformationselective properties of extracellular signal-regulated kinase 1 and 2inhibitors.Biochemistry2015；54:22-31.
SHAUL YD,Seger R.The MEK/ERK cascade:from signaling specificity todiverse functions.Biochim Biophys Acta 2007；1773:1213–26.
SHI H,Hugo W,Kong X,Hong A,Koya RC,Moriceau G,et al.Acquiredresistance and clonal evolution in melanoma during BRAF inhibitortherapy.Cancer Discov 2014；4:80-93.
SHIMA,F,Yoshikawa,Y,Ye,M,Araki,M,Matsumoto,S,Liao,J,Hu,L,Sugimoto,T,Ijiri,Y,Takeda,A,Nishiyama,Y,Sato,C,Muraoka,S,Tamura,A,Osoda,T,Tsuda,K-I,Miyakawa,T,Fukunishi,H,Shimada,J,Kumasaka,Yamamoto,M,Kataoka,T.In silicodiscovery of small-molecule Ras inhibitors that display antitumor activity byblocking the Ras-effector interaction.PNAS.2013；110(20):8182-7.
SCHUBBERT S,Shannon K,Bollag G.Hyperactive Ras in developmentaldisorders and cancer.Nat Rev Cancer 2007；7:295–308.
SUN C,Hobor S,Bertotti A,Zecchin D,Huang S,Galimi F,et al.Intrinsicresistance to MEK inhibition in KRAS mutant lung and colon cancer throughtranscriptional induction of ERBB3.Cell Rep 2014；7:86-93.
TAFLINAR[package insert].Research Triangle Park,NC:GlaxoSmithKline；2015.
TRUNZER K,Pavlick AC,Schuchter L,Gonzalez R,McArthur GA,Hutson TE,etal.Pharmacodynamic effects and mechanisms of resistance to vemurafenib inpatients with metastatic melanoma.J Clin Oncol 2013；31:1767-74.
VILLANUEVA,J.,et al.Acquired resistance to BRAF inhibitors mediatedby a RAF kinase switch in melanoma can be overcome by cotargeting MEK andIGF-1R/PI3K.Cancer Cell.2010；18:683-695.
WAGLE,N.,et al.Dissecting therapeutic resistance to RAF inhibition inmelanoma by tumor genomic profiling.Journal of Clinical Oncology 2011；29(22):3085-3096.
WAGLE N,Van Allen EM,Treacy DJ,Frederick DT,Cooper ZA,Taylor-WeinerA,et al.MAP kinase pathway alterations in BRAF-mutant melanoma patients withacquired resistance to combined RAF/MEK inhibition.Cancer Discov 2014；4:61-8.
Wainstein E,Seger R.The dynamic subcellular localization of ERK:mechanisms of translocation and role in various organelles.Curr Opin CellBiol 2016；39:15-20.
WANG,H.,et al.Identification of the MEK1(F129L)activating mutation asa potential mechanism of acquired resistance to MEK inhibition in humancancers carrying the B-RAF V600E mutation.Cancer Res(2011)；71(16):5535-45.
YANG W,Soares J,Greninger P,Edelman EJ,Lightfoot H,Forbes S,etal.Genomics of Drug Sensitivity in Cancer(GDSC):a resource for therapeuticbiomarker discovery in cancer cells.Nucleic Acids Res 2013；41:D955-D961.
YAO Z,Torres NM,Tao A,Gao Y,Luo L,Li Q,et al.BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivityto Pharmacologic Inhibition.Cancer Cell 2015；28:370-83.
YOHE S.Molecular genetic markers in acute myeloid leukemia.J ClinMed2015；4:460–78.
ZELBORAF[package insert].South San Francisco,CA:Genentech USA,Inc.；2015.
该申请中引用的所有文件都通过引用并入本文，如同在此全文引用一样。
尽管这里已经描述了本发明的示例说明性实施方案，但是应该理解本发明不限于所描述的实施方案，并且本领域技术人员可以在不背离本发明的范围或精神的情况下做出多种其他改变或修改。
序列表
<110> Biomed Valley Discoveries, Inc.
<120> 用于治疗具有非典型BRAF突变的癌症的组合物和方法
<130> C065272/2391211
<140> US 62/506,995
<141> 2017-05-16
<160> 44
<210> 1
<211> 2949
<212> DNA
<213> 智人
<400> 1
cgcctccctt ccccctcccc gcccgacagc ggccgctcgg gccccggctc tcggttataa 60
gatggcggcg ctgagcggtg gcggtggtgg cggcgcggag ccgggccagg ctctgttcaa 120
cggggacatg gagcccgagg ccggcgccgg cgccggcgcc gcggcctctt cggctgcgga 180
ccctgccatt ccggaggagg tgtggaatat caaacaaatg attaagttga cacaggaaca 240
tatagaggcc ctattggaca aatttggtgg ggagcataat ccaccatcaa tatatctgga 300
ggcctatgaa gaatacacca gcaagctaga tgcactccaa caaagagaac aacagttatt 360
ggaatctctg gggaacggaa ctgatttttc tgtttctagc tctgcatcaa tggataccgt 420
tacatcttct tcctcttcta gcctttcagt gctaccttca tctctttcag tttttcaaaa 480
tcccacagat gtggcacgga gcaaccccaa gtcaccacaa aaacctatcg ttagagtctt 540
cctgcccaac aaacagagga cagtggtacc tgcaaggtgt ggagttacag tccgagacag 600
tctaaagaaa gcactgatga tgagaggtct aatcccagag tgctgtgctg tttacagaat 660
tcaggatgga gagaagaaac caattggttg ggacactgat atttcctggc ttactggaga 720
agaattgcat gtggaagtgt tggagaatgt tccacttaca acacacaact ttgtacgaaa 780
aacgtttttc accttagcat tttgtgactt ttgtcgaaag ctgcttttcc agggtttccg 840
ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaagttc cactgatgtg 900
tgttaattat gaccaacttg atttgctgtt tgtctccaag ttctttgaac accacccaat 960
accacaggaa gaggcgtcct tagcagagac tgccctaaca tctggatcat ccccttccgc 1020
acccgcctcg gactctattg ggccccaaat tctcaccagt ccgtctcctt caaaatccat 1080
tccaattcca cagcccttcc gaccagcaga tgaagatcat cgaaatcaat ttgggcaacg 1140
agaccgatcc tcatcagctc ccaatgtgca tataaacaca atagaacctg tcaatattga 1200
tgacttgatt agagaccaag gatttcgtgg tgatggagga tcaaccacag gtttgtctgc 1260
taccccccct gcctcattac ctggctcact aactaacgtg aaagccttac agaaatctcc 1320
aggacctcag cgagaaagga agtcatcttc atcctcagaa gacaggaatc gaatgaaaac 1380
acttggtaga cgggactcga gtgatgattg ggagattcct gatgggcaga ttacagtggg 1440
acaaagaatt ggatctggat catttggaac agtctacaag ggaaagtggc atggtgatgt 1500
ggcagtgaaa atgttgaatg tgacagcacc tacacctcag cagttacaag ccttcaaaaa 1560
tgaagtagga gtactcagga aaacacgaca tgtgaatatc ctactcttca tgggctattc 1620
cacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagct tgtatcacca 1680
tctccatatc attgagacca aatttgagat gatcaaactt atagatattg cacgacagac 1740
tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc tcaagagtaa 1800
taatatattt cttcatgaag acctcacagt aaaaataggt gattttggtc tagctacagt 1860
gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca ttttgtggat 1920
ggcaccagaa gtcatcagaa tgcaagataa aaatccatac agctttcagt cagatgtata 1980
tgcatttgga attgttctgt atgaattgat gactggacag ttaccttatt caaacatcaa 2040
caacagggac cagataattt ttatggtggg acgaggatac ctgtctccag atctcagtaa 2100
ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc tcaaaaagaa 2160
aagagatgag agaccactct ttccccaaat tctcgcctct attgagctgc tggcccgctc 2220
attgccaaaa attcaccgca gtgcatcaga accctccttg aatcgggctg gtttccaaac 2280
agaggatttt agtctatatg cttgtgcttc tccaaaaaca cccatccagg cagggggata 2340
tggtgcgttt cctgtccact gaaacaaatg agtgagagag ttcaggagag tagcaacaaa 2400
aggaaaataa atgaacatat gtttgcttat atgttaaatt gaataaaata ctctcttttt 2460
ttttaaggtg aaccaaagaa cacttgtgtg gttaaagact agatataatt tttccccaaa 2520
ctaaaattta tacttaacat tggattttta acatccaagg gttaaaatac atagacattg 2580
ctaaaaattg gcagagcctc ttctagaggc tttactttct gttccgggtt tgtatcattc 2640
acttggttat tttaagtagt aaacttcagt ttctcatgca acttttgttg ccagctatca 2700
catgtccact agggactcca gaagaagacc ctacctatgc ctgtgtttgc aggtgagaag 2760
ttggcagtcg gttagcctgg gttagataag gcaaactgaa cagatctaat ttaggaagtc 2820
agtagaattt aataattcta ttattattct taataatttt tctataacta tttcttttta 2880
taacaatttg gaaaatgtgg atgtctttta tttccttgaa gcaataaact aagtttcttt 2940
ttataaaaa 2949
<210> 2
<211> 766
<212> PRT
<213> 智人
<400> 2
Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Ala Glu Pro Gly Gln
1 5 10 15
Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala Gly Ala Gly
20 25 30
Ala Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp
35 40 45
Asn Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu
50 55 60
Leu Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu
65 70 75 80
Ala Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu
85 90 95
Gln Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser
100 105 110
Ser Ser Ala Ser Met Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu
115 120 125
Ser Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val
130 135 140
Ala Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe
145 150 155 160
Leu Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr
165 170 175
Val Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro
180 185 190
Glu Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile
195 200 205
Gly Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val
210 215 220
Glu Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys
225 230 235 240
Thr Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe
245 250 255
Gln Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys
260 265 270
Ser Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu
275 280 285
Leu Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu
290 295 300
Ala Ser Leu Ala Glu Thr Ala Leu Thr Ser Gly Ser Ser Pro Ser Ala
305 310 315 320
Pro Ala Ser Asp Ser Ile Gly Pro Gln Ile Leu Thr Ser Pro Ser Pro
325 330 335
Ser Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp
340 345 350
His Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn
355 360 365
Val His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg
370 375 380
Asp Gln Gly Phe Arg Gly Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala
385 390 395 400
Thr Pro Pro Ala Ser Leu Pro Gly Ser Leu Thr Asn Val Lys Ala Leu
405 410 415
Gln Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser
420 425 430
Glu Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp
435 440 445
Asp Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly
450 455 460
Ser Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val
465 470 475 480
Ala Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln
485 490 495
Ala Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn
500 505 510
Ile Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val
515 520 525
Thr Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile
530 535 540
Glu Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr
545 550 555 560
Ala Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp
565 570 575
Leu Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile
580 585 590
Gly Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His
595 600 605
Gln Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val
610 615 620
Ile Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr
625 630 635 640
Ala Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr
645 650 655
Ser Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly
660 665 670
Tyr Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala
675 680 685
Met Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg
690 695 700
Pro Leu Phe Pro Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser
705 710 715 720
Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala
725 730 735
Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys
740 745 750
Thr Pro Ile Gln Ala Gly Gly Tyr Gly Ala Phe Pro Val His
755 760 765
<210> 3
<211> 3906
<212> DNA
<213> 大鼠
<400> 3
atggcggcgc tgagtggcgg cggtggcagc agcagcggtg gcggtggcgg cggcggcggc 60
ggcggtggtg gcggcggcgg cggcggcgcc gaacagggac aggctctgtt caatggcgac 120
atggagccgg aggccggcgc tggcgccgcg gcctcttcgg ccgcggaccc ggccattcct 180
gaagaggtgt ggaatatcaa gcaaatgatt aagttgacac aggaacatat agaggcccta 240
ttggacaagt ttggtgggga gcataaccca ccgtcaatat acctggaggc ctatgaagag 300
tacaccagca agctagatgc ccttcagcag agagagcagc agctgttgga atccctggtt 360
tttcaaactc ccacagatgt atcacggaac aaccccaagt caccacagaa acctatcgtt 420
cgtgtcttcc tgcccaacaa acagaggaca gtggtgcccg caagatgtgg tgtaacggtc 480
cgagacagtc taaagaaagc actaatgatg aggggtctca tcccagagtg ctgtgctgtt 540
tacagaattc aggacggaga gaagaaacca attggctggg acactgacat ttcctggctt 600
actggagagg agctacatgt tgaagtacta gagaatgttc ctctgacaac ccacaacttc 660
gtacggaaaa cttttttcac cttagcattt tgtgactttt gccgaaagct gcttttccag 720
ggtttccgct gtcaaacatg tggttataag tttcaccagc gttgtagtac agaggttcca 780
ctgatgtgtg ttaattatga ccaacttgat ttgctgtttg tctccaagtt ctttgagcat 840
cacccagtac cacaggagga ggccttctca gcagagacta cccttccatc tggatgctct 900
tccgcacccc cctcagactc tattgggccc caaatcctca ccagtccatc tccttcaaaa 960
tccattccaa ttccacagcc cttccggcca gcagatgaag atcatcgcaa tcagtttggg 1020
caacgagacc gctcctcctc cgctcccaat gttcatataa acacaatcga acctgtcaat 1080
attgatgaaa aattcccaga agtggaatta caggatcaaa gggatttgat tagagaccag 1140
gggtttcgtg gggatggagc ccctttgaac cagctgatgc gctgtcttcg gaaataccaa 1200
tcccggactc ccagccccct cctccattct gtccccagtg aaatagtgtt tgattttgag 1260
cctggcccag tgttcagagg gtcaaccaca ggcttgtcgg ccaccccacc tgcctcatta 1320
cctggctcac tcactaacgt gaaagcctta cagaaatctc caggacctca gcgggaaagg 1380
aagtcctcct cctcctcctc ctccacggaa gacagaagtc ggatgaaaac acttggtaga 1440
agagattcaa gtgatgattg ggagattcct gatggacaga ttacagtggg acagagaatt 1500
ggatctgggt cctttggaac tgtctacaag ggaaagtggc atggcgacgt ggcagtgaaa 1560
atgctgaatg tgacagcacc cacacctcag cagttacagg ccttcaaaaa cgaagtcgga 1620
gtactcagga aaactcgaca tgtgaacatc ctccttttca tgggctattc tacaaagcca 1680
cagctggcta ttgttacaca gtggtgtgaa ggctccagct tatatcacca tctccacatc 1740
attgagacca aatttgagat gatcaaactt atagatattg cacggcagac tgcacagggc 1800
atggattact tacacgccaa gtcaatcatc cacagagacc tcaagagtaa taatatattt 1860
cttcatgaag acctcacggt aaaaataggt gactttggtt tagccacagt gaagtcccga 1920
tggagtgggt cccatcagtt tgaacagttg tctggatcta ttttgtggat ggcacccgaa 1980
gtaatcagaa tgcaagataa aaacccatat agctttcagt cagacgtgta tgcatttggg 2040
attgttctgt atgaactgat gactggtcag ctaccttatt caaacatcaa caacagggat 2100
cagataattt ttatggtggg acgaggatac ctatctccag atctcagtaa ggtacggagt 2160
aactgtccaa aagccatgaa gagattaatg gcagagtgcc tcaaaaagaa aagagacgag 2220
agaccactct ttccccaaat tctcgcctct attgagctgc tggcccgctc attgccaaaa 2280
attcaccgca gtgcatcaga accctccttg aatcgggctg gtttccaaac agaagatttt 2340
agtctgtatg cttgtgcttc tccaaaaaca cccatccaag cagggggata tggagaattt 2400
gcagccttca agtagccact ccatcatggc agcatctact ctttatttct taagtcttgt 2460
gttcatacaa tttgttaaca tcaaaacaca gttctgttcc tcaaattttt tttaaagata 2520
caaaattttc aatgcataag ctcgtgtgga acagaatgga atttcctatt caacaaaaga 2580
gggaagaatg ttttaggaac cagaattctc tgctgcccgt gtttcttctt caacacaaat 2640
atcatgtgca tacaactctg cccattccca agaagaaaga ggagagaccc cgaattctgc 2700
ccttttggtg gtcaggcatg atggaaagaa tttgctgctg cagcttggga aaaattgcta 2760
tggaaagtct gccagtcaac tttgcccttc taaccaccag atccatttgt ggctggtcat 2820
ctgatggggc gatttcaatc accaagcatc gttcttgcct gttgtgggat tatgtcgtgg 2880
agcactttcc ctatccacca ccgttaattt ccgagggatg gagtaaatgc agcataccct 2940
ttgtgtagca cctgtccagt cctcaaccaa tgctatcaca gtgaagctct ttaaatttaa 3000
gtggtgggtg agtgttgagg agagactgcc ttgggggcag agaaaagggg atgctgcatc 3060
ttcttcctca cctccagctc tctcacctcg ggttgccttg cacactgggc tccgcctaac 3120
cactcgggct gggcagtgct ggcacacatt gccgcctttt ctcattgggt ccagcaattg 3180
agcagagggt tgggggattg tttcctccac aatgtagcaa attctcagga aaatacagtc 3240
catatcttcc tctcagctct tccagtcacc aaatacttac gtggctcctt tgtccaggac 3300
ataaaacacc gtggacaaca cctaattaaa agcctacaaa actgcttact gacagttttg 3360
aatgtgagac atttgtgtaa tttaaatgta aggtacaggt cttaatttct tctattaagt 3420
ttcttctatt tttatttaaa cgaagaaaat aattttcagg tttaattgga ataaacgaat 3480
acttcccaaa agactatata ccctgaaaat tatatttttg ttaattgtaa acaactttta 3540
aaaaatggtt attatccttt tctctaccta aaattatggg aaatcttagc ataatgacaa 3600
ttatttatac tttttaaata aatggtactt gctggatcca cactaacatc tttgctaaca 3660
ttcccattgt ttcttccaac ttcactccta cactacatcc tccatcctct ttctagtctt 3720
ttatctataa tatgcaacct aaaataaaag tggtggtgtc tccattcatt cttcttcttc 3780
cttttttccc caagcctggt cttcaaaagg ttgggtaatt tagtagctga gttccctagg 3840
tagaaataga actattaggg acattggggt tgtaggaaag cgtgaggcct gtcaccagtt 3900
gttctt 3906
<210> 4
<211> 804
<212> PRT
<213> 大鼠
<400> 4
Met Ala Ala Leu Ser Gly Gly Gly Gly Ser Ser Ser Gly Gly Gly Gly
1 5 10 15
Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu Gln
20 25 30
Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala Gly
35 40 45
Ala Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp
50 55 60
Asn Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu
65 70 75 80
Leu Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu
85 90 95
Ala Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu
100 105 110
Gln Gln Leu Leu Glu Ser Leu Val Phe Gln Thr Pro Thr Asp Val Ser
115 120 125
Arg Asn Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu
130 135 140
Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val
145 150 155 160
Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu
165 170 175
Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly
180 185 190
Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu
195 200 205
Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr
210 215 220
Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln
225 230 235 240
Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser
245 250 255
Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu
260 265 270
Phe Val Ser Lys Phe Phe Glu His His Pro Val Pro Gln Glu Glu Ala
275 280 285
Phe Ser Ala Glu Thr Thr Leu Pro Ser Gly Cys Ser Ser Ala Pro Pro
290 295 300
Ser Asp Ser Ile Gly Pro Gln Ile Leu Thr Ser Pro Ser Pro Ser Lys
305 310 315 320
Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His Arg
325 330 335
Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val His
340 345 350
Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Glu Lys Phe Pro Glu Val
355 360 365
Glu Leu Gln Asp Gln Arg Asp Leu Ile Arg Asp Gln Gly Phe Arg Gly
370 375 380
Asp Gly Ala Pro Leu Asn Gln Leu Met Arg Cys Leu Arg Lys Tyr Gln
385 390 395 400
Ser Arg Thr Pro Ser Pro Leu Leu His Ser Val Pro Ser Glu Ile Val
405 410 415
Phe Asp Phe Glu Pro Gly Pro Val Phe Arg Gly Ser Thr Thr Gly Leu
420 425 430
Ser Ala Thr Pro Pro Ala Ser Leu Pro Gly Ser Leu Thr Asn Val Lys
435 440 445
Ala Leu Gln Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser
450 455 460
Ser Ser Ser Ser Thr Glu Asp Arg Ser Arg Met Lys Thr Leu Gly Arg
465 470 475 480
Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro Asp Gly Gln Ile Thr Val
485 490 495
Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys
500 505 510
Trp His Gly Asp Val Ala Val Lys Met Leu Asn Val Thr Ala Pro Thr
515 520 525
Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu Val Gly Val Leu Arg Lys
530 535 540
Thr Arg His Val Asn Ile Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro
545 550 555 560
Gln Leu Ala Ile Val Thr Gln Trp Cys Glu Gly Ser Ser Leu Tyr His
565 570 575
His Leu His Ile Ile Glu Thr Lys Phe Glu Met Ile Lys Leu Ile Asp
580 585 590
Ile Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr Leu His Ala Lys Ser
595 600 605
Ile Ile His Arg Asp Leu Lys Ser Asn Asn Ile Phe Leu His Glu Asp
610 615 620
Leu Thr Val Lys Ile Gly Asp Phe Gly Leu Ala Thr Val Lys Ser Arg
625 630 635 640
Trp Ser Gly Ser His Gln Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp
645 650 655
Met Ala Pro Glu Val Ile Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe
660 665 670
Gln Ser Asp Val Tyr Ala Phe Gly Ile Val Leu Tyr Glu Leu Met Thr
675 680 685
Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe
690 695 700
Met Val Gly Arg Gly Tyr Leu Ser Pro Asp Leu Ser Lys Val Arg Ser
705 710 715 720
Asn Cys Pro Lys Ala Met Lys Arg Leu Met Ala Glu Cys Leu Lys Lys
725 730 735
Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln Ile Leu Ala Ser Ile Glu
740 745 750
Leu Leu Ala Arg Ser Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro
755 760 765
Ser Leu Asn Arg Ala Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala
770 775 780
Cys Ala Ser Pro Lys Thr Pro Ile Gln Ala Gly Gly Tyr Gly Glu Phe
785 790 795 800
Ala Ala Phe Lys
<210> 5
<211> 9728
<212> DNA
<213> 小鼠
<400> 5
ccctcaggct cggctgcgcc ggggccgccg gcgggttcca gaggtggcct ccgccccggc 60
cgctccgccc acgccccccg cgcctccgcg cccgcctccg cccgccctgc gcctcccttc 120
cccctccccg ccccgcggcg gccgctcggc ccggctcgcg cttcgaagat ggcggcgctg 180
agtggcggcg gtggcagcag cagcggtggc ggcggcggcg gtggcggcgg cggtggcggt 240
ggcgacggcg gcggcggcgc cgagcagggc caggctctgt tcaatggcga catggagccg 300
gaggccggcg ctggcgccgc ggcctcttcg gctgcggacc cggccattcc tgaagaggta 360
tggaatatca agcaaatgat taagttgaca caggaacata tagaggccct attggacaaa 420
tttggtggag agcataaccc accatcaata tacctggagg cctatgaaga gtacaccagc 480
aagctagatg cccttcagca aagagaacag cagcttttgg aatccctggt ttttcaaact 540
cccacagatg catcacggaa caaccccaag tcaccacaga aacctatcgt tagagtcttc 600
ctgcccaaca aacagaggac agtggtaccc gcaagatgtg gtgttacagt tcgagacagt 660
ctaaagaaag cactgatgat gagaggtctc atcccagaat gctgtgctgt ttacagaatt 720
caggatggag agaagaaacc aattggctgg gacacggaca tttcctggct tactggagag 780
gagttacatg ttgaagtact ggagaatgtc ccacttacaa cacacaactt tgtacggaaa 840
acttttttca ccttagcatt ttgtgacttt tgccgaaagc tgcttttcca gggtttccgt 900
tgtcaaacat gtggttataa atttcaccag cgttgtagta cagaggttcc actgatgtgt 960
gtaaattatg accaacttga tttgctgttt gtctccaagt tctttgagca tcacccagta 1020
ccacaggagg aggcctcctt cccagagact gcccttccat ctggatcctc ttccgcaccc 1080
ccctcagact ctactgggcc ccaaatcctc accagtccat ctccttcaaa atccattcca 1140
attccacagc ccttccgacc agcagatgaa gatcatcgca atcagtttgg gcaacgagac 1200
cggtcctcct cagctcccaa tgttcatata aacacaattg agcctgtgaa tatcgatgaa 1260
aaattcccag aagtggaatt acaggatcaa agggatttga ttagagacca ggggtttcgt 1320
ggtgatggag cccccttgaa ccaactgatg cgctgtcttc ggaaatacca atcccggact 1380
cccagccccc tcctccattc tgtccccagt gaaatagtgt ttgattttga gcctggccca 1440
gtgttcagag ggtcaaccac aggcttgtcc gccaccccgc ctgcctcatt acctggctca 1500
ctcactaacg tgaaagcctt acagaaatct ccaggtcctc agcgggaaag gaagtcatct 1560
tcttcctcat cctcggagga cagaagtcgg atgaaaacac ttggtagaag agattcaagt 1620
gatgactggg agattcctga tggacagatt acagtgggac agagaattgg atctgggtca 1680
tttggaactg tctacaaggg aaagtggcat ggtgatgtgg cagtgaaaat gttgaatgtg 1740
acagcaccca cacctcaaca gctacaggcc ttcaaaaatg aagtaggagt gctcaggaaa 1800
actcgacatg tgaatatcct ccttttcatg ggctattcta caaagccaca actggcaatt 1860
gttacacagt ggtgtgaggg ctccagctta tatcaccatc tccacatcat tgagaccaaa 1920
tttgagatga tcaaacttat agatattgct cggcagactg cacagggcat ggattactta 1980
cacgccaagt caatcatcca cagagacctc aagagtaata atatatttct tcatgaagac 2040
ctcacggtaa aaataggtga ctttggtcta gccacagtga aatctcggtg gagtgggtcc 2100
catcagtttg aacagttgtc tggatctatt ttgtggatgg caccagaagt aatcagaatg 2160
caagataaaa acccgtatag ctttcagtca gacgtgtatg cgtttgggat tgttctgtac 2220
gaactgatga ccggccagct accttattca aacatcaaca acagggatca gataattttt 2280
atggtgggac gaggatacct atctccagat ctcagtaagg tacggagtaa ctgtccaaaa 2340
gccatgaaga gattaatggc agagtgcctc aaaaagaaaa gagacgagag accactcttt 2400
ccccaaattc tcgcctccat tgagctgctg gcccgctcat tgccaaaaat tcaccgcagt 2460
gcatcagaac cttccttgaa tcgggctggt ttccaaacag aagattttag tctgtatgct 2520
tgtgcttctc cgaaaacacc catccaagca gggggatatg gagaatttgc agccttcaag 2580
tagccagtcc atcatggcag catctactct ttatttctta agtcttgtgt tcatacagtt 2640
tgttaacatc aaaacacagt tctgttcctc aaaaaatttt ttaaagatac aaaattttca 2700
atgcataagt tcatgtggaa cagaatggaa tttcctattc aacaaaagag ggaagaatgt 2760
tttaggaacc agaattctct gctgcccgtg tttcttcttc aacataacta tcacgtgcat 2820
acaagtctgc ccattcccaa gaagaaagag gagagaccct gaattctgcc cttttggtgg 2880
tcaggcatga tggaaagaat ttgctgctgc agcttgggaa aattgctatg gaaagtctgc 2940
cagtcgactt tgcccttcta accaccagat cagcctgtgg ctggtcatct gatggggcga 3000
tttccatcac caagcatcgt tcttgcctat tctgggatta tgttgtggag cactttccct 3060
gtccagcacc gttcatttct gagggatgga gtaaatgcag cattcccttg tgtagcgcct 3120
gttcagtcct cagcagctgc tgtcacagcg aagcttttta cagttaagtg gtgggggaga 3180
gttgaggaga gcctgcctcg gggcagagaa aagggggtgc tgcatcttct tcctcacctc 3240
cagctctctc acctcgggtt gccttgctca ctgggctccg cctaaccact caggctgctc 3300
agtgctggca cacattgcct tcttttctca ttgggtccag caattgagga gagggttggg 3360
ggattgtttc ctcctcaatg tagcaaattc tcaggaaaat acagtccata tcttcctctc 3420
agctcttcca gtcaccaaat acttacgtgg ctcctttgtc caggacataa aacaccgtgg 3480
acaacaccta attaaaagcc tacaaaactg cttactgaca gttttgaatg tgagacactt 3540
gtgtaattta aatgtaaggt acaggtttta atttctgagt ttcttctatt tttatttaaa 3600
agaagaaaat aattttcagt tttaattgga ataaatgagt acttcccaca agactatata 3660
ccctgaaaat tatatttttg ttaattgtaa acaactttta aagaataatt attatccttt 3720
tctctaccta aaaattatgg ggaatcttag cataatgaca attatttata ctttttaaat 3780
aaatggtact tgctggatcc acactaacat ctttgctaac aatcccattg tttcttccaa 3840
cttaactcct acactacatc ctacatcctc tttctagtct tttatctata atatgcaacc 3900
taaaataaac gtggtggcgt ctccattcat tctccctctt cctgttttcc ccaagcctgg 3960
tcttcaaaag gttgggtaat cggtccctga gctccctagc tggcaatgca actattaggg 4020
acattggagt tgcaggagag caggaagcct gtccccagct gttcttctag aaccctaaat 4080
cttatctttg cacagatcaa aagtatcacc tcgtcacagt tctccttagc ctttacttac 4140
aggtaatata aataaaaatc accatagtag taaagaaaac aactggatgg attgatgacc 4200
agtacctctc agagccagga atcttgaatc tccaggattt atacgtgcaa atttaaggag 4260
atgtacttag caacttcaag ccaagaactt ccaaaatact agcgaatcta aaataaaatg 4320
gaattttgag ttatttttaa agttcaaatt ataattgata ccactatgta tttaagccta 4380
ctcacagcaa gttagatgga ttttgctaaa ctcattgcca gactgtggtg gtggtggtgg 4440
tagtgtgcac ctttaatcca agcaactcag caatcagaat gaggtaaatc tctgtgaata 4500
caaggcctgc ctagtctgca gcgctagttc caggatagcc agggctacac acacaaaaac 4560
cctctctcaa aaaaaacaaa attaattagt tgataataaa aaataactaa agtatcatca 4620
aaggaaggcc tactggaagt tttatatatt cccagtaaat tgaaaaatat tctgaagtta 4680
ttaaccagtt agcaacaatg tgtttttaag tcttacataa acagagcaaa gtcttcaaat 4740
gtttcagagc tgagaagata attgtgcttg atatgaaaaa tagcctctcc atatgatgtg 4800
ccacattgaa aggcgtcatt acccttttaa atacttctta atgtggcttt gttcccttta 4860
cccaggatta gctagaaaga gctaggtagg cttcggccac agttgcacat ttcgggcctg 4920
ctgaagaatg ggagctttga aggctggcct tggtggagga gcccctcagt gctggagggt 4980
ggggcgtgta cgcagcatgg aagtggtcta gacagagtgc aaagggacag acttctttct 5040
cattttagta tagggtgatg tctcacttga aatgagaaag tagagttgat attaaacgaa 5100
gctgtgccca gaaaccaggc tcagggtatt gtgagatttt ctttttaaat agagaatata 5160
aaagatagaa ataaatattt aaaccttcct tcttattttc tatcaaatag atttttttta 5220
tcatttgcaa acaacataaa aaaaggtttc ttttgtgggg ttttctttcc ttcttttttt 5280
tttttttttt tttttaagac tgcagataat cttgttgagc tcctcggaaa atacaaggaa 5340
gtccgtgttt gtgcagagcg ctttatgagt aactgtatag acagtgtggc tgcttcactc 5400
atcccagagg gctgcagctg tcggcccatg aagtggctgc agtgcctcgt gagatctgct 5460
ttgttttgtt tggagtgaag tctttgaaag gtttgagtgc aactatatag gactgttttt 5520
aaataagtag tattcctcat gaactttctc attgttaagc tacaggaccc aaactctacc 5580
actaagatat tattaacctc aaaatgtagt ttatagaagg aatttgcaaa tagaatatcc 5640
agttcgtact tatatgcatc ttcaacaaag attctctgtg acttgttgga tttggttcct 5700
gaacagccca tttctgtatt tgaggttagg agggcataat gaggcatcct aaaagacaat 5760
ctgatataaa ctgtatgcta gatgtatgct ggtaggggag aaagcattct gtaaagacat 5820
gatttaagac ttcagctctg tcaaccagaa accttgtaaa tacttcctgt cttggtgcag 5880
ccccgcccct ttgatcacac gatgttgtct tgtgcttgtc agacactgtc agagctgctg 5940
ttcgtccctc tgcagatctc acctgtcccc actgcacacc cacctcctgc ctcttgcaga 6000
cctcagcatc tagctttagt tggaaacagt tcagggttca ggtgacttct taaaaaaaaa 6060
aaaaaaccct acctcctcag aatgaggtaa tgaatagtta tttatttaaa gtatgaagag 6120
tcaggagcgc tcgaacatga aggtgattta agatggttcc tttcgtgtgt attgtagctg 6180
agcacttgtt tttgtcctaa agggcattat acatttaagc agtgattctg tttaaagatg 6240
tttttcttta aaggtgtagc tcagagtatc tgttgttgga attggtgcca gagtctgctt 6300
aatagatttc agaatcctaa gcttaagtca gtcgcatgaa gttaagtagt tatggtaaca 6360
ctttgctagc catgatataa ttctactttt taggagtagg tttggcaaaa ctgtatgcct 6420
tcaaagtgag ttggccacag ctttgtcaca tgcacagata ctcatctgaa gagactgccc 6480
agctaagagg gcggaaggat accctttttt cctacgattc gcttctttgt ccacgttggc 6540
attgttagta ctagtttatc agcaccttga ccagcagatg tcaaccaata agctattttt 6600
aaaaccatag ccagagatgg agaggtcact gtgagtagaa acagcaggac gcttacagga 6660
gtgaaatggt gtagggaggc tctagaaaaa tatcttgaca atttgccaaa tgatcttact 6720
gtgccttcat gatgcaataa aaaagctaac attttagcag aaatcagtga tttacgaaga 6780
gagtggccag tctggtttaa ctcagctggg ataatatttt tagagtgcaa tttagactgc 6840
gaagataaat gcactaaaga gtttatagcc aattcacatt tgaaaaataa gaaaatggta 6900
aattttcagt gaaatatttt tttaaagcac ataatcccta gtgtagccag aaatatttac 6960
cacatagagc agctaggctg agatacagtc cagtgacatt tctagagaaa ccttttctac 7020
tcccacgggc tcctcaaagc atggaaattt tatacaaaat gtttgacatt ttaagatact 7080
gctgtagttt agttttgaaa tagtatgtgc tgagcagcaa tcatgtacta actcagagag 7140
agaaaacaac aacaaattgt gcatctgatt tgttttcaga gaaatgctgc caacttagat 7200
actgagttct cagagcttca agtgtaaact tgcctcccaa gtcctgtttg caaatgaagt 7260
tggctagtgc tactgactgc tccagcacat gatggaaggc agggggctgt ctctgaagtg 7320
tcttctataa agggacaata gaatagtgag agacctggtc agtgtgtgtc agctggacac 7380
tccatgctat gggacttgca tcttctgtcc tcaccatccc caagacattg tgctttcctc 7440
agttgtcctc tagctgtttc actcagacac caagatgaat tactgatgcc agaaggggcc 7500
aaaatggcca gtgtgttttg ggggttgtat cagttgactg gacaataact ttaatagttt 7560
cagatcattt atttttactt ccattttgac agacatttaa atggaaattt agtcctaact 7620
tttgtcattt gaaaggaaaa attaacagtt cctataagat acttttgagg tggaatctga 7680
catcctaatt ttttttcttt tcagtgggtt tgcagcgagg gtcttgtatg cactaggcaa 7740
gggttctacc actaagccac atttcccagg aaataaaatg ttaacagtta aaacatacac 7800
acaaatacac aaacacctta ttaccacttt agtaaagtga gagatgtgcg tcctttgtct 7860
cagtctccac gatttcagct gccccttgta tgaataactc agtctcgcta aactgtttac 7920
ttttatttac ctggtttgac tagttgcagc tatataacca gttgtgcatg aggacaacag 7980
ccagtgtgtt tgttttgttt ttggtttttt gtggtacatt ttttgtaaag aattctgtag 8040
attgaagtgc tctttgaaaa cagaactgag atatatttat tcttgttagc atcaaaaaac 8100
attttgtgca aatgatttgc ttttcctggc aggctgagta ccatatccag cgcccacaat 8160
tgcgggttcc catctaccat gtccacaggg gagacagacg ggaagcacat gaggggtgtg 8220
tttacagagt tgtaggagtt atgtagttct cttgttgcct tggaaatcac tgttgtttta 8280
agactgttga acccgtgtgt ttggctgggc tgtgagttac atgaagaaac tgcaaactag 8340
catatgcaga caaagctcac agactaggcg taaatggagg aaaatggacc aaaataaggc 8400
agggtgacac ataaaccttg ggcttcggag aaaactaagg gtggagatga actataatca 8460
cctgaataca atgtaagagt gcaataagtg tgcttattct aagctgtgaa cttcttttaa 8520
atcattcctt tctaatacat ttatgtatgt tccattgctg actaaaacca gctatgagaa 8580
catatgcctt tttattcatg ttaactacca gtttaagtgg ctaaccttaa tgtcttattt 8640
atcttcattt tgtattagtt tacataccag gtatgtgtgt gtgctgtact cttcttccct 8700
ttatttgaaa acacttttca ctgggtcatc tccttggcca ttccacaaca caactttggt 8760
ttggctttca atgtcacctt atttgatggc ctgtgtccca gtagcagaat ttatggtatt 8820
cccattgctg gctgctcttc cgaccctttg cttctacagc acttgtctct cctaagatag 8880
tcagaaacta actgatcagg ggatggactt caccattcat cgtgtctctt caattctatt 8940
aaatagacca ctcttgggct ttagaccagg aaaaaggaga cagctctagc catctaccaa 9000
gcctcaccct aaaaggtcac ccgtacttct tggtctgagg acaagtctcc actccagtaa 9060
gggagagggg aggaaatgct tcctgtttga aatgcagtga attcctatgg ctcctgtttc 9120
accacccgca cctatggcaa cccatataca ttcctcttgt ctgtaactgc caaaggttgg 9180
gtttatgtca cttcagttcc actcaagcat tgaaaaggtt ctcatggagt ctggggtgtg 9240
cccagtgaaa agatggggac tttttcatta tccacagacc tctctatacc tgctttgcaa 9300
aaattataat ggagtaacta tttttaaagc ttatttttca attcataaga aaaagacatt 9360
tattttcaat caaatggatg atgtctctta tcccttatcc ctcaatgttt gcttgaattt 9420
tgtttgttcc ctatacctac tccctaattc tttagttcct tcctgctcag gtcccttcat 9480
ttgtactttg gagtttttct catgtaaatt tgtataatgg aaaatattgt tcagtttgga 9540
tagaaagcat ggagaaataa ataaaaaaag atagctgaaa atcaaattga agaaatttat 9600
ttctgtgtaa agttatttaa aaactctgta ttatatttaa agaaaaaagc ccaacccccc 9660
aaaaagtgct atgtaattga tgtgaatatg cgaatactgc tataataaag attgactgca 9720
tggagaaa 9728
<210> 6
<211> 804
<212> PRT
<213> 小鼠
<400> 6
Met Ala Ala Leu Ser Gly Gly Gly Gly Ser Ser Ser Gly Gly Gly Gly
1 5 10 15
Gly Gly Gly Gly Gly Gly Gly Gly Gly Asp Gly Gly Gly Gly Ala Glu
20 25 30
Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala
35 40 45
Gly Ala Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val
50 55 60
Trp Asn Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala
65 70 75 80
Leu Leu Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu
85 90 95
Glu Ala Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg
100 105 110
Glu Gln Gln Leu Leu Glu Ser Leu Val Phe Gln Thr Pro Thr Asp Ala
115 120 125
Ser Arg Asn Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe
130 135 140
Leu Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr
145 150 155 160
Val Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro
165 170 175
Glu Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile
180 185 190
Gly Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val
195 200 205
Glu Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys
210 215 220
Thr Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe
225 230 235 240
Gln Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys
245 250 255
Ser Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu
260 265 270
Leu Phe Val Ser Lys Phe Phe Glu His His Pro Val Pro Gln Glu Glu
275 280 285
Ala Ser Phe Pro Glu Thr Ala Leu Pro Ser Gly Ser Ser Ser Ala Pro
290 295 300
Pro Ser Asp Ser Thr Gly Pro Gln Ile Leu Thr Ser Pro Ser Pro Ser
305 310 315 320
Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His
325 330 335
Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val
340 345 350
His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Glu Lys Phe Pro Glu
355 360 365
Val Glu Leu Gln Asp Gln Arg Asp Leu Ile Arg Asp Gln Gly Phe Arg
370 375 380
Gly Asp Gly Ala Pro Leu Asn Gln Leu Met Arg Cys Leu Arg Lys Tyr
385 390 395 400
Gln Ser Arg Thr Pro Ser Pro Leu Leu His Ser Val Pro Ser Glu Ile
405 410 415
Val Phe Asp Phe Glu Pro Gly Pro Val Phe Arg Gly Ser Thr Thr Gly
420 425 430
Leu Ser Ala Thr Pro Pro Ala Ser Leu Pro Gly Ser Leu Thr Asn Val
435 440 445
Lys Ala Leu Gln Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser
450 455 460
Ser Ser Ser Ser Ser Glu Asp Arg Ser Arg Met Lys Thr Leu Gly Arg
465 470 475 480
Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro Asp Gly Gln Ile Thr Val
485 490 495
Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys
500 505 510
Trp His Gly Asp Val Ala Val Lys Met Leu Asn Val Thr Ala Pro Thr
515 520 525
Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu Val Gly Val Leu Arg Lys
530 535 540
Thr Arg His Val Asn Ile Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro
545 550 555 560
Gln Leu Ala Ile Val Thr Gln Trp Cys Glu Gly Ser Ser Leu Tyr His
565 570 575
His Leu His Ile Ile Glu Thr Lys Phe Glu Met Ile Lys Leu Ile Asp
580 585 590
Ile Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr Leu His Ala Lys Ser
595 600 605
Ile Ile His Arg Asp Leu Lys Ser Asn Asn Ile Phe Leu His Glu Asp
610 615 620
Leu Thr Val Lys Ile Gly Asp Phe Gly Leu Ala Thr Val Lys Ser Arg
625 630 635 640
Trp Ser Gly Ser His Gln Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp
645 650 655
Met Ala Pro Glu Val Ile Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe
660 665 670
Gln Ser Asp Val Tyr Ala Phe Gly Ile Val Leu Tyr Glu Leu Met Thr
675 680 685
Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe
690 695 700
Met Val Gly Arg Gly Tyr Leu Ser Pro Asp Leu Ser Lys Val Arg Ser
705 710 715 720
Asn Cys Pro Lys Ala Met Lys Arg Leu Met Ala Glu Cys Leu Lys Lys
725 730 735
Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln Ile Leu Ala Ser Ile Glu
740 745 750
Leu Leu Ala Arg Ser Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro
755 760 765
Ser Leu Asn Arg Ala Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala
770 775 780
Cys Ala Ser Pro Lys Thr Pro Ile Gln Ala Gly Gly Tyr Gly Glu Phe
785 790 795 800
Ala Ala Phe Lys
<210> 7
<211> 2232
<212> DNA
<213> 兔
<400> 7
atggggaatg tgtggaatat caaacaaatg attaagttga cacaggagca tatagaggcc 60
ctattggaca aatttggtgg ggagcataat ccaccatcaa tatatctgga ggcctacgaa 120
gaatacacca gcaagctaga tgccctccaa caaagagaac agcagttatt ggaatcccta 180
gtttttcaaa atcccacaga tgtgtcacgg agcaacccca agtcaccaca aaaacctatt 240
gttagagtct tcctgcccaa caaacagagg acagtggtac ctgcaagatg tggagttacg 300
gttcgagaca gtctaaagaa agcgctgatg atgagaggtc tgatcccaga atgctgtgct 360
gtttacagaa ttcaggatgg agagaagaag ccaattggct gggacactga tatttcctgg 420
ctcactggag aagagctgca tgtggaagtg ttagagaatg tcccactcac cacacataac 480
tttgtacgga aaactttttt caccttagca ttttgtgact tctgtagaaa gctgcttttc 540
cagggtttcc gctgtcaaac atgtggctac aaatttcacc agcgttgtag tacggaagtt 600
ccactgatgt gtgttaatta tgaccaactt gatttgctgt ttgtctccaa gttctttgaa 660
caccacccag taccacagga ggaggcctcc ttagcagaga ctgccctcac atctgggtca 720
tcgccttccg cacctccctc agactctatt gggcaccaaa ttctcaccag tccgtcccct 780
tcaaaatcca ttccgattcc acagtccttc cgaccagcag atgaagatca tcgaaatcag 840
tttgggcaac gagaccggtc ttcatcagcg cctaatgttc acattaacac aatagaacct 900
gtcaatattg atgaaaaatt cccagaagtg gaattacagg atcaaaggga cttgattaga 960
gaccaagggt ttcgtggtga tggagcccct ttgaaccagc tgatgcgctg tcttcggaaa 1020
taccaatccc ggactcccag tcccctccta ccttctgtcc ccagtgacat agtgtttgat 1080
tttgagcctg gcccagtgtt cagaggatcg accacgggtt tgtctgccac tccccctgcc 1140
tcattacctg gctcactcac tagtgtgaaa gctgtacaga gatccccagg acctcagcga 1200
gagaggaagt cgtcttcctc ctcagaagac aggaatcgaa tgaaaactct tggtagacgg 1260
gattcaagtg atgattggga gattcctgat gggcagatca ccgtgggaca gagaattgga 1320
tctggatcat ttggaaccgt ctacaaggga aaatggcacg gtgatgtggc agtaaaaatg 1380
ttgaatgtga cagcacctac acctcagcag ttacaggcct tcaaaaatga agtaggagta 1440
ctcaggaaaa cacgacatgt gaatatccta cttttcatgg gctattccac aaagccacag 1500
ctggctattg ttacccagtg gtgtgagggc tccagtttat atcaccatct ccacatcatt 1560
gagaccaaat tcgagatgat caaacttata gatattgcac ggcagactgc acagggcatg 1620
gattacttac acgccaagtc aatcatccac agagacctca agagtaataa tatatttctt 1680
catgaagacc tcacagtaaa aataggtgat tttggtctag ccacagtgaa atctcgatgg 1740
agtgggtccc atcagtttga acaattgtct ggatccattt tgtggatggc accagaagta 1800
atcagaatgc aagacaaaaa cccatatagc tttcagtcag atgtatatgc atttgggatt 1860
gttctgtatg aattgatgac tgggcagtta ccttactcaa acatcaacaa cagggaccag 1920
atcattttta tggtgggacg tggctacctg tctccagacc tcagtaaggt acggagtaac 1980
tgtccgaaag ccatgaagag attaatggca gagtgcctca aaaagaaaag agatgagaga 2040
ccactctttc cccaaattct cgcctccatt gagctgctgg cccgctcatt gccaaaaatc 2100
caccgcagtg catcagaacc ctccttgaat cgggctggtt tccagacaga ggattttagt 2160
ctatatgctt gtgcttctcc aaaaacaccc atccaggcag ggggatatgg agaatttgca 2220
gccttcaagt ag 2232
<210> 8
<211> 743
<212> PRT
<213> 兔
<400> 8
Met Gly Asn Val Trp Asn Ile Lys Gln Met Ile Lys Leu Thr Gln Glu
1 5 10 15
His Ile Glu Ala Leu Leu Asp Lys Phe Gly Gly Glu His Asn Pro Pro
20 25 30
Ser Ile Tyr Leu Glu Ala Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala
35 40 45
Leu Gln Gln Arg Glu Gln Gln Leu Leu Glu Ser Leu Val Phe Gln Asn
50 55 60
Pro Thr Asp Val Ser Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile
65 70 75 80
Val Arg Val Phe Leu Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg
85 90 95
Cys Gly Val Thr Val Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg
100 105 110
Gly Leu Ile Pro Glu Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu
115 120 125
Lys Lys Pro Ile Gly Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu
130 135 140
Glu Leu His Val Glu Val Leu Glu Asn Val Pro Leu Thr Thr His Asn
145 150 155 160
Phe Val Arg Lys Thr Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg
165 170 175
Lys Leu Leu Phe Gln Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe
180 185 190
His Gln Arg Cys Ser Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp
195 200 205
Gln Leu Asp Leu Leu Phe Val Ser Lys Phe Phe Glu His His Pro Val
210 215 220
Pro Gln Glu Glu Ala Ser Leu Ala Glu Thr Ala Leu Thr Ser Gly Ser
225 230 235 240
Ser Pro Ser Ala Pro Pro Ser Asp Ser Ile Gly His Gln Ile Leu Thr
245 250 255
Ser Pro Ser Pro Ser Lys Ser Ile Pro Ile Pro Gln Ser Phe Arg Pro
260 265 270
Ala Asp Glu Asp His Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser
275 280 285
Ser Ala Pro Asn Val His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp
290 295 300
Glu Lys Phe Pro Glu Val Glu Leu Gln Asp Gln Arg Asp Leu Ile Arg
305 310 315 320
Asp Gln Gly Phe Arg Gly Asp Gly Ala Pro Leu Asn Gln Leu Met Arg
325 330 335
Cys Leu Arg Lys Tyr Gln Ser Arg Thr Pro Ser Pro Leu Leu Pro Ser
340 345 350
Val Pro Ser Asp Ile Val Phe Asp Phe Glu Pro Gly Pro Val Phe Arg
355 360 365
Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro Pro Ala Ser Leu Pro Gly
370 375 380
Ser Leu Thr Ser Val Lys Ala Val Gln Arg Ser Pro Gly Pro Gln Arg
385 390 395 400
Glu Arg Lys Ser Ser Ser Ser Ser Glu Asp Arg Asn Arg Met Lys Thr
405 410 415
Leu Gly Arg Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro Asp Gly Gln
420 425 430
Ile Thr Val Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly Thr Val Tyr
435 440 445
Lys Gly Lys Trp His Gly Asp Val Ala Val Lys Met Leu Asn Val Thr
450 455 460
Ala Pro Thr Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu Val Gly Val
465 470 475 480
Leu Arg Lys Thr Arg His Val Asn Ile Leu Leu Phe Met Gly Tyr Ser
485 490 495
Thr Lys Pro Gln Leu Ala Ile Val Thr Gln Trp Cys Glu Gly Ser Ser
500 505 510
Leu Tyr His His Leu His Ile Ile Glu Thr Lys Phe Glu Met Ile Lys
515 520 525
Leu Ile Asp Ile Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr Leu His
530 535 540
Ala Lys Ser Ile Ile His Arg Asp Leu Lys Ser Asn Asn Ile Phe Leu
545 550 555 560
His Glu Asp Leu Thr Val Lys Ile Gly Asp Phe Gly Leu Ala Thr Val
565 570 575
Lys Ser Arg Trp Ser Gly Ser His Gln Phe Glu Gln Leu Ser Gly Ser
580 585 590
Ile Leu Trp Met Ala Pro Glu Val Ile Arg Met Gln Asp Lys Asn Pro
595 600 605
Tyr Ser Phe Gln Ser Asp Val Tyr Ala Phe Gly Ile Val Leu Tyr Glu
610 615 620
Leu Met Thr Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn Arg Asp Gln
625 630 635 640
Ile Ile Phe Met Val Gly Arg Gly Tyr Leu Ser Pro Asp Leu Ser Lys
645 650 655
Val Arg Ser Asn Cys Pro Lys Ala Met Lys Arg Leu Met Ala Glu Cys
660 665 670
Leu Lys Lys Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln Ile Leu Ala
675 680 685
Ser Ile Glu Leu Leu Ala Arg Ser Leu Pro Lys Ile His Arg Ser Ala
690 695 700
Ser Glu Pro Ser Leu Asn Arg Ala Gly Phe Gln Thr Glu Asp Phe Ser
705 710 715 720
Leu Tyr Ala Cys Ala Ser Pro Lys Thr Pro Ile Gln Ala Gly Gly Tyr
725 730 735
Gly Glu Phe Ala Ala Phe Lys
740
<210> 9
<211> 2186
<212> DNA
<213> 豚鼠
<400> 9
atggcggcgc tcagcggcgg cggtggcgcg gagcagggcc aggctctgtt caacggggac 60
atggagctcg aggccggcgc cggcgccgca gcctcttcgg ctgcagaccc tgccattccc 120
gaggaggtat ggaatatcaa acaaatgatt aagttgacgc aggaacacat agaggcccta 180
ttggacaaat ttggtggaga gcataatcca ccatcaatat acctggaggc ctatgaagaa 240
tacaccagca aactagatgc cctccaacaa agagaacagc agttactgga atccctcggg 300
aatggaactg atttttctgt ttctagctct gcatcactgg acaccgttac atcttcttct 360
tcttctagcc tttcagtact accttcatct ctttcagttt ttcaaaatcc tacagatgtg 420
tcacggagca accccaaatc accacaaaaa cctattgtta gagtcttcct gcccaacaaa 480
cagaggacag tggtacctgc aaggtgtgga gttacagtcc gagacagtct gaagaaagca 540
ctcatgatga gaggtcttat cccagagtgc tgtgctgtgt acagaattca ggatggagaa 600
aagaaaccaa ttggctggga cactgacatt tcctggctta ctggggaaga attacatgta 660
gaagtattgg agaatgttcc acttacaaca cacaattttg tatgtatctt tatatttttt 720
ttgctgtttg tctccaagtt ctttgaacac cacccaatac cacaggagga ggcttcctta 780
gcagagacca cccttacatc tggatcatcc ccttctgcac ccccctcaga gtccattggg 840
cccccaattc tcaccagccc atctccttca aaatccattc caattccaca gcctttccgg 900
ccaggagagg aagatcatcg aaatcaattt gggcagcgag accggtcctc atctgctccc 960
aatgtgcata taaacacaat agaacctgtc aatattgatg atttgattag agaccaaggg 1020
tttcgtagtg atggaggatc aactacaggt ttgtctgcca ccccacctgc ctcattacct 1080
ggctcactca ctaatgtgaa agccttacag aaatctccag gacctcagcg agaaaggaag 1140
tcatcttcat cctcagaaga cagaaatcga atgaaaacgc ttggtagacg ggactcaagt 1200
gatgattggg agattcctga tgggcagatt acagtgggac aaagaattgg atctgggtca 1260
tttggaacag tctacaaggg gaagtggcat ggtgacgtgg cagtgaaaat gttgaatgtg 1320
acagcaccca cacctcaaca gttacaggcc ttcaaaaatg aagtaggagt actcaggaaa 1380
acacgacatg tgaatatcct actcttcatg ggctattcca caaagccaca gctagctatt 1440
gttacccagt ggtgtgaggg ctccagctta taccaccatc tccacatcat cgagaccaaa 1500
tttgagatga tcaaacttat agatattgca cgacagactg cccagggcat ggattactta 1560
cacgccaagt caatcatcca cagagacctc aagagtaata atatatttct tcacgaagac 1620
ctcacggtta aaataggtga ttttggtcta gccacagtga aatctcgatg gagtgggtcc 1680
catcagtttg aacagttgtc tggatccatt ttgtggatgg caccagaagt aatcagaatg 1740
cgagataaaa acccatacag ttttcagtcc gatgtatatg catttgggat tgttctatat 1800
gaattgatga ctgggcagtt accctattca aatatcaaca acagggacca gataattttt 1860
atggtgggac gaggatatct atctccagat ctcagcaagg tacggagtaa ctgtccaaaa 1920
gccatgaaga ggttaatggc ggagtgcctc aaaaagaaaa gagatgagag accactcttt 1980
ccccaaattc tcgcctctat tgagctgctg gcccgctcat tgccaaaaat tcaccgcagt 2040
gcatcagaac cctccttgaa tcgggctggt ttccaaacag aggattttag tctctatgct 2100
tgtgcttctc caaaaacacc catccaggca gggggatatg gtgcgtttcc tgtccactga 2160
tgcaaattaa atgagtgaga aataaa 2186
<210> 10
<211> 719
<212> PRT
<213> 豚鼠
<400> 10
Met Ala Ala Leu Ser Gly Gly Gly Gly Ala Glu Gln Gly Gln Ala Leu
1 5 10 15
Phe Asn Gly Asp Met Glu Leu Glu Ala Gly Ala Gly Ala Ala Ala Ser
20 25 30
Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn Ile Lys Gln
35 40 45
Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu Asp Lys Phe
50 55 60
Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala Tyr Glu Glu
65 70 75 80
Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln Gln Leu Leu
85 90 95
Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser Ser Ala Ser
100 105 110
Leu Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser Val Leu Pro
115 120 125
Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser Arg Ser Asn
130 135 140
Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu Pro Asn Lys
145 150 155 160
Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val Arg Asp Ser
165 170 175
Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu Cys Cys Ala
180 185 190
Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly Trp Asp Thr
195 200 205
Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu Val Leu Glu
210 215 220
Asn Val Pro Leu Thr Thr His Asn Phe Val Cys Ile Phe Ile Phe Phe
225 230 235 240
Leu Leu Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu
245 250 255
Glu Ala Ser Leu Ala Glu Thr Thr Leu Thr Ser Gly Ser Ser Pro Ser
260 265 270
Ala Pro Pro Ser Glu Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser
275 280 285
Pro Ser Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Gly Glu Glu
290 295 300
Asp His Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro
305 310 315 320
Asn Val His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile
325 330 335
Arg Asp Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser
340 345 350
Ala Thr Pro Pro Ala Ser Leu Pro Gly Ser Leu Thr Asn Val Lys Ala
355 360 365
Leu Gln Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser
370 375 380
Ser Glu Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser
385 390 395 400
Asp Asp Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile
405 410 415
Gly Ser Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp
420 425 430
Val Ala Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu
435 440 445
Gln Ala Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val
450 455 460
Asn Ile Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile
465 470 475 480
Val Thr Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile
485 490 495
Ile Glu Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln
500 505 510
Thr Ala Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg
515 520 525
Asp Leu Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys
530 535 540
Ile Gly Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser
545 550 555 560
His Gln Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu
565 570 575
Val Ile Arg Met Arg Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val
580 585 590
Tyr Ala Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro
595 600 605
Tyr Ser Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg
610 615 620
Gly Tyr Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys
625 630 635 640
Ala Met Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu
645 650 655
Arg Pro Leu Phe Pro Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg
660 665 670
Ser Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg
675 680 685
Ala Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro
690 695 700
Lys Thr Pro Ile Gln Ala Gly Gly Tyr Gly Ala Phe Pro Val His
705 710 715
<210> 11
<211> 3229
<212> DNA
<213> 狗
<400> 11
gtaatgctgg attttcatgg aataagtttg acctgtgctg cagtggcctc cagcaaggta 60
cccgcaagat gtggagttac agtccgggac agtctaaaga aagctctgat gatgagaggt 120
ctaatcccag agtgctgtgc tgtttacaga attcaggatg gagagaagaa accgattggc 180
tgggacactg atatttcctg gctcactgga gaggaattgc atgtagaagt gttggaaaat 240
gttccgctta ccacacacaa ctttgtacgg aaaacttttt tcaccttagc attttgtgac 300
ttttgtcgaa agctgctttt ccagggtttt cgctgtcaaa catgtggtta taaatttcac 360
cagcgttgta gtacagaggt tccactgatg tgtgttaatt atgaccaact tgatttgctg 420
tttgtctcca agttctttga acaccaccca ataccacagg aggaggcctc catagcagag 480
actgccctta cgtctggatc atccccttct gctcccccct ccgattctcc tgggccccca 540
attctgacca gtccgtctcc ttcaaaatcc attccaattc cacagccttt ccgaccagca 600
gatgaagatc atcgaaatca gtttggacaa cgagaccggt cctcatcagc tccaaatgtg 660
catataaaca caatagaacc cgtcaacatt gatgacttga ttagagacca agggtttcgt 720
agtgatggag gatcaaccac aggtttgtct gccacccccc ctgcctcatt gcctggctca 780
ctcactaatg taaaagcatt acagaaatct ccaggacctc agcgggaaag aaaatcatct 840
tcatcctcag aagataggaa tcgaatgaaa acacttggta gacgggattc aagtgatgat 900
tgggagatac ctgatgggca gatcacagtg ggacagagaa ttggatccgg gtcatttggg 960
acagtctaca agggaaagtg gcatggtgac gtggcagtga aaatgttgaa tgtgacagca 1020
cccacacctc agcagttaca ggccttcaaa aatgaagtag gagtactcag gaaaactcga 1080
catgtgaata tcctactctt tatgggctat tcaacaaagc cccaactggc tattgttacc 1140
cagtggtgtg agggctccag cttatatcac catctccaca tcattgagac caaatttgag 1200
atgataaagc ttatagatat tgcacggcag actgcacagg gcatggatta cttacacgcc 1260
aagtcaatca tccacagaga cctcaagagt aataatattt ttcttcatga agacctcaca 1320
gtaaaaatag gtgattttgg tctagccaca gtgaaatctc gatggagtgg gtcccatcag 1380
tttgaacagt tgtctggatc cattttgtgg atggcaccag aagtgatccg aatgcaagac 1440
aaaaacccat atagcttcca gtcagatgta tacgcatttg ggattgttct atatgaattg 1500
atgacagggc agttacctta ttcaaacatc aacaacaggg accagataat ttttatggtg 1560
ggacgaggat atctttctcc agatctcagt aaggtacgga gtaactgtcc aaaagccatg 1620
aagagattga tggcagagtg cctaaaaaag aaaagagatg agaggccact ctttccccaa 1680
attctcgcct ctattgagct gctggcccgc tcattgccaa aaattcaccg cagtgcatca 1740
gaaccctcct tgaatcgggc tggcttccaa acagaggatt ttagtctcta tgcttgcgct 1800
tctccaaaaa cacccatcca ggcaggggga tacggagaat ttgcagcctt caagtagcca 1860
caccatcatg gcaacaacta ctcttatttc ttaagtcttg tgttcgtaca atttgttaac 1920
atcaaaacac agttctgttc ctcaaatctt tttttaaaga tacagaattt tcaatgcata 1980
agctggtgtg gaacagaatg gaatttccca tccaacaaaa gagggaagaa tgttttagga 2040
accagaattc tctgctgcca gtgtttcttc ttcaacacaa ataccacgtg catacaagtc 2100
tgcccactcc caggaaggaa gaggagagcc tgagttctga ccttttgatg gtcaggcatg 2160
atggaaagaa actgctgcta cagcttggga gattggctgt ggagagcctg cccgtcagct 2220
ctgcccttct aaccgccaga tgagtgtgtg gctggtcacc tgacagggca gctgcaatcg 2280
ccaagcatcg ttctctttcc tgtcctggga ttttgtcgtg gagctctttc cccctagtca 2340
ccaccggttc atttctgagg gatggaacaa aaatgcagca tggcctttct gtgtggtgca 2400
tgtccggtct ttgacaaatt tttatcaagt gaagctcttg tatttaaatg gagaatgaga 2460
ggcgaggggg ggggatcacg ttttggtgta ggggcaaagg gaatgctgca tctttttcct 2520
gacccactgg gtttctggcc tttgtttcct tgctcactga gggtgtctgc ctataaccac 2580
gcaggctgga aagtgctggc acacattgcc ttctcttctc actgggtcca gcaatgaaga 2640
caagtgttgg ggattttttt ttttgccctc cacaatgtag caagttctca ggaaaataca 2700
gttaatatct tcctcctaag ctcttccagt catcaagtac ttatgtggct actttgtcca 2760
gggcacaaaa tgccatggcg gtatccaatt aaaagcctac aaaactgctt gataacagtt 2820
ttgaatgtgt gagacattta tgtaatttaa atgtaaggta caagttttaa tttctgagtt 2880
tctctattat atttttatta aaaagaaaat aattttcaga tttaattgaa ttggaataaa 2940
ataatacttc ccaccagaat tatatatcct ggaaaattgt atttttgtta tataaacaac 3000
ttttaaagaa agatcattat ccttttctct acctaaatat ggggagtctt agcataatga 3060
cagatattta taatttttaa attaatggta cttgctggat ccacactaac atctttgcta 3120
atatctcatg ttttcctcca acttactcct acactacatc ctccatcctc tttccagtct 3180
tttatctaga atatgcaacc taaaataaaa atggtggtgt ctccattca 3229
<210> 12
<211> 617
<212> PRT
<213> 狗
<400> 12
Met Leu Asp Phe His Gly Ile Ser Leu Thr Cys Ala Ala Val Ala Ser
1 5 10 15
Ser Lys Val Pro Ala Arg Cys Gly Val Thr Val Arg Asp Ser Leu Lys
20 25 30
Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu Cys Cys Ala Val Tyr
35 40 45
Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly Trp Asp Thr Asp Ile
50 55 60
Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu Val Leu Glu Asn Val
65 70 75 80
Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr Phe Phe Thr Leu Ala
85 90 95
Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln Gly Phe Arg Cys Gln
100 105 110
Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser Thr Glu Val Pro Leu
115 120 125
Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu Phe Val Ser Lys Phe
130 135 140
Phe Glu His His Pro Ile Pro Gln Glu Glu Ala Ser Ile Ala Glu Thr
145 150 155 160
Ala Leu Thr Ser Gly Ser Ser Pro Ser Ala Pro Pro Ser Asp Ser Pro
165 170 175
Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser Lys Ser Ile Pro Ile
180 185 190
Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His Arg Asn Gln Phe Gly
195 200 205
Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val His Ile Asn Thr Ile
210 215 220
Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp Gln Gly Phe Arg Ser
225 230 235 240
Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro Pro Ala Ser Leu
245 250 255
Pro Gly Ser Leu Thr Asn Val Lys Ala Leu Gln Lys Ser Pro Gly Pro
260 265 270
Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu Asp Arg Asn Arg Met
275 280 285
Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro Asp
290 295 300
Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly Thr
305 310 315 320
Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala Val Lys Met Leu Asn
325 330 335
Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu Val
340 345 350
Gly Val Leu Arg Lys Thr Arg His Val Asn Ile Leu Leu Phe Met Gly
355 360 365
Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr Gln Trp Cys Glu Gly
370 375 380
Ser Ser Leu Tyr His His Leu His Ile Ile Glu Thr Lys Phe Glu Met
385 390 395 400
Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr
405 410 415
Leu His Ala Lys Ser Ile Ile His Arg Asp Leu Lys Ser Asn Asn Ile
420 425 430
Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly Asp Phe Gly Leu Ala
435 440 445
Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln Phe Glu Gln Leu Ser
450 455 460
Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile Arg Met Gln Asp Lys
465 470 475 480
Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala Phe Gly Ile Val Leu
485 490 495
Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn Arg
500 505 510
Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr Leu Ser Pro Asp Leu
515 520 525
Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met Lys Arg Leu Met Ala
530 535 540
Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln Ile
545 550 555 560
Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser Leu Pro Lys Ile His Arg
565 570 575
Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala Gly Phe Gln Thr Glu Asp
580 585 590
Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys Thr Pro Ile Gln Ala Gly
595 600 605
Gly Tyr Gly Glu Phe Ala Ala Phe Lys
610 615
<210> 13
<211> 1889
<212> DNA
<213> 狗
<400> 13
ggaatatcaa acaaatgatt aagttgacac aggaacatat agaagcccta ttggacaagt 60
ttggtgggga gcataatcca ccatcaatat atctggaggc ctatgaagaa tacaccagca 120
aactagatgc cctccaacag cgagaacaac agttattgga atccctgggg aatggaactg 180
atttttctgt ttctagctct gcatcaacgg acaccgttac atcttcttcc tcttctagcc 240
tttcagtgct accttcatct ctttcagttt ttcaaaatcc cacagatata tcacggagca 300
atcccaagtc accacaaaaa cctatcgtta gagtcttcct gcccaataaa cagaggacgg 360
tggtacccgc aagatgtgga gttacagtcc gggacagtct aaagaaagct ctgatgatga 420
gaggtctaat cccagagtgc tgtgctgttt acagaattca ggatggagag aagaaaccga 480
ttggctggga cactgatatt tcctggctca ctggagagga attgcatgta gaagtgttgg 540
aaaatgttcc gcttaccaca cacaactttg tacggaaaac ttttttcacc ttagcatttt 600
gtgacttttg tcgaaagctg cttttccagg gttttcgctg tcaaacatgt ggttataaat 660
ttcaccagcg ttgtagtaca gaggttccac tgatgtgtgt taattatgac caacttgatt 720
tgctgtttgt ctccaagttc tttgaacacc acccaatacc acaggaggag gcctccatag 780
cagagactgc ccttacgtct ggatcatccc cttctgctcc cccctccgat tctcctgggc 840
ccccaattct gaccagtccg tctccttcaa aatccattcc aattccacag cctttccgac 900
cagcagatga agatcatcga aatcagtttg gacaacgaga ccggtcctca tcagctccaa 960
atgtgcatat aaacacaata gaacccgtca acattgatga cttgattaga gaccaagggt 1020
ttcgtagtga tggaggatca accacaggtt tgtctgccac cccccctgcc tcattgcctg 1080
gctcactcac taatgtaaaa gcattacaga aatctccagg acctcagcgg gaaagaaaat 1140
catcttcatc ctcagaagat aggaatcgaa tgaaaacact tggtagacgg gattcaagtg 1200
atgattggga gatacctgat gggcagatca cagtgggaca gagaattgga tccgggtcat 1260
ttgggacagt ctacaaggga aagtggcatg gtgacgtggc agtgaaaatg ttgaatgtga 1320
cagcacccac acctcagcag ttacaggcct tcaaaaatga agtaggagta ctcaggaaaa 1380
ctcgacatgt gaatatccta ctctttatgg gctattcaac aaagccccaa ctggctattg 1440
ttacccagtg gtgtgagggc tccagcttat atcaccatct ccacatcatt gagaccaaat 1500
ttgagatgat aaagcttata gatattgcac ggcagactgc acagggcatg gattacttac 1560
acgccaagtc aatcatccac agagacctca agagtaataa tatttttctt catgaagacc 1620
tcacagtaaa aataggtgat tttggtctag ccacagtgaa atctcgatgg agtgggtccc 1680
atcagtttga acagttgtct ggatccattt tgtggatggc accagaagtg atccgaatgc 1740
aagacaaaaa cccatatagc ttccagtcag atgtatacgc atttgggatt gttctatatg 1800
aattgatgac agggcagtta ccttattcaa acatcaacaa cagggaccag ctcagatcat 1860
gatcacggtg tcatgagatc aagccccac 1889
<210> 14
<211> 615
<212> PRT
<213> 狗
<400> 14
Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu Asp Lys Phe
1 5 10 15
Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala Tyr Glu Glu
20 25 30
Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln Gln Leu Leu
35 40 45
Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser Ser Ala Ser
50 55 60
Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser Val Leu Pro
65 70 75 80
Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Ile Ser Arg Ser Asn
85 90 95
Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu Pro Asn Lys
100 105 110
Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val Arg Asp Ser
115 120 125
Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu Cys Cys Ala
130 135 140
Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly Trp Asp Thr
145 150 155 160
Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu Val Leu Glu
165 170 175
Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr Phe Phe Thr
180 185 190
Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln Gly Phe Arg
195 200 205
Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser Thr Glu Val
210 215 220
Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu Phe Val Ser
225 230 235 240
Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala Ser Ile Ala
245 250 255
Glu Thr Ala Leu Thr Ser Gly Ser Ser Pro Ser Ala Pro Pro Ser Asp
260 265 270
Ser Pro Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser Lys Ser Ile
275 280 285
Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His Arg Asn Gln
290 295 300
Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val His Ile Asn
305 310 315 320
Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp Gln Gly Phe
325 330 335
Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro Pro Ala
340 345 350
Ser Leu Pro Gly Ser Leu Thr Asn Val Lys Ala Leu Gln Lys Ser Pro
355 360 365
Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu Asp Arg Asn
370 375 380
Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp Trp Glu Ile
385 390 395 400
Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser Gly Ser Phe
405 410 415
Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala Val Lys Met
420 425 430
Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala Phe Lys Asn
435 440 445
Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile Leu Leu Phe
450 455 460
Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr Gln Trp Cys
465 470 475 480
Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu Thr Lys Phe
485 490 495
Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala Gln Gly Met
500 505 510
Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu Lys Ser Asn
515 520 525
Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly Asp Phe Gly
530 535 540
Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln Phe Glu Gln
545 550 555 560
Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile Arg Met Gln
565 570 575
Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala Phe Gly Ile
580 585 590
Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser Asn Ile Asn
595 600 605
Asn Arg Asp Gln Leu Arg Ser
610 615
<210> 15
<211> 3521
<212> DNA
<213> 猫
<220>
<221> misc_feature
<222> (630)..(649)
<223> n是a, c, g或t
<400> 15
atgcctaacc tcagtctctg ccaccacggc caatttgctc atgtgcccac tgtgtcggca 60
ctgggatatt ttgtgatttg ccttggccat tgtccactgt ccttgacatt gcctgaagga 120
gaaccactga tgctaatgtt gaaggtgacc tttgcaggct ctccactact cataccaaag 180
atgcggcccc ctgataatcc cagagccact gtctgcacat gggcaaaaca ggctacattc 240
tgtgcagact ggggagaaag gttccaagaa cacagtgcca tagttttggg cagagagttt 300
caacacagca tagtgtctat ggcagtatct ggatttggcc gggggaagtg cccaagagga 360
gacagtcagg ctgtgtccta cggccaagga cctgcactta tttttgcatg cagtggttta 420
gcacagggaa gagaacgaag taggaaatcg gagccatgga aacggcagag cggaggaaac 480
gtgcacgcgc gagggtgggc acgaaaggaa agaaccctcc ccagaagact gcgcgagggc 540
gctcctagga ttacgtcacg caccccgcga aaactgaaat gtactgtgtg tggtctttta 600
attgaactat cttccttatg tgcacttaan nnnnnnnnnn nnnnnnnnng cggcggcggc 660
ggtggcgcgg agcagggcca ggctctgttc aacggggaca tggagcccga agccggcgcc 720
gcggcctctt cggctgcgga ccctgccatt cccgaggagg tgtggaatat caaacaaatg 780
attaagttga cacaggaaca tatagaggcc ctattggaca aatttggtgg ggagcataat 840
ccaccatcaa tatatctaga ggcctatgaa gaatacacca gcaagctaga tgccctccaa 900
cagagagaac aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc 960
tctgcatcaa cagacaccgt tacatcttcc tcctcttcta gcctttcagt gctaccttca 1020
tctctttcag tttttcaaaa ccccacagat gtgtcacgga gcaatcccaa gtcaccacag 1080
aaacctatcg ttagagtctt cctgcctaat aaacagagga cagtggtacc tgcaagatgt 1140
ggagttacag tccgggacag tctaaagaaa gctctgatga tgagaggtct aatccctgag 1200
tgctgtgctg tttacagaat tcaggatgga gagaagaaac caattggctg ggacactgat 1260
atctcctggc tcaccggaga ggaattgcat gtagaagtgt tggaaaatgt tccacttaca 1320
actcacaact ttgtatgtac ggaaaacgtt ttcaccttag cattttgtga cttttgtcga 1380
aagctgcttt tccaaggttt tcgctgtcaa acgtgtggtt ataaatttca ccagcgttgt 1440
agtacagagg ttccactgat gtgtgttaat tatgaccaac ttgatttgct gtttgtctcc 1500
aagttctttg aacaccaccc aataccacag gaggaggcct ccatagcaga gactgcccta 1560
acgtctggat cgtccccttc tgcccccccc tccgattcta ctgggcccca aattctcacc 1620
agtccgtctc cttcaaaatc cattccaatt ccacagcctt tccgaccagc agatgaagat 1680
catcgaaatc aatttggaca gcgagaccgg tcctcatcag ctccaaatgt gcatataaat 1740
acaatagaac ctgtcaatat tgatgacttg attagagacc aggggtttcg tagtgatgga 1800
ggatcaacca caggcttgtc tgccaccccc cctgcctcat tgccgggctc tctcactaat 1860
gtaaaagcat tacagaaatc tccagggcct cagcgggaaa ggaaatcttc ttcatcctca 1920
gaagatagga atcgaatgaa aacacttggt agaagggatt caagtgatga ttgggagatt 1980
cctgatgggc agatcacagt gggacagaga attggatccg ggtcatttgg gacagtctac 2040
aagggaaagt ggcatggtga tgtggcagtg aaaatgttga atgtgacagc acccacacct 2100
cagcagttac aggccttcaa aaatgaagta ggagtactca ggaaaactcg gcatgtgaac 2160
atcctgctct tcatgggcta ttcaacaaag ccccagctgg ctattgtcac ccagtggtgt 2220
gagggctcca gcttatacca ccatctccac atcatcgaga ccaaattcga gatgatcaag 2280
ctgatagata ttgctcggca gactgcgcag ggcatggatt acttacacgc caagtcaatc 2340
atccacagag acctcaagag taataatatt tttcttcacg aagacctcac agtaaaaata 2400
ggtgattttg gtctagccac agtgaaatct cgatggagtg ggtcccatca gtttgaacag 2460
ttgtctggat ccattttgtg gatggcacca gaagtaattc gaatgcaaga taaaaaccca 2520
tatagctttc agtcagatgt atatgcattt gggattgttc tatatgaatt gatgactgga 2580
cagttacctt attcaaacat caacaacagg gaccagataa tttttatggt gggacgagga 2640
tatctttctc cagatctcag taaggtacga agtaactgtc caaaagccat gaagagattg 2700
atggcagagt gcctaaaaaa gaaaagagat gagaggccac tgtttcccca aattcttgcc 2760
tctattgagc tgctggcccg ctcattgcca aaaattcacc gcagtgcatc agaaccctcc 2820
ttgaatcggg ctggcttcca gacagaggat tttagtctct atgcttgtgc ttctccaaaa 2880
acacccatcc aggcaggggg atatggtgcg tttcccgtcc actgagataa gttagatgag 2940
tgcgcgagtg cagggggccg gggccaagga ggtggaaatg tgcgtgcttc tgtactaagt 3000
tggatagcat cttctttttt aaaaaaagat gaaccaaaga atgtgtatgt ttttaaagac 3060
tagatataat tatttcctga tctaaaatgt atacttagct ttggattttc aatatccaag 3120
ggttttcaaa atgcacagac attgctgaac atttgcagta cctcttctgg aggctttact 3180
tcctgttaca aattggtttt gtttactggc ttatcctaat tattaaactt caattaaact 3240
tttctcctgc accttttgtt atgagctatc acatgtccct tagggactcg caagagcagt 3300
actgcccccg tgtacgggct tgcaggtaga aaggggatga cgggttttaa cacctgtgtg 3360
aggcaaggca gtccgaacag atctcattta ggaagccacg agagttgaat aagttatttt 3420
tattcttagt attttttctg taactacttt ttattataac ttggaaaata tggatgtcct 3480
ttatacacct tagcaataga ctgaatttct ttttataaat t 3521
<210> 16
<211> 974
<212> PRT
<213> 猫
<220>
<221> misc_feature
<222> (210)..(217)
<223> Xaa可以是任何天然存在的氨基酸
<400> 16
Met Pro Asn Leu Ser Leu Cys His His Gly Gln Phe Ala His Val Pro
1 5 10 15
Thr Val Ser Ala Leu Gly Tyr Phe Val Ile Cys Leu Gly His Cys Pro
20 25 30
Leu Ser Leu Thr Leu Pro Glu Gly Glu Pro Leu Met Leu Met Leu Lys
35 40 45
Val Thr Phe Ala Gly Ser Pro Leu Leu Ile Pro Lys Met Arg Pro Pro
50 55 60
Asp Asn Pro Arg Ala Thr Val Cys Thr Trp Ala Lys Gln Ala Thr Phe
65 70 75 80
Cys Ala Asp Trp Gly Glu Arg Phe Gln Glu His Ser Ala Ile Val Leu
85 90 95
Gly Arg Glu Phe Gln His Ser Ile Val Ser Met Ala Val Ser Gly Phe
100 105 110
Gly Arg Gly Lys Cys Pro Arg Gly Asp Ser Gln Ala Val Ser Tyr Gly
115 120 125
Gln Gly Pro Ala Leu Ile Phe Ala Cys Ser Gly Leu Ala Gln Gly Arg
130 135 140
Glu Arg Ser Arg Lys Ser Glu Pro Trp Lys Arg Gln Ser Gly Gly Asn
145 150 155 160
Val His Ala Arg Gly Trp Ala Arg Lys Glu Arg Thr Leu Pro Arg Arg
165 170 175
Leu Arg Glu Gly Ala Pro Arg Ile Thr Ser Arg Thr Pro Arg Lys Leu
180 185 190
Lys Cys Thr Val Cys Gly Leu Leu Ile Glu Leu Ser Ser Leu Cys Ala
195 200 205
Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Gly Gly Gly Gly Ala Glu
210 215 220
Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala
225 230 235 240
Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn
245 250 255
Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu
260 265 270
Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala
275 280 285
Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln
290 295 300
Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser
305 310 315 320
Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser
325 330 335
Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser
340 345 350
Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu
355 360 365
Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val
370 375 380
Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu
385 390 395 400
Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly
405 410 415
Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu
420 425 430
Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Cys Thr Glu
435 440 445
Asn Val Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe
450 455 460
Gln Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys
465 470 475 480
Ser Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu
485 490 495
Leu Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu
500 505 510
Ala Ser Ile Ala Glu Thr Ala Leu Thr Ser Gly Ser Ser Pro Ser Ala
515 520 525
Pro Pro Ser Asp Ser Thr Gly Pro Gln Ile Leu Thr Ser Pro Ser Pro
530 535 540
Ser Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp
545 550 555 560
His Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn
565 570 575
Val His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg
580 585 590
Asp Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala
595 600 605
Thr Pro Pro Ala Ser Leu Pro Gly Ser Leu Thr Asn Val Lys Ala Leu
610 615 620
Gln Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser
625 630 635 640
Glu Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp
645 650 655
Asp Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly
660 665 670
Ser Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val
675 680 685
Ala Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln
690 695 700
Ala Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn
705 710 715 720
Ile Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val
725 730 735
Thr Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile
740 745 750
Glu Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr
755 760 765
Ala Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp
770 775 780
Leu Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile
785 790 795 800
Gly Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His
805 810 815
Gln Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val
820 825 830
Ile Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr
835 840 845
Ala Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr
850 855 860
Ser Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly
865 870 875 880
Tyr Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala
885 890 895
Met Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg
900 905 910
Pro Leu Phe Pro Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser
915 920 925
Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala
930 935 940
Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys
945 950 955 960
Thr Pro Ile Gln Ala Gly Gly Tyr Gly Ala Phe Pro Val His
965 970
<210> 17
<211> 3853
<212> DNA
<213> 牛
<400> 17
ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc 60
cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc 120
ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg 180
ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg 240
agcagggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt 300
cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga 360
cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat ccaccatcaa 420
tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac 480
aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa 540
cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag 600
tttttcaaaa tcccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg 660
ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag 720
tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg 780
tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc 840
ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact 900
ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc 960
agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc 1020
cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac 1080
accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat 1140
ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt 1200
caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt 1260
ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg 1320
tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag 1380
gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc 1440
agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc 1500
gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga 1560
tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc 1620
atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg 1680
ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca 1740
tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt 1800
tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg 1860
cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc 1920
tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc 1980
tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca 2040
ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt 2100
cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt 2160
caaatatcaa caacagggac cagataattt ttatggtggg acgaggatat ctgtctccag 2220
atctcagtaa ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc 2280
taaaaaagaa aagagatgaa agaccactct ttccccaaat tctcgcctct attgagctgc 2340
tggcccgctc attgccaaaa attcaccgca gtgcatcaga accctccttg aatcgggctg 2400
gcttccaaac agaggatttt agtctatatg cttgtgcttc tccaaaaaca cccattcagg 2460
cagggggata tggtacgttt cctgttcact gaaacaaacc gagtgagtga cagcatgtag 2520
gagggtaggg acaaaagaaa gtgaacaaat gtttgcttat atatttgtta aattgaatag 2580
gattttcttt ttctttaaag gtgaacaaga gaacatgtgt gtttttaaag tttggatata 2640
gttttcttcc cagtctaaaa cccatagtta gcattacatt ttcaacatcg aatttttttt 2700
taattcatag acattgctga aaatttataa taccttttcc agaggcttta cttcccattc 2760
caagtttgtt ttgtttactt ggttagtcta atcattaaac tttaaacttt ccccacctac 2820
cttttgctgt tagctatccc gcatccatta ggggctccaa gaacagcact gtctgcgtgt 2880
gtgtgttggc aggtgggaag ctgatggtaa gttaggctgt gttagtgaag gtaaactgac 2940
caggtctaat taggagtcac tagaattgaa taagcttatt tttattaata ttttttctta 3000
taactatttc tttttgtaat aatttagaaa atataattgt tctttattcc cttacagcag 3060
tataaattat tggtgcaggt aaccaaagat attactgagg agtggcatgt ttgacatgag 3120
tgacatggtt taactttgga tttttagtta atatttcttt atatattaag gatgtcttac 3180
acattataga agtcaaattt actgacaaag gtattgcctc ctcttcctcc ccaaaaacac 3240
agcaaaattc tctgggaact cgtagcattg ttggttttct tttggatgac tatggttgcc 3300
aaacaaccaa gtaattgatt ttttttaaat tattattgct ttagattata ctcacctctc 3360
atgatgcctg ttagcaatca cctttatcca tgtgtcttgt aaaatatctt tcctccttat 3420
attctttgcc caacaagagt ctacttgtta tgaatgagta ctattttctt tttttgattc 3480
cccagtataa ttagtatgtt tagtgctttc taggacttcc actttcttat gttaaaaaaa 3540
aaaacaaact aatgtggcag tcagtatatt cttactgtga atcagagtct ttactgggaa 3600
tcaaagtgaa agaagcagct gttctgactt cagagtcagc ctagggacca aaaccagcct 3660
cttaaataca ccttcattta ttcagtttgg atttgtgatg attttcatta tagctgacag 3720
ttcaaggtta ttcagtggca cacagatagc atctgcataa atgcctttct tcttgaaaat 3780
aaaggagaaa attgggaaga ctttacacca atagtttagt ctttaagtac cacagataac 3840
acacaccata aat 3853
<210> 18
<211> 764
<212> PRT
<213> 牛
<400> 18
Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu Gln
1 5 10 15
Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala Ala
20 25 30
Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn Ile
35 40 45
Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu Asp
50 55 60
Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala Tyr
65 70 75 80
Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln Gln
85 90 95
Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser Ser
100 105 110
Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser Val
115 120 125
Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser Arg
130 135 140
Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu Pro
145 150 155 160
Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val Arg
165 170 175
Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu Cys
180 185 190
Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly Trp
195 200 205
Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu Val
210 215 220
Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr Phe
225 230 235 240
Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln Gly
245 250 255
Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser Thr
260 265 270
Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu Phe
275 280 285
Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala Ser
290 295 300
Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro Pro
305 310 315 320
Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser Lys
325 330 335
Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His Arg
340 345 350
Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val His
355 360 365
Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp Gln
370 375 380
Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro
385 390 395 400
Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln Lys
405 410 415
Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu Asp
420 425 430
Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp Trp
435 440 445
Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser Gly
450 455 460
Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala Val
465 470 475 480
Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala Phe
485 490 495
Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile Leu
500 505 510
Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr Gln
515 520 525
Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu Thr
530 535 540
Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala Gln
545 550 555 560
Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu Lys
565 570 575
Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly Asp
580 585 590
Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln Phe
595 600 605
Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile Arg
610 615 620
Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala Phe
625 630 635 640
Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser Asn
645 650 655
Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr Leu
660 665 670
Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met Lys
675 680 685
Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro Leu
690 695 700
Phe Pro Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser Leu Pro
705 710 715 720
Lys Ile His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala Gly Phe
725 730 735
Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys Thr Pro
740 745 750
Ile Gln Ala Gly Gly Tyr Gly Thr Phe Pro Val His
755 760
<210> 19
<211> 4936
<212> DNA
<213> 牛
<400> 19
ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc 60
cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc 120
ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg 180
ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg 240
agcagggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt 300
cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga 360
cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat ccaccatcaa 420
tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac 480
aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa 540
cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag 600
tttttcaaaa tcccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg 660
ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag 720
tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg 780
tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc 840
ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact 900
ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc 960
agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc 1020
cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac 1080
accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat 1140
ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt 1200
caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt 1260
ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg 1320
tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag 1380
gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc 1440
agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc 1500
gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga 1560
tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc 1620
atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg 1680
ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca 1740
tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt 1800
tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg 1860
cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc 1920
tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc 1980
tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca 2040
ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt 2100
cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt 2160
caaatatcaa caacagggac cagataattt ttatggtggg acgaggatat ctgtctccag 2220
atctcagtaa ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc 2280
taaaaaagaa aagagatgaa agaccactct ttccccaagt aggaaagact ctcctaagca 2340
agagacaaaa ttcagaagtt atcagggaaa aagataagca gattctcgcc tctattgagc 2400
tgctggcccg ctcattgcca aaaattcacc gcagtgcatc agaaccctcc ttgaatcggg 2460
ctggcttcca aacagaggat tttagtctat atgcttgtgc ttctccaaaa acacccattc 2520
aggcaggggg atatgaagca gatttggctc ttacatcaaa taaaaataga gtagaagttg 2580
ggatttagag atttcctgac atgcaagaag gaataagcaa gaaaaaaagg tttgttttcc 2640
ccaaatcata tctattgtct tttacttcta ttttttctta aattttttgt gatttcagag 2700
acatgtagag ttttattgat acctaaacta tgagttcttt tttttttttt tttttcatta 2760
ttttgatttt tttggccaag aggcatatgg gatcttagct tgagaaagca acaattttct 2820
tgatgtcatt ttgggtgagg gcacatattg ctgtgaacag tgtggtgata gccaccaggg 2880
accaaactca cacccgctgc attgaaaggt gaagtcttaa acactggacc agcagagaaa 2940
ttcctactct atgagttctt tttgtcatcc cctccccgca ccctccaccc ccaacctaaa 3000
gtctgatgat gaaatcaaca actattccat tagaagcagt agattctggt agcatgatct 3060
ttagtttgtt agtaagattt tgtgctttgt ggggttgtgt cgttttaagg ctaatattta 3120
agtttgtcaa atagaatgct gttcagattg taaaaatgag taataaacat ctgaagtttt 3180
ttttaagtta tttttaacat ggtatataca gttgagctta gagtttatca ttttctgata 3240
ttctcttact tagtagatga attctagcca ttttttataa agatttctgt taagcaaatc 3300
ctgttttcac atgggcttcc tttaagggat tttagattct gctggatatg gtgactgctc 3360
ataagactgt tgaaaattac ttttaagatg tattagaata cttctgaaaa aaaatagcaa 3420
ccttaaaacc ataagcaaaa gtagtaaggg tgtttataca tttctagagt ccctgtttag 3480
gtaatagcct cctatgattg tactttaaat gttttgctct ccaaggtttt agtaacttgg 3540
ctttttttct aatcagtgcc aaactccccc agttttttta actttaaata tgaggtaata 3600
aatcttttac ccttccttga tcttttgact tataatacct tggtcagttg tttcttaaaa 3660
ggaatcctta aatggaaaga gacaatatca ctgtctgcag ttctgattag tagttttatt 3720
cagaatggaa aaacagatta ttcatttttg aaaattgttc aggggtatgt tcattgttag 3780
gaccttggac tttggagtca gtgcctagct atgcattcca ggtctgccat tttctggctg 3840
tgaaattttg gacaagttac ttaaccactt taaaccccag ctttaagaag taaattaacc 3900
ccagtaaatt aagaagtaat agcagccact tcgtagagtt gttatgaggc tcagatgcag 3960
tgcaaatgtg tataaagtat tcagggagtc acctggtata ctataataga cactagaata 4020
gttgccaata ttatcagcat acaatctgag gattctgtca gccaatcatt agcaatctgt 4080
tgtttgttgg gacatgccag tgttctccag ttgaaatcag tagcaatcta aaaatggata 4140
gattattcct catttaaata gtgtgttcat ataagtgatt gcttggatcc ttatcagaag 4200
ttgctgttac tgaaaaatga taaggctgac taaattgtga tagttgtcag ttactaacca 4260
actcccagaa atgaataaga ggaacctatc tctagttcct agtagaaggt atggacaaaa 4320
tagtaggtga aaaataatgt cttgaacccc caaattaagt aagctttaaa gagtacaata 4380
cctcaaaggg tctttgcggt ttaaaatttg tatgctgaga atgatgttca ttgacatgtg 4440
cctatatgta attttttgat agtttaaaag gtgaaatgaa ctacagatgg gagaggtctg 4500
aattttcttg ccttcagtca aatgtgtaat gtggacatat tatttgacct gtgaatttta 4560
tcttttaaaa aagattaatt cctgcttctt ccttcctaat agttgcatta taataatgaa 4620
aatgagttga taatttgggg ggaaagtatt ctacaaatca accttattat tttaccattg 4680
gtttctgaga aattttgttc atttgaaccg tttatagctt gattagaatc atagcatgta 4740
aaacccaact gagggattat ctgcagactt aatgtagtat tatgtaagtt gtcttctttc 4800
atttcgacct tttttgcttt tgttgttgct agatctgtag tatgtagcta gtcacctttc 4860
agcgaggttt cagcgaggct tttctgtgtc tctaggttat ttgagataac ttttttaaaa 4920
ttagctcttg tcctcc 4936
<210> 20
<211> 797
<212> PRT
<213> 牛
<400> 20
Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu
1 5 10 15
Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala
20 25 30
Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn
35 40 45
Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu
50 55 60
Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala
65 70 75 80
Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln
85 90 95
Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser
100 105 110
Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser
115 120 125
Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser
130 135 140
Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu
145 150 155 160
Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val
165 170 175
Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu
180 185 190
Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly
195 200 205
Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu
210 215 220
Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr
225 230 235 240
Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln
245 250 255
Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser
260 265 270
Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu
275 280 285
Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala
290 295 300
Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro
305 310 315 320
Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser
325 330 335
Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His
340 345 350
Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val
355 360 365
His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp
370 375 380
Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr
385 390 395 400
Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln
405 410 415
Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu
420 425 430
Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp
435 440 445
Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser
450 455 460
Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala
465 470 475 480
Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala
485 490 495
Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile
500 505 510
Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr
515 520 525
Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu
530 535 540
Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala
545 550 555 560
Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu
565 570 575
Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly
580 585 590
Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln
595 600 605
Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile
610 615 620
Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala
625 630 635 640
Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser
645 650 655
Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr
660 665 670
Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met
675 680 685
Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro
690 695 700
Leu Phe Pro Gln Val Gly Lys Thr Leu Leu Ser Lys Arg Gln Asn Ser
705 710 715 720
Glu Val Ile Arg Glu Lys Asp Lys Gln Ile Leu Ala Ser Ile Glu Leu
725 730 735
Leu Ala Arg Ser Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro Ser
740 745 750
Leu Asn Arg Ala Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys
755 760 765
Ala Ser Pro Lys Thr Pro Ile Gln Ala Gly Gly Tyr Glu Ala Asp Leu
770 775 780
Ala Leu Thr Ser Asn Lys Asn Arg Val Glu Val Gly Ile
785 790 795
<210> 21
<211> 4154
<212> DNA
<213> 牛
<400> 21
ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc 60
cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc 120
ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg 180
ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg 240
agcagggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt 300
cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga 360
cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat ccaccatcaa 420
tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac 480
aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa 540
cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag 600
tttttcaaaa tcccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg 660
ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag 720
tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg 780
tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc 840
ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact 900
ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc 960
agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc 1020
cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac 1080
accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat 1140
ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt 1200
caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt 1260
ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg 1320
tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag 1380
gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc 1440
agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc 1500
gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga 1560
tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc 1620
atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg 1680
ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca 1740
tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt 1800
tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg 1860
cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc 1920
tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc 1980
tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca 2040
ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt 2100
cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt 2160
caaatatcaa caacagggac cagataattt ttatggtggg acgaggatat ctgtctccag 2220
atctcagtaa ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc 2280
taaaaaagaa aagagatgaa agaccactct ttccccaagt aggaaagact ctcctaagca 2340
agagacaaaa ttcagaagtt atcagggaaa aagataagca gattctcgcc tctattgagc 2400
tgctggcccg ctcattgcca aaaattcacc gcagtgcatc agaaccctcc ttgaatcggg 2460
ctggcttcca aacagaggat tttagtctat atgcttgtgc ttctccaaaa acacccattc 2520
aggcaggggg atatggctga gcacattgtc catcacccac aagtggctgg ttctcatcgc 2580
agaatctacg tagggaatcg ggcgtgaaat tcacttaaga gatagagcag aggaagtgtt 2640
ctgtttacag gaatggagat gagagttatg agtaagttgc ttagtcagtt ggctttgttt 2700
tgaaaattat tgtgttatat ttgtgttaac ctacttgtgt tttgacagta tatgtcacat 2760
aggaagaaac ctcagactag cataataaca aagctcagac taggcacaga tgtacacaga 2820
atggaccaaa atgggatggg ggaaggtatg ggaataagtc taggggtagg gaaaaattga 2880
tgtgagggtg ggaaataaac tgtaattacc tgaaataaaa tgtaagagtg caataagtgt 2940
gctttttatt ctaagctgtg aatgggtttt ttaaaaaaag cattccttcc caatgcattt 3000
gcctatgttc catagctgat taaaaccagc tatataaaca tatgcctttt tattcatgtt 3060
aattaccaat ataaatggct aacctttacg tcttatttat cttcatgtta tgttagttta 3120
catacaggga tgtgtgtgtg tgtgtatgct ataaattttc cctccttcgt ttaaaaacgc 3180
gtttgttgga tcctctctgt ttccttaggc catgccacag ctcatagtct cagcttggcc 3240
ttcctgtcac ctgatctgaa ggactatcac agtgacgtag ctcgttcatt ggttgtacac 3300
actctaaccc ttttccttgc tcagcaatta ctgtgtcttc taaaacagga gtgtacaacc 3360
atgagattgc aattaattgt ttgacatatg tccctttgaa ttctatttat tagttatgat 3420
tgattgctct ttggtttgga ccaagaaaaa cgaaatccca cctccccacc ttttcactta 3480
tttcttactt tgaggacaat tctgtaagag agaggaaagg gaactccttc atgttttaac 3540
tgcagcaagt taatggccct ggtttacacc aaacattatg gtgattcaca ttcacattcc 3600
tctcctctct tgctgccaga ggtttgggtt ttgttcagtt ctgctcaagc actgaaaaag 3660
ttttcatgga gtctggagag tgcccagtga aaagatggtt tttaattgtc cacagacctt 3720
tctgttcctg ctttgcaaaa attacaaagg agtaactatt tttaaagctt atttttcaat 3780
tcataaaaaa gacatttatt ttcagtcaga tgatgtctcc ttgtccctta atcctcaatg 3840
tttgcttgaa tctttttttt ttttctgatt ttctcccatc cccacttctt gatacttctt 3900
gagttctctt tcctgctcag gtcctttcat ttgtactttg gagttttttc tcatgtaaat 3960
ttgtacaatg gaaaatattg ttcagtttgg atagaacgca tggagaatta aataaaaaag 4020
atagctgaaa ttcagattga aatttatttg tgtaaagtta tttaaaaact ctgtactata 4080
taaaaggcaa aaaaagttct atgtacttga tgtgaatatg cgaatactgc tataataaag 4140
attgactgca tgga 4154
<210> 22
<211> 781
<212> PRT
<213> 牛
<400> 22
Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu
1 5 10 15
Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala
20 25 30
Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn
35 40 45
Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu
50 55 60
Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala
65 70 75 80
Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln
85 90 95
Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser
100 105 110
Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser
115 120 125
Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser
130 135 140
Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu
145 150 155 160
Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val
165 170 175
Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu
180 185 190
Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly
195 200 205
Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu
210 215 220
Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr
225 230 235 240
Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln
245 250 255
Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser
260 265 270
Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu
275 280 285
Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala
290 295 300
Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro
305 310 315 320
Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser
325 330 335
Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His
340 345 350
Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val
355 360 365
His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp
370 375 380
Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr
385 390 395 400
Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln
405 410 415
Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu
420 425 430
Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp
435 440 445
Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser
450 455 460
Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala
465 470 475 480
Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala
485 490 495
Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile
500 505 510
Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr
515 520 525
Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu
530 535 540
Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala
545 550 555 560
Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu
565 570 575
Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly
580 585 590
Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln
595 600 605
Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile
610 615 620
Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala
625 630 635 640
Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser
645 650 655
Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr
660 665 670
Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met
675 680 685
Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro
690 695 700
Leu Phe Pro Gln Val Gly Lys Thr Leu Leu Ser Lys Arg Gln Asn Ser
705 710 715 720
Glu Val Ile Arg Glu Lys Asp Lys Gln Ile Leu Ala Ser Ile Glu Leu
725 730 735
Leu Ala Arg Ser Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro Ser
740 745 750
Leu Asn Arg Ala Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys
755 760 765
Ala Ser Pro Lys Thr Pro Ile Gln Ala Gly Gly Tyr Gly
770 775 780
<210> 23
<211> 7914
<212> DNA
<213> 牛
<400> 23
ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc 60
cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc 120
ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg 180
ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg 240
agcagggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt 300
cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga 360
cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat ccaccatcaa 420
tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac 480
aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa 540
cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag 600
tttttcaaaa tcccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg 660
ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag 720
tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg 780
tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc 840
ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact 900
ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc 960
agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc 1020
cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac 1080
accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat 1140
ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt 1200
caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt 1260
ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg 1320
tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag 1380
gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc 1440
agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc 1500
gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga 1560
tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc 1620
atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg 1680
ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca 1740
tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt 1800
tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg 1860
cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc 1920
tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc 1980
tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca 2040
ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt 2100
cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt 2160
caaatatcaa caacagggac cagataattt ttatggtggg acgaggatat ctgtctccag 2220
atctcagtaa ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc 2280
taaaaaagaa aagagatgaa agaccactct ttccccaaat tctcgcctct attgagctgc 2340
tggcccgctc attgccaaaa attcaccgca gtgcatcaga accctccttg aatcgggctg 2400
gcttccaaac agaggatttt agtctatatg cttgtgcttc tccaaaaaca cccattcagg 2460
cagggggata tggagaattt gcagccttca agtagccaca ccatcatgac agcatctact 2520
cttatttctt aagtcttgtg ttcgtacaat ttgttaacat caaaacacag ttctgttcct 2580
caactctttt taaagttaaa atttttcagt gcataagctg gtgtggaaca gaaggaaatt 2640
tcccatccaa caaaagaggg aagaatgttt taggaaccag aattctctgc tgccagtgtt 2700
tcttcttcaa cacaaatatc acaagtctgc ccactcccag gaagaaagag gagagaccct 2760
gagttctgac cttttgatgg tcaggcatga tggaaagaaa ctgctgctac agcttgggag 2820
atttgctctg ggaagtctgc cagtcaactt tgcccttcta accaccagat caatatgtgg 2880
ctgatcatct gatggggcag ttgcaatcac caagccttgt tctctttcct gttctgggat 2940
tgtgttgtgg aacccttttc cctagccacc accagttcat ttctgaggga tggaacaaaa 3000
atgcagcatg cccttcctgt gtggtgcatg ttcagtcctt gacaaatttt taccaaaatg 3060
aagctacttt atttaaaagg agggtgagag gtgaggaggt cactttgggt gtggcggaaa 3120
gggaatgctg catctttttc ctgggctgct ggggctctgg ccttggcttg ccagccggaa 3180
gcgctggcac gcatcgcctt cttttcccat tgggtccagc aatgaagacg agtgtttggg 3240
gttttttttt tctccaccat gtagcaagtt ctcaggaaaa tacaattgat atcttcctcc 3300
taagctcttc caatcagtca ccaagtactt atgtggttac tttgtccagg gcacaaaatg 3360
cctgtatcta attaaaagcc tacaaaactg cttgataaca gttttgaatg tgagacattt 3420
atgtaattta aatgtaaggt acaagtttta atttctgagt ttcttctatt atatttttat 3480
taaaaaaaga aaataatttt cagattgaat tggagtaaaa taatattact tcccactaga 3540
attatatatc ctggaaaatt gtatttttgt tacataagca gcttttaaag aaagatcatt 3600
acccttttct ctacataaat atatggggag tcttagccta atgacaaata tttataattt 3660
ttaaattaat ggtacttgct ggatccatac taacatcttt actaatacct cattgtttct 3720
tccaacttac tcctacacta catcctacat cttcttccta gtcttttatc tagaatatgc 3780
aacctcaaat aaaaatggtg gtgtcctcat tcattctcct ccttcctttt ttcccaagcc 3840
tgatcttcaa aaggttggtt aatttggcag ctgagttcct ccccaggcag agaatagacc 3900
aattttaggt gtattgggac tgagggagga tgtgtaaaga ttaacatcag taaagaaccg 3960
ctgtggagta attaagaact ttgttcttta taactggaga atataaccta accctaacat 4020
ccctcagcct ttactaaagt gtggcgtaaa tcacagtagt agcaaagaaa gtgactctgg 4080
atgtgttcct ggccagtacc tcccttatca tgaatgtaga ctctctcatc aagatttagg 4140
aatataaatc aaatcaaatg tgcccagcca agctatgtag taagggactt gaacaatatt 4200
aggcagaacc tataaaataa atcagggaat tagaaattat ttaaagtttt caaattgtaa 4260
attgccccgg tgtctttcag cctactgcca ttatttttgc tacaatacct acatttcaga 4320
ggagggccta ctgaaaattc catgcaagtg gaaaataatc ctcaagttat taatgagttt 4380
gaaaagcaat gagttcttaa gtctttgtga gtagagcaag atcctacaaa attcagaaat 4440
agtaaaaatg gattcatgct gatttgaaga gcatctgtgt gcataatata atgctgcatc 4500
tcttttaaaa gcagtctatt tttcttttta aatttgtccc catagatgct tttgaacatg 4560
aacatgctta tgttaccttt tccgaggttg ggaagagcca ggagctctca ggcagggccc 4620
cctccctcag ctgggcagga gctgctcagg aggagctagt tatagaggaa gcttagcgtt 4680
ggcattttca aaattcaagg tgataacgct ttcttcttcc tttctgtttt agaatagatt 4740
gctgtctgat ttgaaaaagg gaaatagatt tgatctcaaa tgaatctgtg cccagaagcc 4800
aggctcaggg tattcagaga tttgtatagt gccctcaaaa aataacaaaa ttttagcttt 4860
ccttttttct tcttttctcc atcaaattct tttttctcta gtttacaaat gacatggaaa 4920
aggaatttcc cctgagtttt gtatgccttt ttttttttgg cttagactat agataggcgt 4980
gttgagctcc taagaaaata caaggaggaa ctctttgttg tgcagagcac tttatgagta 5040
gtttgtgtgg ataatatgtg actgcttccc tgacgagctt gtgaggctgt acttatgtct 5100
ttcctgtaag gcagcttcag tgccttctgt agtgtatata aggaaagatt acgccttctg 5160
aaaaatctca gagcaaccat aagattattt taaaatatgt agtatgactg atggactttt 5220
tcatcattaa attagtctag catctaaact tttaccactg aaataatatt gaccaaaaag 5280
caatttataa aaggtatttg tgaatagaaa atacaatgtg atcatttgta cttatgtgca 5340
ccttaaaaga ggaattctgt ctagctgtca aattctggtt ccttaacatc cagtccttga 5400
ttgtgattga gatctggtag gacgtgctgg ggcacgctag cagataaaat cccgtatact 5460
ttaggataga tgttacattt atgtcagtgt tggcaaagag cattgtgtag taataaagaa 5520
ttcaagactt cagcaatgtc aacctgaaac tttgtaaata tttcctagat tgttatttga 5580
tgcagtcaca gctctttatc acacaatgtt gtctttccct catcaggcaa ttttagaact 5640
gctgcacacc cctcctcaga tctcacctgc ccctcctgta cattcacctc tccagccttg 5700
tgcacacctc atttagcttt agtttgaaac acattgcagg gttcaggtga cctcttcaaa 5760
aactacctcc tcagaatgag gtaatgaata gttatttatt ttaaaatatg aaaagtcagg 5820
agctctagaa tatgaagatg atctaagatt ttaactttta tgtatacttg ttgagcactc 5880
tccttttgtc ctaaagggca ttatacattt aagcagtaat actgaaaaat gtagctcaga 5940
gtaactgaat gttgttgaaa gtggtgccag aatctgtttt aggggtacgt atcagaatct 6000
taatcttaaa tcggttacat gaaattaaat agttaatggt aacacttgac taacagatat 6060
aattttaatt ttcggtaggc ttttagcaag acagtaagta catcttcata atgagttagc 6120
cacagcttca tcacatgcac agattttcct gttgagagac tgcccagtta agagggtaga 6180
atgatgaacc atttttcagg attctcttct ttgtccaaac tggcattgtg agtgctagaa 6240
tatcagcact ttcaaactag tgattccaac tattaggcta ttaaaaagca aaacaaacca 6300
aacaaaccat agccagacat gggaagttta ctatgagtat aaacagcaaa tagcttacag 6360
gtcatacatt gaaatggtgt aggtaaggcg ttagaaaaat accttgacaa tttgccaaat 6420
gatcttactg tgccttcatg atgcaataaa aaaaaaaaaa atttagcata aatcagtgat 6480
ttgtgaagag agcagccacc ctggtctaac tcagctgtgt taatattttt tagcgtgcaa 6540
tttagactgc aaagataaat gcactaaaga gtttatagcc aaaatcacat ttaaaaaatg 6600
agagaaaaca caggtaaatt ttcagtgaac aaaattattt ttttaaagta cataatccct 6660
agtatagtca gatatattta tcacatagag caaataggtt gaaatcacaa ttcagtgaca 6720
tttctagaga aactttttct actcccatag gttcttcaaa gcatggaact tttatataac 6780
agaaatgtgt gacggtcatt ttaaattgct gtagtttggg gctgaagtac tgtgtgctgg 6840
gcagcaatca catgtattaa ctagtgagaa aggagaaatt aagatatagg acagaatttg 6900
attttcttgt tcccagatta ctgctgccaa cctagacact gagtttccag aggctgaaac 6960
gtaaacttgc agctcagcaa ctgttttgca aagttagtgg gactgtcctg cttatgctgt 7020
tcaaaaatgc tctgagggcc aggtggggcc tccaggggct cctctctgag gggacatcag 7080
actagctaac gacctggcgg gcggatgtga accggacaca ctccatggtg tgcttcttgt 7140
atcggtccct cgccaccctc aagaaaggct tcagcgggtt ctctagacgt ctccactaag 7200
gtgtgttact aacagccatg ggttgttgag cacccgagga gtgcaatagc atctctgcat 7260
gattgtatat tggcccgaag agaatgaagt ggccagtgta ctcatgttcc atgttgctag 7320
ctctggtaaa ctgaaaatac tggtaagatt tttgttttat cagtacacta gagagtaagc 7380
tttgttttgt tgtttttaga taatgttttc acttccattt ggaaagacat ttaaattgag 7440
tttcagtcct aaattttgcc agtcatggta attagcagtt tctatcaggt atttttaagg 7500
tagaagagga tagaaacata agttctaaaa gcttaaggta accgtggttt attttaaaat 7560
gtttaggggt ggttagtctc tacctcaaaa aaagtgagtg aatcttttat ttcagcattc 7620
acaagttcgg ctgttgtttt tgtaatacat ttttttttta accttttgac ccccctttac 7680
ctaagtgtca atgtagtttt attaattact aagtcagttt cattaaaatg tttatttagc 7740
agttttgact aattgcaatg attaatatag ccagttgtgc atgaggacac agccagtgag 7800
tatatctggg ttttttttgt gatgcttttt ttcttaagac ttctgtagat ttatgaagta 7860
ctcattgaaa acaactaaaa tacgtttatt cgtgttaata tggaaaaaaa aaaa 7914
<210> 24
<211> 766
<212> PRT
<213> 牛
<400> 24
Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu
1 5 10 15
Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala
20 25 30
Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn
35 40 45
Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu
50 55 60
Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala
65 70 75 80
Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln
85 90 95
Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser
100 105 110
Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser
115 120 125
Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser
130 135 140
Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu
145 150 155 160
Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val
165 170 175
Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu
180 185 190
Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly
195 200 205
Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu
210 215 220
Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr
225 230 235 240
Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln
245 250 255
Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser
260 265 270
Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu
275 280 285
Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala
290 295 300
Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro
305 310 315 320
Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser
325 330 335
Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His
340 345 350
Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val
355 360 365
His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp
370 375 380
Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr
385 390 395 400
Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln
405 410 415
Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu
420 425 430
Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp
435 440 445
Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser
450 455 460
Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala
465 470 475 480
Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala
485 490 495
Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile
500 505 510
Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr
515 520 525
Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu
530 535 540
Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala
545 550 555 560
Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu
565 570 575
Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly
580 585 590
Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln
595 600 605
Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile
610 615 620
Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala
625 630 635 640
Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser
645 650 655
Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr
660 665 670
Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met
675 680 685
Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro
690 695 700
Leu Phe Pro Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser Leu
705 710 715 720
Pro Lys Ile His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala Gly
725 730 735
Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys Thr
740 745 750
Pro Ile Gln Ala Gly Gly Tyr Gly Glu Phe Ala Ala Phe Lys
755 760 765
<210> 25
<211> 4670
<212> DNA
<213> 牛
<400> 25
ggtgtgtcat agtgcagcag attgaatgca gaagatatga aaattcagat gtcttctgtt 60
aaggtgtgga atatcaaaca aatgattaag ttgacacagg agcatataga ggccctattg 120
gacaaatttg gtggggagca taatccacca tcaatatatc tggaggccta tgaagaatac 180
accagcaagc tagatgccct ccaacaaaga gaacaacagt tattggaatc cctggggaat 240
ggaactgatt tttctgtttc tagctctgca tcaacggaca ccgttacatc ttcttcctct 300
tctagccttt cagtgctgcc ttcatctctt tcagtttttc aaaatcccac agatgtgtca 360
cggagcaacc ccaagtcacc acaaaaacct atcgttagag tcttcctgcc caataaacag 420
aggacagtgg tacctgcacg gtgtggagtc acagtccggg acagcctgaa gaaggcactg 480
atgatgagag gtctaatccc agagtgctgt gctgtttaca gaattcagga tggggagaag 540
aaaccaattg gctgggacac tgatatttcc tggcttactg gagaggagtt gcatgtagaa 600
gtgttggaga atgttccact tacaacacac aactttgtac ggaaaacttt tttcacctta 660
gcattttgtg acttctgtag aaagctgctt ttccagggat tccgctgtca aacatgtggt 720
tataaatttc accagcgttg tagtacagag gttccactga tgtgtgttaa ttatgaccaa 780
ctagatttgc tgtttgtctc caagttcttt gaacaccacc caataccaca ggaggaggcc 840
tccttagcag agactaccct tccatgtggc tcatcccctt ctgcaccccc ctccgattct 900
attgggcccc caattctcac cagtccatct ccttcaaaat ccattccaat tccacagcct 960
ttccgaccag cagatgaaga tcatcgaaat cagtttggac aacgagaccg gtcctcatca 1020
gctccaaatg tgcatataaa cacaatagaa cccgtcaata ttgatgactt gattagagac 1080
caagggtttc gtagtgatgg aggatcaacc acaggtttat ccgccacacc ccctgcctca 1140
ttacctggct cactctctaa tgtgaaagca ttgcagaaat ctccaggacc tcagcgagaa 1200
agaaagtcct cttcatcctc agaagacagg aatcgaatga aaacgcttgg tagacgggat 1260
tcaagtgacg attgggagat tcctgatgga cagatcacag tgggacaaag aattggatca 1320
gggtcatttg ggacagtcta caagggaaag tggcatggtg atgtggcagt gaaaatgttg 1380
aatgtgacag cacccacacc tcagcagtta caggccttca aaaatgaagt aggagtactc 1440
aggaaaacgc gacatgtgaa tatcctcctc ttcatgggtt attcaacaaa gccacaactg 1500
gctattgtta cccagtggtg tgagggctcc agtttatatc atcatctcca catcattgag 1560
accaaattcg agatgatcaa acttatagat attgcacggc agactgcaca gggcatggat 1620
tacttacacg ccaagtcaat catccacaga gacctcaaga gtaataatat ttttcttcat 1680
gaagacctca cagtaaaaat aggtgatttt ggtctagcca cagtgaaatc tcgatggagt 1740
gggtcccatc agtttgaaca gttgtctgga tccattttgt ggatggcacc agaagtaatc 1800
agaatgcaag ataaaaaccc atatagcttt cagtcagatg tatatgcatt tgggattgtt 1860
ctgtatgaat tgatgaccgg acagttacct tattcaaata tcaacaacag ggaccagata 1920
atttttatgg tgggacgagg atatctgtct ccagatctca gtaaggtacg gagtaactgt 1980
ccaaaagcca tgaagagatt aatggcagag tgcctaaaaa agaaaagaga tgaaagacca 2040
ctctttcccc aagtaggaaa gactctccta agcaagagac aaaattcaga agttatcagg 2100
gaaaaagata agcagattct cgcctctatt gagctgctgg cccgctcatt gccaaaaatt 2160
caccgcagtg catcagaacc ctccttgaat cgggctggct tccaaacaga ggattttagt 2220
ctatatgctt gtgcttctcc aaaaacaccc attcaggcag ggggatatga agcagatttg 2280
gctcttacat caaataaaaa tagagtagaa gttgggattt agagatttcc tgacatgcaa 2340
gaaggaataa gcaagaaaaa aaggtttgtt ttccccaaat catatctatt gtcttttact 2400
tctatttttt cttaaatttt ttgtgatttc agagacatgt agagttttat tgatacctaa 2460
actatgagtt cttttttttt tttttttttc attattttga tttttttggc caagaggcat 2520
atgggatctt agcttgagaa agcaacaatt ttcttgatgt cattttgggt gagggcacat 2580
attgctgtga acagtgtggt gatagccacc agggaccaaa ctcacacccg ctgcattgaa 2640
aggtgaagtc ttaaacactg gaccagcaga gaaattccta ctctatgagt tctttttgtc 2700
atcccctccc cgcaccctcc acccccaacc taaagtctga tgatgaaatc aacaactatt 2760
ccattagaag cagtagattc tggtagcatg atctttagtt tgttagtaag attttgtgct 2820
ttgtggggtt gtgtcgtttt aaggctaata tttaagtttg tcaaatagaa tgctgttcag 2880
attgtaaaaa tgagtaataa acatctgaag ttttttttaa gttattttta acatggtata 2940
tacagttgag cttagagttt atcattttct gatattctct tacttagtag atgaattcta 3000
gccatttttt ataaagattt ctgttaagca aatcctgttt tcacatgggc ttcctttaag 3060
ggattttaga ttctgctgga tatggtgact gctcataaga ctgttgaaaa ttacttttaa 3120
gatgtattag aatacttctg aaaaaaaata gcaaccttaa aaccataagc aaaagtagta 3180
agggtgttta tacatttcta gagtccctgt ttaggtaata gcctcctatg attgtacttt 3240
aaatgttttg ctctccaagg ttttagtaac ttggcttttt ttctaatcag tgccaaactc 3300
ccccagtttt tttaacttta aatatgaggt aataaatctt ttacccttcc ttgatctttt 3360
gacttataat accttggtca gttgtttctt aaaaggaatc cttaaatgga aagagacaat 3420
atcactgtct gcagttctga ttagtagttt tattcagaat ggaaaaacag attattcatt 3480
tttgaaaatt gttcaggggt atgttcattg ttaggacctt ggactttgga gtcagtgcct 3540
agctatgcat tccaggtctg ccattttctg gctgtgaaat tttggacaag ttacttaacc 3600
actttaaacc ccagctttaa gaagtaaatt aaccccagta aattaagaag taatagcagc 3660
cacttcgtag agttgttatg aggctcagat gcagtgcaaa tgtgtataaa gtattcaggg 3720
agtcacctgg tatactataa tagacactag aatagttgcc aatattatca gcatacaatc 3780
tgaggattct gtcagccaat cattagcaat ctgttgtttg ttgggacatg ccagtgttct 3840
ccagttgaaa tcagtagcaa tctaaaaatg gatagattat tcctcattta aatagtgtgt 3900
tcatataagt gattgcttgg atccttatca gaagttgctg ttactgaaaa atgataaggc 3960
tgactaaatt gtgatagttg tcagttacta accaactccc agaaatgaat aagaggaacc 4020
tatctctagt tcctagtaga aggtatggac aaaatagtag gtgaaaaata atgtcttgaa 4080
cccccaaatt aagtaagctt taaagagtac aatacctcaa agggtctttg cggtttaaaa 4140
tttgtatgct gagaatgatg ttcattgaca tgtgcctata tgtaattttt tgatagttta 4200
aaaggtgaaa tgaactacag atgggagagg tctgaatttt cttgccttca gtcaaatgtg 4260
taatgtggac atattatttg acctgtgaat tttatctttt aaaaaagatt aattcctgct 4320
tcttccttcc taatagttgc attataataa tgaaaatgag ttgataattt ggggggaaag 4380
tattctacaa atcaacctta ttattttacc attggtttct gagaaatttt gttcatttga 4440
accgtttata gcttgattag aatcatagca tgtaaaaccc aactgaggga ttatctgcag 4500
acttaatgta gtattatgta agttgtcttc tttcatttcg accttttttg cttttgttgt 4560
tgctagatct gtagtatgta gctagtcacc tttcagcgag gtttcagcga ggcttttctg 4620
tgtctctagg ttatttgaga taactttttt aaaattagct cttgtcctcc 4670
<210> 26
<211> 761
<212> PRT
<213> 牛
<400> 26
Met Lys Ile Gln Met Ser Ser Val Lys Val Trp Asn Ile Lys Gln Met
1 5 10 15
Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu Asp Lys Phe Gly
20 25 30
Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala Tyr Glu Glu Tyr
35 40 45
Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln Gln Leu Leu Glu
50 55 60
Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser Ser Ala Ser Thr
65 70 75 80
Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser Val Leu Pro Ser
85 90 95
Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser Arg Ser Asn Pro
100 105 110
Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu Pro Asn Lys Gln
115 120 125
Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val Arg Asp Ser Leu
130 135 140
Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu Cys Cys Ala Val
145 150 155 160
Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly Trp Asp Thr Asp
165 170 175
Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu Val Leu Glu Asn
180 185 190
Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr Phe Phe Thr Leu
195 200 205
Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln Gly Phe Arg Cys
210 215 220
Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser Thr Glu Val Pro
225 230 235 240
Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu Phe Val Ser Lys
245 250 255
Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala Ser Leu Ala Glu
260 265 270
Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro Pro Ser Asp Ser
275 280 285
Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser Lys Ser Ile Pro
290 295 300
Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His Arg Asn Gln Phe
305 310 315 320
Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val His Ile Asn Thr
325 330 335
Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp Gln Gly Phe Arg
340 345 350
Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro Pro Ala Ser
355 360 365
Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln Lys Ser Pro Gly
370 375 380
Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu Asp Arg Asn Arg
385 390 395 400
Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro
405 410 415
Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly
420 425 430
Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala Val Lys Met Leu
435 440 445
Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu
450 455 460
Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile Leu Leu Phe Met
465 470 475 480
Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr Gln Trp Cys Glu
485 490 495
Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu Thr Lys Phe Glu
500 505 510
Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala Gln Gly Met Asp
515 520 525
Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu Lys Ser Asn Asn
530 535 540
Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly Asp Phe Gly Leu
545 550 555 560
Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln Phe Glu Gln Leu
565 570 575
Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile Arg Met Gln Asp
580 585 590
Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala Phe Gly Ile Val
595 600 605
Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn
610 615 620
Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr Leu Ser Pro Asp
625 630 635 640
Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met Lys Arg Leu Met
645 650 655
Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln
660 665 670
Val Gly Lys Thr Leu Leu Ser Lys Arg Gln Asn Ser Glu Val Ile Arg
675 680 685
Glu Lys Asp Lys Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser
690 695 700
Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala
705 710 715 720
Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys
725 730 735
Thr Pro Ile Gln Ala Gly Gly Tyr Glu Ala Asp Leu Ala Leu Thr Ser
740 745 750
Asn Lys Asn Arg Val Glu Val Gly Ile
755 760
<210> 27
<211> 4816
<212> DNA
<213> 牛
<400> 27
ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc 60
cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc 120
ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg 180
ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg 240
agcagggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt 300
cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga 360
cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat ccaccatcaa 420
tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac 480
aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa 540
cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag 600
tttttcaaaa tcccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg 660
ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag 720
tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg 780
tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc 840
ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact 900
ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc 960
agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc 1020
cactgatgtg tgttaattat gaccaactag agcccccaat tctcaccagt ccatctcctt 1080
caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt 1140
ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg 1200
tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag 1260
gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc 1320
agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc 1380
gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga 1440
tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc 1500
atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg 1560
ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca 1620
tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt 1680
tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg 1740
cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc 1800
tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc 1860
tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca 1920
ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt 1980
cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt 2040
caaatatcaa caacagggac cagataattt ttatggtggg acgaggatat ctgtctccag 2100
atctcagtaa ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc 2160
taaaaaagaa aagagatgaa agaccactct ttccccaagt aggaaagact ctcctaagca 2220
agagacaaaa ttcagaagtt atcagggaaa aagataagca gattctcgcc tctattgagc 2280
tgctggcccg ctcattgcca aaaattcacc gcagtgcatc agaaccctcc ttgaatcggg 2340
ctggcttcca aacagaggat tttagtctat atgcttgtgc ttctccaaaa acacccattc 2400
aggcaggggg atatgaagca gatttggctc ttacatcaaa taaaaataga gtagaagttg 2460
ggatttagag atttcctgac atgcaagaag gaataagcaa gaaaaaaagg tttgttttcc 2520
ccaaatcata tctattgtct tttacttcta ttttttctta aattttttgt gatttcagag 2580
acatgtagag ttttattgat acctaaacta tgagttcttt tttttttttt tttttcatta 2640
ttttgatttt tttggccaag aggcatatgg gatcttagct tgagaaagca acaattttct 2700
tgatgtcatt ttgggtgagg gcacatattg ctgtgaacag tgtggtgata gccaccaggg 2760
accaaactca cacccgctgc attgaaaggt gaagtcttaa acactggacc agcagagaaa 2820
ttcctactct atgagttctt tttgtcatcc cctccccgca ccctccaccc ccaacctaaa 2880
gtctgatgat gaaatcaaca actattccat tagaagcagt agattctggt agcatgatct 2940
ttagtttgtt agtaagattt tgtgctttgt ggggttgtgt cgttttaagg ctaatattta 3000
agtttgtcaa atagaatgct gttcagattg taaaaatgag taataaacat ctgaagtttt 3060
ttttaagtta tttttaacat ggtatataca gttgagctta gagtttatca ttttctgata 3120
ttctcttact tagtagatga attctagcca ttttttataa agatttctgt taagcaaatc 3180
ctgttttcac atgggcttcc tttaagggat tttagattct gctggatatg gtgactgctc 3240
ataagactgt tgaaaattac ttttaagatg tattagaata cttctgaaaa aaaatagcaa 3300
ccttaaaacc ataagcaaaa gtagtaaggg tgtttataca tttctagagt ccctgtttag 3360
gtaatagcct cctatgattg tactttaaat gttttgctct ccaaggtttt agtaacttgg 3420
ctttttttct aatcagtgcc aaactccccc agttttttta actttaaata tgaggtaata 3480
aatcttttac ccttccttga tcttttgact tataatacct tggtcagttg tttcttaaaa 3540
ggaatcctta aatggaaaga gacaatatca ctgtctgcag ttctgattag tagttttatt 3600
cagaatggaa aaacagatta ttcatttttg aaaattgttc aggggtatgt tcattgttag 3660
gaccttggac tttggagtca gtgcctagct atgcattcca ggtctgccat tttctggctg 3720
tgaaattttg gacaagttac ttaaccactt taaaccccag ctttaagaag taaattaacc 3780
ccagtaaatt aagaagtaat agcagccact tcgtagagtt gttatgaggc tcagatgcag 3840
tgcaaatgtg tataaagtat tcagggagtc acctggtata ctataataga cactagaata 3900
gttgccaata ttatcagcat acaatctgag gattctgtca gccaatcatt agcaatctgt 3960
tgtttgttgg gacatgccag tgttctccag ttgaaatcag tagcaatcta aaaatggata 4020
gattattcct catttaaata gtgtgttcat ataagtgatt gcttggatcc ttatcagaag 4080
ttgctgttac tgaaaaatga taaggctgac taaattgtga tagttgtcag ttactaacca 4140
actcccagaa atgaataaga ggaacctatc tctagttcct agtagaaggt atggacaaaa 4200
tagtaggtga aaaataatgt cttgaacccc caaattaagt aagctttaaa gagtacaata 4260
cctcaaaggg tctttgcggt ttaaaatttg tatgctgaga atgatgttca ttgacatgtg 4320
cctatatgta attttttgat agtttaaaag gtgaaatgaa ctacagatgg gagaggtctg 4380
aattttcttg ccttcagtca aatgtgtaat gtggacatat tatttgacct gtgaatttta 4440
tcttttaaaa aagattaatt cctgcttctt ccttcctaat agttgcatta taataatgaa 4500
aatgagttga taatttgggg ggaaagtatt ctacaaatca accttattat tttaccattg 4560
gtttctgaga aattttgttc atttgaaccg tttatagctt gattagaatc atagcatgta 4620
aaacccaact gagggattat ctgcagactt aatgtagtat tatgtaagtt gtcttctttc 4680
atttcgacct tttttgcttt tgttgttgct agatctgtag tatgtagcta gtcacctttc 4740
agcgaggttt cagcgaggct tttctgtgtc tctaggttat ttgagataac ttttttaaaa 4800
ttagctcttg tcctcc 4816
<210> 28
<211> 757
<212> PRT
<213> 牛
<400> 28
Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu
1 5 10 15
Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala
20 25 30
Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn
35 40 45
Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu
50 55 60
Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala
65 70 75 80
Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln
85 90 95
Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser
100 105 110
Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser
115 120 125
Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser
130 135 140
Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu
145 150 155 160
Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val
165 170 175
Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu
180 185 190
Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly
195 200 205
Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu
210 215 220
Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr
225 230 235 240
Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln
245 250 255
Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser
260 265 270
Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Glu Pro Pro
275 280 285
Ile Leu Thr Ser Pro Ser Pro Ser Lys Ser Ile Pro Ile Pro Gln Pro
290 295 300
Phe Arg Pro Ala Asp Glu Asp His Arg Asn Gln Phe Gly Gln Arg Asp
305 310 315 320
Arg Ser Ser Ser Ala Pro Asn Val His Ile Asn Thr Ile Glu Pro Val
325 330 335
Asn Ile Asp Asp Leu Ile Arg Asp Gln Gly Phe Arg Ser Asp Gly Gly
340 345 350
Ser Thr Thr Gly Leu Ser Ala Thr Pro Pro Ala Ser Leu Pro Gly Ser
355 360 365
Leu Ser Asn Val Lys Ala Leu Gln Lys Ser Pro Gly Pro Gln Arg Glu
370 375 380
Arg Lys Ser Ser Ser Ser Ser Glu Asp Arg Asn Arg Met Lys Thr Leu
385 390 395 400
Gly Arg Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro Asp Gly Gln Ile
405 410 415
Thr Val Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly Thr Val Tyr Lys
420 425 430
Gly Lys Trp His Gly Asp Val Ala Val Lys Met Leu Asn Val Thr Ala
435 440 445
Pro Thr Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu Val Gly Val Leu
450 455 460
Arg Lys Thr Arg His Val Asn Ile Leu Leu Phe Met Gly Tyr Ser Thr
465 470 475 480
Lys Pro Gln Leu Ala Ile Val Thr Gln Trp Cys Glu Gly Ser Ser Leu
485 490 495
Tyr His His Leu His Ile Ile Glu Thr Lys Phe Glu Met Ile Lys Leu
500 505 510
Ile Asp Ile Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr Leu His Ala
515 520 525
Lys Ser Ile Ile His Arg Asp Leu Lys Ser Asn Asn Ile Phe Leu His
530 535 540
Glu Asp Leu Thr Val Lys Ile Gly Asp Phe Gly Leu Ala Thr Val Lys
545 550 555 560
Ser Arg Trp Ser Gly Ser His Gln Phe Glu Gln Leu Ser Gly Ser Ile
565 570 575
Leu Trp Met Ala Pro Glu Val Ile Arg Met Gln Asp Lys Asn Pro Tyr
580 585 590
Ser Phe Gln Ser Asp Val Tyr Ala Phe Gly Ile Val Leu Tyr Glu Leu
595 600 605
Met Thr Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn Arg Asp Gln Ile
610 615 620
Ile Phe Met Val Gly Arg Gly Tyr Leu Ser Pro Asp Leu Ser Lys Val
625 630 635 640
Arg Ser Asn Cys Pro Lys Ala Met Lys Arg Leu Met Ala Glu Cys Leu
645 650 655
Lys Lys Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln Val Gly Lys Thr
660 665 670
Leu Leu Ser Lys Arg Gln Asn Ser Glu Val Ile Arg Glu Lys Asp Lys
675 680 685
Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser Leu Pro Lys Ile
690 695 700
His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala Gly Phe Gln Thr
705 710 715 720
Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys Thr Pro Ile Gln
725 730 735
Ala Gly Gly Tyr Glu Ala Asp Leu Ala Leu Thr Ser Asn Lys Asn Arg
740 745 750
Val Glu Val Gly Ile
755
<210> 29
<211> 2499
<212> DNA
<213> 牛
<400> 29
ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc 60
cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc 120
ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg 180
ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg 240
agcagggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt 300
cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga 360
cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat ccaccatcaa 420
tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac 480
aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa 540
cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag 600
tttttcaaaa tcccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg 660
ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag 720
tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg 780
tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc 840
ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact 900
ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc 960
agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc 1020
cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac 1080
accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat 1140
ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt 1200
caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt 1260
ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg 1320
tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag 1380
gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc 1440
agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc 1500
gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga 1560
tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc 1620
atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg 1680
ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca 1740
tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt 1800
tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg 1860
cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc 1920
tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc 1980
tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca 2040
ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt 2100
cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt 2160
caaatatcaa caacagggac cagataattt ttatggtggg acgaggatat ctgtctccag 2220
atctcagtaa ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc 2280
taaaaaagaa aagagatgaa agaccactct ttccccaagt aggaaagact ctcctaagca 2340
agagacaaaa ttcagaagtt atcagggaaa aagataagca ggaaaagtat gtttctttag 2400
tacattccag gcatttggga ttacagtaaa aacaatattc tcgcctctat tgagctgctg 2460
gcccgctcat tgccaaaaat tcaccgcagt gcatcagaa 2499
<210> 30
<211> 744
<212> PRT
<213> 牛
<400> 30
Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu
1 5 10 15
Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala
20 25 30
Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn
35 40 45
Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu
50 55 60
Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala
65 70 75 80
Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln
85 90 95
Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser
100 105 110
Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser
115 120 125
Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser
130 135 140
Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu
145 150 155 160
Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val
165 170 175
Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu
180 185 190
Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly
195 200 205
Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu
210 215 220
Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr
225 230 235 240
Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln
245 250 255
Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser
260 265 270
Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu
275 280 285
Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala
290 295 300
Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro
305 310 315 320
Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser
325 330 335
Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His
340 345 350
Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val
355 360 365
His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp
370 375 380
Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr
385 390 395 400
Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln
405 410 415
Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu
420 425 430
Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp
435 440 445
Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser
450 455 460
Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala
465 470 475 480
Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala
485 490 495
Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile
500 505 510
Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr
515 520 525
Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu
530 535 540
Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala
545 550 555 560
Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu
565 570 575
Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly
580 585 590
Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln
595 600 605
Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile
610 615 620
Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala
625 630 635 640
Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser
645 650 655
Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr
660 665 670
Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met
675 680 685
Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro
690 695 700
Leu Phe Pro Gln Val Gly Lys Thr Leu Leu Ser Lys Arg Gln Asn Ser
705 710 715 720
Glu Val Ile Arg Glu Lys Asp Lys Gln Glu Lys Tyr Val Ser Leu Val
725 730 735
His Ser Arg His Leu Gly Leu Gln
740
<210> 31
<211> 2404
<212> DNA
<213> 牛
<400> 31
ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc 60
cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc 120
ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg 180
ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg 240
agcagggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt 300
cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga 360
cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat ccaccatcaa 420
tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac 480
aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa 540
cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag 600
tttttcaaaa tcccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg 660
ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag 720
tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg 780
tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc 840
ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact 900
ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc 960
agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc 1020
cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac 1080
accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat 1140
ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt 1200
caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt 1260
ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg 1320
tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag 1380
gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc 1440
agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc 1500
gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga 1560
tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc 1620
atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg 1680
ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca 1740
tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt 1800
tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg 1860
cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc 1920
tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc 1980
tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca 2040
ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt 2100
cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt 2160
caaatatcaa caacagggac cagataattt ttatggtggg acgaggatat ctgtctccag 2220
atctcagtaa ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc 2280
taaaaaagaa aagagatgaa agaccactct ttccccaaga tctctcttcc caccatagac 2340
acaaaaattt cagatggcta caggtttaca tgtaaaaaac agaattataa caaatgattt 2400
ttat 2404
<210> 32
<211> 726
<212> PRT
<213> 牛
<400> 32
Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu
1 5 10 15
Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala
20 25 30
Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn
35 40 45
Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu
50 55 60
Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala
65 70 75 80
Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln
85 90 95
Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser
100 105 110
Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser
115 120 125
Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser
130 135 140
Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu
145 150 155 160
Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val
165 170 175
Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu
180 185 190
Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly
195 200 205
Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu
210 215 220
Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr
225 230 235 240
Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln
245 250 255
Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser
260 265 270
Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu
275 280 285
Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala
290 295 300
Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro
305 310 315 320
Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser
325 330 335
Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His
340 345 350
Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val
355 360 365
His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp
370 375 380
Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr
385 390 395 400
Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln
405 410 415
Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu
420 425 430
Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp
435 440 445
Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser
450 455 460
Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala
465 470 475 480
Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala
485 490 495
Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile
500 505 510
Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr
515 520 525
Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu
530 535 540
Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala
545 550 555 560
Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu
565 570 575
Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly
580 585 590
Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln
595 600 605
Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile
610 615 620
Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala
625 630 635 640
Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser
645 650 655
Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr
660 665 670
Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met
675 680 685
Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro
690 695 700
Leu Phe Pro Gln Asp Leu Ser Ser His His Arg His Lys Asn Phe Arg
705 710 715 720
Trp Leu Gln Val Tyr Met
725
<210> 33
<211> 2331
<212> DNA
<213> 牛
<400> 33
ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc 60
cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc 120
ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg 180
ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg 240
agcagggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt 300
cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga 360
cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat ccaccatcaa 420
tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac 480
aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa 540
cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag 600
tttttcaaaa tcccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg 660
ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag 720
tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg 780
tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc 840
ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact 900
ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc 960
agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc 1020
cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac 1080
accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat 1140
ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt 1200
caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt 1260
ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg 1320
tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag 1380
gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc 1440
agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc 1500
gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga 1560
tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc 1620
atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg 1680
ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca 1740
tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt 1800
tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg 1860
cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc 1920
tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc 1980
tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca 2040
ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt 2100
cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt 2160
caaatatcaa caacagggac caggtgcttt gtcctccatg ggagtgtaat aaatgctgtg 2220
caagggctta cttcccatga gagaagtgag tgaccaacag aaggataatt tttatggtgg 2280
gacgaggata tctgtctcca gatctcagta aggtacggag taactgtcca a 2331
<210> 34
<211> 681
<212> PRT
<213> 牛
<400> 34
Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu
1 5 10 15
Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala
20 25 30
Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn
35 40 45
Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu
50 55 60
Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala
65 70 75 80
Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln
85 90 95
Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser
100 105 110
Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser
115 120 125
Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser
130 135 140
Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu
145 150 155 160
Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val
165 170 175
Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu
180 185 190
Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly
195 200 205
Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu
210 215 220
Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr
225 230 235 240
Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln
245 250 255
Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser
260 265 270
Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu
275 280 285
Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala
290 295 300
Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro
305 310 315 320
Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser
325 330 335
Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His
340 345 350
Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val
355 360 365
His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp
370 375 380
Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr
385 390 395 400
Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln
405 410 415
Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu
420 425 430
Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp
435 440 445
Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser
450 455 460
Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala
465 470 475 480
Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala
485 490 495
Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile
500 505 510
Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr
515 520 525
Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu
530 535 540
Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala
545 550 555 560
Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu
565 570 575
Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly
580 585 590
Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln
595 600 605
Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile
610 615 620
Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala
625 630 635 640
Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser
645 650 655
Asn Ile Asn Asn Arg Asp Gln Val Leu Cys Pro Pro Trp Glu Cys Asn
660 665 670
Lys Cys Cys Ala Arg Ala Tyr Phe Pro
675 680
<210> 35
<211> 2319
<212> DNA
<213> 牛
<400> 35
ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc 60
cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc 120
ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg 180
ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg 240
agcagggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt 300
cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga 360
cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat ccaccatcaa 420
tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac 480
aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa 540
cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag 600
tttttcaaaa tcccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg 660
ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag 720
tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg 780
tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc 840
ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact 900
ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc 960
agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc 1020
cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac 1080
accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat 1140
ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt 1200
caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt 1260
ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg 1320
tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag 1380
gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc 1440
agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc 1500
gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga 1560
tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc 1620
atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg 1680
ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca 1740
tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt 1800
tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg 1860
cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc 1920
tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc 1980
tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca 2040
ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt 2100
cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt 2160
caaatatcaa caacagggac caggtgcttt gtcctccatg ggagtgtaat aaatgctgtg 2220
caagggctta cttcccatga gagaagtgag tgaccaacag aaggtctgtg caaggaaaag 2280
agacaaagcc acggatcaga agcacatggc cataactga 2319
<210> 36
<211> 681
<212> PRT
<213> 牛
<400> 36
Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu
1 5 10 15
Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala
20 25 30
Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn
35 40 45
Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu
50 55 60
Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala
65 70 75 80
Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln
85 90 95
Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser
100 105 110
Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser
115 120 125
Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser
130 135 140
Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu
145 150 155 160
Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val
165 170 175
Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu
180 185 190
Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly
195 200 205
Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu
210 215 220
Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr
225 230 235 240
Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln
245 250 255
Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser
260 265 270
Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu
275 280 285
Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala
290 295 300
Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro
305 310 315 320
Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser
325 330 335
Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His
340 345 350
Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val
355 360 365
His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp
370 375 380
Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr
385 390 395 400
Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln
405 410 415
Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu
420 425 430
Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp
435 440 445
Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser
450 455 460
Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala
465 470 475 480
Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala
485 490 495
Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile
500 505 510
Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr
515 520 525
Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu
530 535 540
Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala
545 550 555 560
Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu
565 570 575
Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly
580 585 590
Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln
595 600 605
Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile
610 615 620
Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala
625 630 635 640
Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser
645 650 655
Asn Ile Asn Asn Arg Asp Gln Val Leu Cys Pro Pro Trp Glu Cys Asn
660 665 670
Lys Cys Cys Ala Arg Ala Tyr Phe Pro
675 680
<210> 37
<211> 2661
<212> DNA
<213> 牛
<400> 37
tcagctgcgc cgggtctcac aagacggttc ccgaggtggc ccaggcgccg tcccaccgcc 60
gacgccgccc gggccgcccg ggccgtccct ccccgctgcc ccccgtcctc cgcctccgcc 120
tccccccgcc ctcagcctcc cttccccctc cccgcccagc agcggtcgct cgggcccggc 180
tctcggttat aagatggcgg cgctgagtgg cggcggcggc ggcggcggcg gtggcgcgga 240
gcagggccag gctctgttca acggggacat ggagcccgag gccggcgccg cggcctcttc 300
ggctgcggac cccgccattc ccgaggaggt gtggaatatc aaacaaatga ttaagttgac 360
acaggagcat atagaggccc tattggacaa atttggtggg gagcataatc caccatcaat 420
atatctggag gcctatgaag aatacaccag caagctagat gccctccaac aaagagaaca 480
acagttattg gaatccctgg ggaatggaac tgatttttct gtttctagct ctgcatcaac 540
ggacaccgtt acatcttctt cctcttctag cctttcagtg ctgccttcat ctctttcagt 600
ttttcaaaat cccacagatg tgtcacggag caaccccaag tcaccacaaa aacctatcgt 660
tagagtcttc ctgcccaata aacagaggac agtggtacct gcacggtgtg gagtcacagt 720
ccgggacagc ctgaagaagg cactgatgat gagaggtcta atcccagagt gctgtgctgt 780
ttacagaatt caggatgggg agaagaaacc aattggctgg gacactgata tttcctggct 840
tactggagag gagttgcatg tagaagtgtt ggagaatgtt ccacttacaa cacacaactt 900
tgtacggaaa acttttttca ccttagcatt ttgtgacttc tgtagaaagc tgcttttcca 960
gggattccgc tgtcaaacat gtggttataa atttcaccag cgttgtagta cagaggttcc 1020
actgatgtgt gttaattatg accaactaga tttgctgttt gtctccaagt tctttgaaca 1080
ccacccaata ccacaggagg aggcctcctt agcagagact acccttccat gtggctcatc 1140
cccttctgca cccccctccg attctattgg gcccccaatt ctcaccagtc catctccttc 1200
aaaatccatt ccaattccac agcctttccg accagcagat gaagatcatc gaaatcagtt 1260
tggacaacga gaccggtcct catcagctcc aaatgtgcat ataaacacaa tagaacccgt 1320
caatattgat gacttgatta gagaccaagg gtttcgtagt gatggaggat caaccacagg 1380
tttatccgcc acaccccctg cctcattacc tggctcactc tctaatgtga aagcattgca 1440
gaaatctcca ggacctcagc gagaaagaaa gtcctcttca tcctcagaag acaggaatcg 1500
aatgaaaacg cttggtagac gggattcaag tgacgattgg gagattcctg atggacagat 1560
cacagtggga caaagaattg gatcagggtc atttgggaca gtctacaagg gaaagtggca 1620
tggtgatgtg gcagtgaaaa tgttgaatgt gacagcaccc acacctcagc agttacaggc 1680
cttcaaaaat gaagtaggag tactcaggaa aacgcgacat gtgaatatcc tcctcttcat 1740
gggttattca acaaagccac aactggctat tgttacccag tggtgtgagg gctccagttt 1800
atatcatcat ctccacatca ttgagaccaa attcgagatg atcaaactta tagatattgc 1860
acggcagact gcacagggca tggattactt acacgccaag tcaatcatcc acagagacct 1920
caagagtaat aatatttttc ttcatgaaga cctcacagta aaaataggtg attttggtct 1980
agccacagtg aaatctcgat ggagtgggtc ccatcagttt gaacagttgt ctggatccat 2040
tttgtggatg gcaccagaag taatcagaat gcaagataaa aacccatata gctttcagtc 2100
agatgtatat gcatttggga ttgttctgta tgaattgatg accggacagt taccttattc 2160
aaatatcaac aacagggacc agtctgtgca aggaaaagag acaaagccac ggatcagaag 2220
cacatggcca taactgaaga ttttgtgaac tctcacaagg aaaaaatttg ctctttgaac 2280
aataagaagg aactcactaa aatgtaactg agaactgttc aacaggttga aagctgaaag 2340
atgccattgg aactgacaaa atgtttctta aacataaatg atgaaacagt gaaactacat 2400
aatatctcct ctggctgaaa cattcaagaa gtttaaaatg cttaagttaa aaataaaatc 2460
ctagtaaaca atggacttac tgtgcaacat agagaatatc ttacgataac ctgtaatgga 2520
aaagaatctg aaaaagaatg tatataactg aatcactttg ctgtaaacta gaatctgaca 2580
caacactgta aatcactaca cttttctgtt gcatgccaaa gattatttaa taacgtcatt 2640
aaaaaattat tttaataatt a 2661
<210> 38
<211> 679
<212> PRT
<213> 牛
<400> 38
Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu
1 5 10 15
Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala
20 25 30
Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn
35 40 45
Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu
50 55 60
Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala
65 70 75 80
Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln
85 90 95
Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser
100 105 110
Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser
115 120 125
Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser
130 135 140
Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu
145 150 155 160
Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val
165 170 175
Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu
180 185 190
Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly
195 200 205
Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu
210 215 220
Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr
225 230 235 240
Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln
245 250 255
Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser
260 265 270
Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu
275 280 285
Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala
290 295 300
Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro
305 310 315 320
Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser
325 330 335
Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His
340 345 350
Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val
355 360 365
His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp
370 375 380
Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr
385 390 395 400
Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln
405 410 415
Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu
420 425 430
Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp
435 440 445
Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser
450 455 460
Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala
465 470 475 480
Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala
485 490 495
Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile
500 505 510
Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr
515 520 525
Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu
530 535 540
Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala
545 550 555 560
Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu
565 570 575
Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly
580 585 590
Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln
595 600 605
Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile
610 615 620
Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala
625 630 635 640
Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser
645 650 655
Asn Ile Asn Asn Arg Asp Gln Ser Val Gln Gly Lys Glu Thr Lys Pro
660 665 670
Arg Ile Arg Ser Thr Trp Pro
675
<210> 39
<211> 7434
<212> DNA
<213> 牛
<400> 39
acaccgttac atcttcttcc tcttctagcc tttcagtgct gccttcatct ctttcagttt 60
ttcaaaatcc cacagatgtg tcacggagca accccaagtc accacaaaaa cctatcgtta 120
gagtcttcct gcccaataaa cagaggacag tggtacctgc acggtgtgga gtcacagtcc 180
gggacagcct gaagaaggca ctgatgatga gaggtctaat cccagagtgc tgtgctgttt 240
acagaattca ggatggggag aagaaaccaa ttggctggga cactgatatt tcctggctta 300
ctggagagga gttgcatgta gaagtgttgg agaatgttcc acttacaaca cacaactttg 360
tacggaaaac ttttttcacc ttagcatttt gtgacttctg tagaaagctg cttttccagg 420
gattccgctg tcaaacatgt ggttataaat ttcaccagcg ttgtagtaca gaggttccac 480
tgatgtgtgt taattatgac caactagatt tgctgtttgt ctccaagttc tttgaacacc 540
acccaatacc acaggaggag gcctccttag cagagactac ccttccatgt ggctcatccc 600
cttctgcacc cccctccgat tctattgggc ccccaattct caccagtcca tctccttcaa 660
aatccattcc aattccacag cctttccgac cagcagatga agatcatcga aatcagtttg 720
gacaacgaga ccggtcctca tcagctccaa atgtgcatat aaacacaata gaacccgtca 780
atattgatga cttgattaga gaccaagggt ttcgtagtga tggaggatca accacaggtt 840
tatccgccac accccctgcc tcattacctg gctcactctc taatgtgaaa gcattgcaga 900
aatctccagg acctcagcga gaaagaaagt cctcttcatc ctcagaagac aggaatcgaa 960
tgaaaacgct tggtagacgg gattcaagtg acgattggga gattcctgat ggacagatca 1020
cagtgggaca aagaattgga tcagggtcat ttgggacagt ctacaaggga aagtggcatg 1080
gtgatgtggc agtgaaaatg ttgaatgtga cagcacccac acctcagcag ttacaggcct 1140
tcaaaaatga agtaggagta ctcaggaaaa cgcgacatgt gaatatcctc ctcttcatgg 1200
gttattcaac aaagccacaa ctggctattg ttacccagtg gtgtgagggc tccagtttat 1260
atcatcatct ccacatcatt gagaccaaat tcgagatgat caaacttata gatattgcac 1320
ggcagactgc acagggcatg gattacttac acgccaagtc aatcatccac agagacctca 1380
agagtaataa tatttttctt catgaagacc tcacagtaaa aataggtgat tttggtctag 1440
ccacagtgaa atctcgatgg agtgggtccc atcagtttga acagttgtct ggatccattt 1500
tgtggatggc accagaagta atcagaatgc aagataaaaa cccatatagc tttcagtcag 1560
atgtatatgc atttgggatt gttctgtatg aattgatgac cggacagtta ccttattcaa 1620
atatcaacaa cagggaccag ataattttta tggtgggacg aggatatctg tctccagatc 1680
tcagtaaggt acggagtaac tgtccaaaag ccatgaagag attaatggca gagtgcctaa 1740
aaaagaaaag agatgaaaga ccactctttc cccaagtagg aaagactctc ctaagcaaga 1800
gacaaaattc agaagttatc agggaaaaag ataagcagat tctcgcctct attgagctgc 1860
tggcccgctc attgccaaaa attcaccgca gtgcatcaga accctccttg aatcgggctg 1920
gcttccaaac agaggatttt agtctatatg cttgtgcttc tccaaaaaca cccattcagg 1980
cagggggata tggagaattt gcagccttca agtagccaca ccatcatgac agcatctact 2040
cttatttctt aagtcttgtg ttcgtacaat ttgttaacat caaaacacag ttctgttcct 2100
caactctttt taaagttaaa atttttcagt gcataagctg gtgtggaaca gaaggaaatt 2160
tcccatccaa caaaagaggg aagaatgttt taggaaccag aattctctgc tgccagtgtt 2220
tcttcttcaa cacaaatatc acaagtctgc ccactcccag gaagaaagag gagagaccct 2280
gagttctgac cttttgatgg tcaggcatga tggaaagaaa ctgctgctac agcttgggag 2340
atttgctctg ggaagtctgc cagtcaactt tgcccttcta accaccagat caatatgtgg 2400
ctgatcatct gatggggcag ttgcaatcac caagccttgt tctctttcct gttctgggat 2460
tgtgttgtgg aacccttttc cctagccacc accagttcat ttctgaggga tggaacaaaa 2520
atgcagcatg cccttcctgt gtggtgcatg ttcagtcctt gacaaatttt taccaaaatg 2580
aagctacttt atttaaaagg agggtgagag gtgaggaggt cactttgggt gtggcggaaa 2640
gggaatgctg catctttttc ctgggctgct ggggctctgg ccttggcttg ccagccggaa 2700
gcgctggcac gcatcgcctt cttttcccat tgggtccagc aatgaagacg agtgtttggg 2760
gttttttttt tctccaccat gtagcaagtt ctcaggaaaa tacaattgat atcttcctcc 2820
taagctcttc caatcagtca ccaagtactt atgtggttac tttgtccagg gcacaaaatg 2880
cctgtatcta attaaaagcc tacaaaactg cttgataaca gttttgaatg tgagacattt 2940
atgtaattta aatgtaaggt acaagtttta atttctgagt ttcttctatt atatttttat 3000
taaaaaaaga aaataatttt cagattgaat tggagtaaaa taatattact tcccactaga 3060
attatatatc ctggaaaatt gtatttttgt tacataagca gcttttaaag aaagatcatt 3120
acccttttct ctacataaat atatggggag tcttagccta atgacaaata tttataattt 3180
ttaaattaat ggtacttgct ggatccatac taacatcttt actaatacct cattgtttct 3240
tccaacttac tcctacacta catcctacat cttcttccta gtcttttatc tagaatatgc 3300
aacctcaaat aaaaatggtg gtgtcctcat tcattctcct ccttcctttt ttcccaagcc 3360
tgatcttcaa aaggttggtt aatttggcag ctgagttcct ccccaggcag agaatagacc 3420
aattttaggt gtattgggac tgagggagga tgtgtaaaga ttaacatcag taaagaaccg 3480
ctgtggagta attaagaact ttgttcttta taactggaga atataaccta accctaacat 3540
ccctcagcct ttactaaagt gtggcgtaaa tcacagtagt agcaaagaaa gtgactctgg 3600
atgtgttcct ggccagtacc tcccttatca tgaatgtaga ctctctcatc aagatttagg 3660
aatataaatc aaatcaaatg tgcccagcca agctatgtag taagggactt gaacaatatt 3720
aggcagaacc tataaaataa atcagggaat tagaaattat ttaaagtttt caaattgtaa 3780
attgccccgg tgtctttcag cctactgcca ttatttttgc tacaatacct acatttcaga 3840
ggagggccta ctgaaaattc catgcaagtg gaaaataatc ctcaagttat taatgagttt 3900
gaaaagcaat gagttcttaa gtctttgtga gtagagcaag atcctacaaa attcagaaat 3960
agtaaaaatg gattcatgct gatttgaaga gcatctgtgt gcataatata atgctgcatc 4020
tcttttaaaa gcagtctatt tttcttttta aatttgtccc catagatgct tttgaacatg 4080
aacatgctta tgttaccttt tccgaggttg ggaagagcca ggagctctca ggcagggccc 4140
cctccctcag ctgggcagga gctgctcagg aggagctagt tatagaggaa gcttagcgtt 4200
ggcattttca aaattcaagg tgataacgct ttcttcttcc tttctgtttt agaatagatt 4260
gctgtctgat ttgaaaaagg gaaatagatt tgatctcaaa tgaatctgtg cccagaagcc 4320
aggctcaggg tattcagaga tttgtatagt gccctcaaaa aataacaaaa ttttagcttt 4380
ccttttttct tcttttctcc atcaaattct tttttctcta gtttacaaat gacatggaaa 4440
aggaatttcc cctgagtttt gtatgccttt ttttttttgg cttagactat agataggcgt 4500
gttgagctcc taagaaaata caaggaggaa ctctttgttg tgcagagcac tttatgagta 4560
gtttgtgtgg ataatatgtg actgcttccc tgacgagctt gtgaggctgt acttatgtct 4620
ttcctgtaag gcagcttcag tgccttctgt agtgtatata aggaaagatt acgccttctg 4680
aaaaatctca gagcaaccat aagattattt taaaatatgt agtatgactg atggactttt 4740
tcatcattaa attagtctag catctaaact tttaccactg aaataatatt gaccaaaaag 4800
caatttataa aaggtatttg tgaatagaaa atacaatgtg atcatttgta cttatgtgca 4860
ccttaaaaga ggaattctgt ctagctgtca aattctggtt ccttaacatc cagtccttga 4920
ttgtgattga gatctggtag gacgtgctgg ggcacgctag cagataaaat cccgtatact 4980
ttaggataga tgttacattt atgtcagtgt tggcaaagag cattgtgtag taataaagaa 5040
ttcaagactt cagcaatgtc aacctgaaac tttgtaaata tttcctagat tgttatttga 5100
tgcagtcaca gctctttatc acacaatgtt gtctttccct catcaggcaa ttttagaact 5160
gctgcacacc cctcctcaga tctcacctgc ccctcctgta cattcacctc tccagccttg 5220
tgcacacctc atttagcttt agtttgaaac acattgcagg gttcaggtga cctcttcaaa 5280
aactacctcc tcagaatgag gtaatgaata gttatttatt ttaaaatatg aaaagtcagg 5340
agctctagaa tatgaagatg atctaagatt ttaactttta tgtatacttg ttgagcactc 5400
tccttttgtc ctaaagggca ttatacattt aagcagtaat actgaaaaat gtagctcaga 5460
gtaactgaat gttgttgaaa gtggtgccag aatctgtttt aggggtacgt atcagaatct 5520
taatcttaaa tcggttacat gaaattaaat agttaatggt aacacttgac taacagatat 5580
aattttaatt ttcggtaggc ttttagcaag acagtaagta catcttcata atgagttagc 5640
cacagcttca tcacatgcac agattttcct gttgagagac tgcccagtta agagggtaga 5700
atgatgaacc atttttcagg attctcttct ttgtccaaac tggcattgtg agtgctagaa 5760
tatcagcact ttcaaactag tgattccaac tattaggcta ttaaaaagca aaacaaacca 5820
aacaaaccat agccagacat gggaagttta ctatgagtat aaacagcaaa tagcttacag 5880
gtcatacatt gaaatggtgt aggtaaggcg ttagaaaaat accttgacaa tttgccaaat 5940
gatcttactg tgccttcatg atgcaataaa aaaaaaaaaa atttagcata aatcagtgat 6000
ttgtgaagag agcagccacc ctggtctaac tcagctgtgt taatattttt tagcgtgcaa 6060
tttagactgc aaagataaat gcactaaaga gtttatagcc aaaatcacat ttaaaaaatg 6120
agagaaaaca caggtaaatt ttcagtgaac aaaattattt ttttaaagta cataatccct 6180
agtatagtca gatatattta tcacatagag caaataggtt gaaatcacaa ttcagtgaca 6240
tttctagaga aactttttct actcccatag gttcttcaaa gcatggaact tttatataac 6300
agaaatgtgt gacggtcatt ttaaattgct gtagtttggg gctgaagtac tgtgtgctgg 6360
gcagcaatca catgtattaa ctagtgagaa aggagaaatt aagatatagg acagaatttg 6420
attttcttgt tcccagatta ctgctgccaa cctagacact gagtttccag aggctgaaac 6480
gtaaacttgc agctcagcaa ctgttttgca aagttagtgg gactgtcctg cttatgctgt 6540
tcaaaaatgc tctgagggcc aggtggggcc tccaggggct cctctctgag gggacatcag 6600
actagctaac gacctggcgg gcggatgtga accggacaca ctccatggtg tgcttcttgt 6660
atcggtccct cgccaccctc aagaaaggct tcagcgggtt ctctagacgt ctccactaag 6720
gtgtgttact aacagccatg ggttgttgag cacccgagga gtgcaatagc atctctgcat 6780
gattgtatat tggcccgaag agaatgaagt ggccagtgta ctcatgttcc atgttgctag 6840
ctctggtaaa ctgaaaatac tggtaagatt tttgttttat cagtacacta gagagtaagc 6900
tttgttttgt tgtttttaga taatgttttc acttccattt ggaaagacat ttaaattgag 6960
tttcagtcct aaattttgcc agtcatggta attagcagtt tctatcaggt atttttaagg 7020
tagaagagga tagaaacata agttctaaaa gcttaaggta accgtggttt attttaaaat 7080
gtttaggggt ggttagtctc tacctcaaaa aaagtgagtg aatcttttat ttcagcattc 7140
acaagttcgg ctgttgtttt tgtaatacat ttttttttta accttttgac ccccctttac 7200
ctaagtgtca atgtagtttt attaattact aagtcagttt cattaaaatg tttatttagc 7260
agttttgact aattgcaatg attaatatag ccagttgtgc atgaggacac agccagtgag 7320
tatatctggg ttttttttgt gatgcttttt ttcttaagac ttctgtagat ttatgaagta 7380
ctcattgaaa acaactaaaa tacgtttatt cgtgttaata tggaaaaaaa aaaa 7434
<210> 40
<211> 603
<212> PRT
<213> 牛
<400> 40
Met Met Arg Gly Leu Ile Pro Glu Cys Cys Ala Val Tyr Arg Ile Gln
1 5 10 15
Asp Gly Glu Lys Lys Pro Ile Gly Trp Asp Thr Asp Ile Ser Trp Leu
20 25 30
Thr Gly Glu Glu Leu His Val Glu Val Leu Glu Asn Val Pro Leu Thr
35 40 45
Thr His Asn Phe Val Arg Lys Thr Phe Phe Thr Leu Ala Phe Cys Asp
50 55 60
Phe Cys Arg Lys Leu Leu Phe Gln Gly Phe Arg Cys Gln Thr Cys Gly
65 70 75 80
Tyr Lys Phe His Gln Arg Cys Ser Thr Glu Val Pro Leu Met Cys Val
85 90 95
Asn Tyr Asp Gln Leu Asp Leu Leu Phe Val Ser Lys Phe Phe Glu His
100 105 110
His Pro Ile Pro Gln Glu Glu Ala Ser Leu Ala Glu Thr Thr Leu Pro
115 120 125
Cys Gly Ser Ser Pro Ser Ala Pro Pro Ser Asp Ser Ile Gly Pro Pro
130 135 140
Ile Leu Thr Ser Pro Ser Pro Ser Lys Ser Ile Pro Ile Pro Gln Pro
145 150 155 160
Phe Arg Pro Ala Asp Glu Asp His Arg Asn Gln Phe Gly Gln Arg Asp
165 170 175
Arg Ser Ser Ser Ala Pro Asn Val His Ile Asn Thr Ile Glu Pro Val
180 185 190
Asn Ile Asp Asp Leu Ile Arg Asp Gln Gly Phe Arg Ser Asp Gly Gly
195 200 205
Ser Thr Thr Gly Leu Ser Ala Thr Pro Pro Ala Ser Leu Pro Gly Ser
210 215 220
Leu Ser Asn Val Lys Ala Leu Gln Lys Ser Pro Gly Pro Gln Arg Glu
225 230 235 240
Arg Lys Ser Ser Ser Ser Ser Glu Asp Arg Asn Arg Met Lys Thr Leu
245 250 255
Gly Arg Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro Asp Gly Gln Ile
260 265 270
Thr Val Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly Thr Val Tyr Lys
275 280 285
Gly Lys Trp His Gly Asp Val Ala Val Lys Met Leu Asn Val Thr Ala
290 295 300
Pro Thr Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu Val Gly Val Leu
305 310 315 320
Arg Lys Thr Arg His Val Asn Ile Leu Leu Phe Met Gly Tyr Ser Thr
325 330 335
Lys Pro Gln Leu Ala Ile Val Thr Gln Trp Cys Glu Gly Ser Ser Leu
340 345 350
Tyr His His Leu His Ile Ile Glu Thr Lys Phe Glu Met Ile Lys Leu
355 360 365
Ile Asp Ile Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr Leu His Ala
370 375 380
Lys Ser Ile Ile His Arg Asp Leu Lys Ser Asn Asn Ile Phe Leu His
385 390 395 400
Glu Asp Leu Thr Val Lys Ile Gly Asp Phe Gly Leu Ala Thr Val Lys
405 410 415
Ser Arg Trp Ser Gly Ser His Gln Phe Glu Gln Leu Ser Gly Ser Ile
420 425 430
Leu Trp Met Ala Pro Glu Val Ile Arg Met Gln Asp Lys Asn Pro Tyr
435 440 445
Ser Phe Gln Ser Asp Val Tyr Ala Phe Gly Ile Val Leu Tyr Glu Leu
450 455 460
Met Thr Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn Arg Asp Gln Ile
465 470 475 480
Ile Phe Met Val Gly Arg Gly Tyr Leu Ser Pro Asp Leu Ser Lys Val
485 490 495
Arg Ser Asn Cys Pro Lys Ala Met Lys Arg Leu Met Ala Glu Cys Leu
500 505 510
Lys Lys Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln Val Gly Lys Thr
515 520 525
Leu Leu Ser Lys Arg Gln Asn Ser Glu Val Ile Arg Glu Lys Asp Lys
530 535 540
Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser Leu Pro Lys Ile
545 550 555 560
His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala Gly Phe Gln Thr
565 570 575
Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys Thr Pro Ile Gln
580 585 590
Ala Gly Gly Tyr Gly Glu Phe Ala Ala Phe Lys
595 600
<210> 41
<211> 2295
<212> DNA
<213> 马
<220>
<221> misc_feature
<222> (79)..(79)
<223> n是a, c, g或t
<400> 41
atgaagacgc tgagcggcgg cggcggcggc gcggagcagg gccaggctct gttcaacggg 60
gacatggaac ccggaggcnc cgcgccggcg cccgcggcct cgtcggccgc ggaccctgcc 120
attcccgagg aggtatggaa tatcaaacaa atgattaaat tgacacagga acatatagag 180
gccctattgg acaaatttgg tggggagcat aatccaccat caatatatct ggaggcctat 240
gaagaataca ccagcaagct agatgccctc caacaaagag aacaacagtt attggaatcc 300
ctggggaatg gaactgattt ttctgtttct agttctgcat caacggacac cgttacatct 360
tcttcctctt ctagcctttc agtgctacct tcatctcttt cagtttttca aaatcccaca 420
gatgtgtcac ggagcaaccc taagtcacca caaaaaccta tcgttagagt cttcctgccc 480
aacaaacaga ggacagtggt acctgcaagg tgtggcgtta cagtccggga cagtctaaag 540
aaagcactga tgatgagagg tctaatccca gagtgctgtg ctgtttacag aattcaggat 600
ggagagaaga aaccaattgg ctgggacact gatatttcct ggctcactgg agaggaattg 660
catgtagaag tgttggagaa tgttccactt acaacacaca actttgtacg gaaaactttt 720
ttcaccttag cattttgtga cttttgtcga aagctgcttt tccagggttt ccgctgtcaa 780
acatgtggtt ataaatttca ccagcgttgt agtacagagg ttccactgat gtgtgttaat 840
tatgaccaac ttgatttgct gtttgtctcc aagttctttg aacaccaccc agtatcacag 900
gaggaggcct ccttagcaga gactgccctt acatctggat catccccttc tgcacccccc 960
tccgattcca ttgggcccca aattctcacc agtccatctc cttcaaaatc cattccaatt 1020
ccacagcctt tccgaccagc agatgaagat catcgaaatc agtttggaca acgagaccgg 1080
tcctcatcag ctccaaatgt acatataaac acaatagaac ctgtcaatat tgatgacttg 1140
attagagacc aagggtttcg tagtgatgga ggatcaacca caggtttatc tgccaccccc 1200
cctgcctcat tacctggctc actcactaat gtgaaggcat tacagaaatc tccaggacct 1260
caacgggaaa ggaaatcatc ttcatcctca gaagacagga atcgaatgaa aactcttggt 1320
agacgggatt caagtgacga ttgggagatt cctgatgggc agatcacagt gggacaaaga 1380
attggatctg ggtcatttgg gacagtctac aagggaaagt ggcatggtga tgtggcagtg 1440
aaaatgttga atgtgacagc acccacacct cagcagttac aggccttcaa aaatgaagta 1500
ggagtactca ggaaaactcg acatgtgaat atcctactct tcatgggcta ttcaacaaag 1560
ccacaactgg ctattgttac ccagtggtgt gagggctcca gcttatatca ccatctccac 1620
atcattgaga ccaaatttga gatgatcaaa cttatagata ttgctcggca aactgcacag 1680
ggcatggatt acttacacgc caagtcaatc atccacagag acctcaagag taataatatt 1740
tttcttcatg aagacctcac agtaaaaata ggtgattttg gtctagccac agtgaaatct 1800
cgatggagtg ggtcccatca gtttgaacag ttgtctggat ccattttgtg gatggcacca 1860
gaagtaatca gaatgcaaga taaaaacccg tatagctttc aatcagatgt atatgccttt 1920
gggattgttc tgtatgaatt gatgactgga cagttacctt attcaaacat caacaacagg 1980
gaccagataa tttttatggt gggaagagga tatctatctc cagatctcag taaggtacgg 2040
agtaactgtc caaaagccat gaagagatta atggcagagt gcctaaaaaa gaaaagagac 2100
gagagaccac tcttccccca aattctcgcc tctattgagc tgctggcccg ctcattgcca 2160
aaaattcacc gcagtgcatc agagccctcc ttgaatcggg ctggcttcca gacagaggat 2220
tttagtctat atgcttgtgc ttctccgaaa acacccatcc aggcaggggg atatggtgcg 2280
tttcctgtcc actga 2295
<210> 42
<211> 764
<212> PRT
<213> 马
<220>
<221> misc_feature
<222> (27)..(27)
<223> Xaa可以是任何天然存在的氨基酸
<400> 42
Met Lys Thr Leu Ser Gly Gly Gly Gly Gly Ala Glu Gln Gly Gln Ala
1 5 10 15
Leu Phe Asn Gly Asp Met Glu Pro Gly Gly Xaa Ala Pro Ala Pro Ala
20 25 30
Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn Ile
35 40 45
Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu Asp
50 55 60
Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala Tyr
65 70 75 80
Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln Gln
85 90 95
Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser Ser
100 105 110
Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser Val
115 120 125
Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser Arg
130 135 140
Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu Pro
145 150 155 160
Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val Arg
165 170 175
Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu Cys
180 185 190
Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly Trp
195 200 205
Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu Val
210 215 220
Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr Phe
225 230 235 240
Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln Gly
245 250 255
Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser Thr
260 265 270
Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu Phe
275 280 285
Val Ser Lys Phe Phe Glu His His Pro Val Ser Gln Glu Glu Ala Ser
290 295 300
Leu Ala Glu Thr Ala Leu Thr Ser Gly Ser Ser Pro Ser Ala Pro Pro
305 310 315 320
Ser Asp Ser Ile Gly Pro Gln Ile Leu Thr Ser Pro Ser Pro Ser Lys
325 330 335
Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His Arg
340 345 350
Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val His
355 360 365
Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp Gln
370 375 380
Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro
385 390 395 400
Pro Ala Ser Leu Pro Gly Ser Leu Thr Asn Val Lys Ala Leu Gln Lys
405 410 415
Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu Asp
420 425 430
Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp Trp
435 440 445
Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser Gly
450 455 460
Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala Val
465 470 475 480
Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala Phe
485 490 495
Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile Leu
500 505 510
Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr Gln
515 520 525
Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu Thr
530 535 540
Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala Gln
545 550 555 560
Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu Lys
565 570 575
Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly Asp
580 585 590
Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln Phe
595 600 605
Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile Arg
610 615 620
Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala Phe
625 630 635 640
Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser Asn
645 650 655
Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr Leu
660 665 670
Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met Lys
675 680 685
Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro Leu
690 695 700
Phe Pro Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser Leu Pro
705 710 715 720
Lys Ile His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala Gly Phe
725 730 735
Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys Thr Pro
740 745 750
Ile Gln Ala Gly Gly Tyr Gly Ala Phe Pro Val His
755 760
<210> 43
<211> 2678
<212> DNA
<213> 鸡
<400> 43
tccccctccc tcgccccagc gcttcgatcc aagatggcgg cgctgagcag cggcagcagc 60
gccgaggggg cctcgctctt caacggggac atggagcccg agccgccgcc gcccgtgctg 120
ggcgcctgct acgccgggag cggcggcggc gacccggcca tcccggagga ggtgtggaat 180
atcaaacaga tgattaaatt aacacaagaa catatagaag cgctgttaga caagtttgga 240
ggagagcata acccaccatc aatatattta gaggcctatg aggagtacac cagcaaacta 300
gatgctctac agcagagaga acagcagtta ttggaatcca tgggaaatgg aactgatttc 360
tctgtttcca gttcagcttc aacggacaca gttgcatcat cttcctcctc tagcctctct 420
gtagcacctt catccctttc agtttatcaa aatcctactg atatgtcgcg gaataaccct 480
aagtctccac agaagcctat tgttagagtc ttcctgccca acaagcaaag gactgtggtt 540
ccggcaagat gtggggtgac agtccgagac agcctgaaga aagctctgat gatgagaggt 600
cttattccag aatgctgtgc tgtttacaga atacaggatg gagagaagaa gccaattggc 660
tgggacactg acatttcctg gctaaccgga gaggagttac acgtggaggt cttggagaat 720
gtgccactca caacacacaa ttttgtacga aaaacattct tcacgttagc gttctgcgac 780
ttctgtcgaa agctgctttt ccagggattc cgatgccaga catgtggcta caaatttcac 840
cagcgctgta gcacagaagt gccactgatg tgtgttaact acgaccaact cgatttgctg 900
tttgtctcca agttctttga acatcacccc atatcgcagg aggagaccac cttaggagag 960
accaccccgg catcgggatc gtacccctca gtgcccccat cagattctgt tggaccacca 1020
attctcccta gtccttctcc ttcaaaatcc attccaatcc cacagccctt ccgaccagca 1080
gatgaagacc atcggaatca gtttgggcaa cgcgaccgat cctcttcagc tcccaatgtt 1140
cacatcaata caattgagcc agtcaatatt gatgacttga ttagagacca gggtgtacga 1200
ggagagggag cccctttgaa ccagctgatg cgctgtcttc ggaaatacca atcccggact 1260
cccagtcccc tccttcattc tgtccccagt gaaatagtgt ttgattttga gcctggccca 1320
gtgttcagag gttcaactgc aggtttgtct gcaacacctc ctgcatcttt gcctgggtca 1380
cttaccaatg tgaaagcatt acagaaatca ccaggccccc aacgggaaag gaaatcatcc 1440
tcatcctcag aagacagaaa taggatgaaa acccttggtc gacgagattc aagtgatgat 1500
tgggaaatac cagatgggca gatcacagtt ggacaaagga taggatctgg atcatttgga 1560
acagtctaca aaggaaagtg gcatggtgac gtggcagtga aaatgttgaa tgttacagca 1620
cccacacctc aacagttaca ggctttcaaa aatgaagtag gagtgctcag gaaaacacgg 1680
catgtgaata tcctactttt tatgggttat tcaacaaaac ctcagttggc tattgttaca 1740
cagtggtgtg aggggtccag cttatatcac catctgcaca taattgagac caagtttgaa 1800
atgatcaaac taattgatat tgcacgacag actgcacaag gcatggatta tttgcatgcc 1860
aagtcaatca tccacagaga cctcaagagt aataatattt ttcttcatga agacctcaca 1920
gtaaaaatag gtgacttcgg tctggctaca gtgaaatcac gatggagtgg atctcatcaa 1980
tttgaacagt tatctggatc aattctatgg atggcaccgg aagtgatcag gatgcaagac 2040
aaaaacccat atagctttca gtcagatgtg tatgcattcg ggattgtgct ttatgaactg 2100
atgactggac agttaccata ctcaaacatc aacaacaggg accagataat ttttatggtg 2160
ggacgaggat atctatctcc agacctcagt aaagtaagaa gtaactgtcc aaaagctatg 2220
aagagactaa tggcagaatg cttgaaaaag aaaagagatg agagacctct ttttccacag 2280
attcttgcct ccattgagct tctggcccgg tcgttgccaa aaattcaccg cagtgcatct 2340
gagccgtcac taaaccgggc tggcttccag accgaggatt tcagtctgta tgcttgtgct 2400
tctccaaaaa cgcccatcca agcaggggga tacggtgggt ttccagtaca ctgaaaagaa 2460
atgtgaaagc gtgtgcctgt ttgctcatgt gctggtgtgt tcctgtgtgt gcaacgcata 2520
cgtacgttct cagttcctac cagcgacttt ttaaggttta ctgagggaat gaagactcat 2580
ttcctaacat ggggcattga acgtcctgag cacaagtcag tgctggtaag gaatgtcttg 2640
ggaacagctg gcaagaagaa ttagaaggta cttaaagg 2678
<210> 44
<211> 806
<212> PRT
<213> 鸡
<400> 44
Met Ala Ala Leu Ser Ser Gly Ser Ser Ala Glu Gly Ala Ser Leu Phe
1 5 10 15
Asn Gly Asp Met Glu Pro Glu Pro Pro Pro Pro Val Leu Gly Ala Cys
20 25 30
Tyr Ala Gly Ser Gly Gly Gly Asp Pro Ala Ile Pro Glu Glu Val Trp
35 40 45
Asn Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu
50 55 60
Leu Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu
65 70 75 80
Ala Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu
85 90 95
Gln Gln Leu Leu Glu Ser Met Gly Asn Gly Thr Asp Phe Ser Val Ser
100 105 110
Ser Ser Ala Ser Thr Asp Thr Val Ala Ser Ser Ser Ser Ser Ser Leu
115 120 125
Ser Val Ala Pro Ser Ser Leu Ser Val Tyr Gln Asn Pro Thr Asp Met
130 135 140
Ser Arg Asn Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe
145 150 155 160
Leu Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr
165 170 175
Val Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro
180 185 190
Glu Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile
195 200 205
Gly Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val
210 215 220
Glu Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys
225 230 235 240
Thr Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe
245 250 255
Gln Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys
260 265 270
Ser Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu
275 280 285
Leu Phe Val Ser Lys Phe Phe Glu His His Pro Ile Ser Gln Glu Glu
290 295 300
Thr Thr Leu Gly Glu Thr Thr Pro Ala Ser Gly Ser Tyr Pro Ser Val
305 310 315 320
Pro Pro Ser Asp Ser Val Gly Pro Pro Ile Leu Pro Ser Pro Ser Pro
325 330 335
Ser Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp
340 345 350
His Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn
355 360 365
Val His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg
370 375 380
Asp Gln Gly Val Arg Gly Glu Gly Ala Pro Leu Asn Gln Leu Met Arg
385 390 395 400
Cys Leu Arg Lys Tyr Gln Ser Arg Thr Pro Ser Pro Leu Leu His Ser
405 410 415
Val Pro Ser Glu Ile Val Phe Asp Phe Glu Pro Gly Pro Val Phe Arg
420 425 430
Gly Ser Thr Ala Gly Leu Ser Ala Thr Pro Pro Ala Ser Leu Pro Gly
435 440 445
Ser Leu Thr Asn Val Lys Ala Leu Gln Lys Ser Pro Gly Pro Gln Arg
450 455 460
Glu Arg Lys Ser Ser Ser Ser Ser Glu Asp Arg Asn Arg Met Lys Thr
465 470 475 480
Leu Gly Arg Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro Asp Gly Gln
485 490 495
Ile Thr Val Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly Thr Val Tyr
500 505 510
Lys Gly Lys Trp His Gly Asp Val Ala Val Lys Met Leu Asn Val Thr
515 520 525
Ala Pro Thr Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu Val Gly Val
530 535 540
Leu Arg Lys Thr Arg His Val Asn Ile Leu Leu Phe Met Gly Tyr Ser
545 550 555 560
Thr Lys Pro Gln Leu Ala Ile Val Thr Gln Trp Cys Glu Gly Ser Ser
565 570 575
Leu Tyr His His Leu His Ile Ile Glu Thr Lys Phe Glu Met Ile Lys
580 585 590
Leu Ile Asp Ile Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr Leu His
595 600 605
Ala Lys Ser Ile Ile His Arg Asp Leu Lys Ser Asn Asn Ile Phe Leu
610 615 620
His Glu Asp Leu Thr Val Lys Ile Gly Asp Phe Gly Leu Ala Thr Val
625 630 635 640
Lys Ser Arg Trp Ser Gly Ser His Gln Phe Glu Gln Leu Ser Gly Ser
645 650 655
Ile Leu Trp Met Ala Pro Glu Val Ile Arg Met Gln Asp Lys Asn Pro
660 665 670
Tyr Ser Phe Gln Ser Asp Val Tyr Ala Phe Gly Ile Val Leu Tyr Glu
675 680 685
Leu Met Thr Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn Arg Asp Gln
690 695 700
Ile Ile Phe Met Val Gly Arg Gly Tyr Leu Ser Pro Asp Leu Ser Lys
705 710 715 720
Val Arg Ser Asn Cys Pro Lys Ala Met Lys Arg Leu Met Ala Glu Cys
725 730 735
Leu Lys Lys Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln Ile Leu Ala
740 745 750
Ser Ile Glu Leu Leu Ala Arg Ser Leu Pro Lys Ile His Arg Ser Ala
755 760 765
Ser Glu Pro Ser Leu Asn Arg Ala Gly Phe Gln Thr Glu Asp Phe Ser
770 775 780
Leu Tyr Ala Cys Ala Ser Pro Lys Thr Pro Ile Gln Ala Gly Gly Tyr
785 790 795 800
Gly Gly Phe Pro Val His
805

Claims (23)

1.BVD-523或其药学上可接受的盐在制备用于在携带非V600E/K BRAF突变的受试者中治疗或缓解癌症的影响的药物中的用途，其中
(1)所述非V600E/K BRAF突变是D594突变，所述癌症选自唾液管癌、阴道癌和非小细胞肺癌；
(2)所述非V600E/K BRAF突变是G469突变，所述癌症选自腺样囊性癌、阑尾癌、小肠癌、鳞状细胞癌和血管肉瘤；
(3)所述非V600E/K BRAF突变是K601E突变，所述癌症为前列腺癌；
(4)所述非V600E/K BRAF突变是L597突变，所述癌症选自非小细胞肺癌和结肠直肠癌；
(5)所述非V600E/K BRAF突变是T599重复，所述癌症为非小细胞肺癌；
(6)所述非V600E/K BRAF突变是L485W突变，所述癌症为胆囊癌；
(7)所述非V600E/K BRAF突变是F247L突变，所述癌症为结肠直肠癌；
(8)所述非V600E/K BRAF突变是G466V突变，所述癌症为非小细胞肺癌。
2.根据权利要求1的用途，其中受试者是哺乳动物。
3.根据权利要求2的用途，其中哺乳动物选自灵长类动物、农场动物和家养动物。
4.根据权利要求2的用途，其中哺乳动物是人。
5.根据权利要求1的用途，其中所述药物进一步包括选自MEK抑制剂、HDAC抑制剂及其组合的至少一种另外的治疗剂。
6.根据权利要求5的用途，其中MEK抑制剂选自炭疽毒素、蒽醌、ARRY-142886(6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺)、ARRY-438162、AS-1940477、AS-703988、bentamapimod、BI-847325、E-6201、GDC-0623、GDC-0973(考比替尼)、L783277、炭疽毒素的致死因子部分、PD 098059(2-(2'-氨基-3'-甲氧苯基)-氧萘-4-酮)、PD 184352(CI-1040)、PD-0325901、PD318088、PD334581、6-甲氧基-7-(3-吗啉-4-基-丙氧基)-4-(4-苯氧基-苯基氨基)-喹啉-3-甲腈、4-[3-氯-4-(1-甲基-1H-咪唑-2-基硫烷基)-苯基氨基]-6-甲氧基-7-(3-吗啉-4-基-丙氧基)-喹啉-3-甲腈、pimasertib、RDEA119、、RG422、R0092210、R04987655、R05126766、)、SL327、TAK-733、曲美替尼、U0126(1,4-二氨基-2,3-二氰基-1,4-双(2-氨基苯硫基)丁二烯)、WX-554、YopJ多肽、其药学上可接受的盐及其组合。
7.根据权利要求5的用途，其中HDAC抑制剂选自艾贝司他(PCI-24781)、吉诺司他、恩替司他、扶林司他、CI-994、CUDC-101、恩替司他、BML-210、M344、NVP-LAQ824、帕比司他、Pracinosat(SB939)、Mocetinostat、Resminostat、罗米地辛、贝利司他、其药学上可接受的盐及其组合。
8.根据权利要求1的用途，其中所述药物进一步包括选自抗体、抗体片段、抗体缀合物、细胞毒性剂、毒素、放射性核素、免疫调控剂、光活化治疗剂、放射增敏剂、激素、抗血管生成剂及其组合的至少一种另外的治疗剂。
9.根据权利要求8的用途，其中抗体、其片段或其缀合物选自利妥昔单抗(Rituxan)、布伦妥昔单抗维多汀(Adcetriz)、阿多曲妥珠单抗艾坦肽(Kadcyla)、西妥昔单抗(Erbitux)、贝伐单抗(Avastin)、替伊莫单抗(Zevalin)、维多珠单抗(Entyvio)、伊匹单抗(Yervoy)、纳武单抗(Opdivo)、派姆单抗(Keytruda)、阿伦单抗、阿特朱单抗(Tecentriq)、阿维鲁单抗(Bavencio)、德鲁瓦单抗(Imfinzi)、B-701、奥法木单抗、阿托珠单抗(Gazyva)、帕尼单抗、plozalizumab、BI-754091、OREG-103、COM-701、BI-754111及其组合。
10.根据权利要求8的用途，其中细胞毒性剂选自环磷酰胺、甲氯乙胺、尿嘧啶氮芥、美法仑、苯丁酸甲氯乙胺、异环磷酰胺、卡莫司汀、洛莫司汀、链脲霉素、白消安、替莫唑胺、顺铂、卡铂、奥沙利铂、奈达铂、沙铂、三硝酸四铂、阿霉素、柔红霉素、伊达比星、米托蒽醌、甲氨蝶呤、培美曲塞、6-巯基嘌呤、达卡巴嗪、氟达拉滨、5-氟尿嘧啶、阿拉伯糖胞嘧啶、卡培他滨、吉西他滨、地西他滨、长春花生物碱、紫杉醇(Taxol)、多西他赛(Taxotere)、依沙贝比隆(Ixempra)、放线菌素、蒽环类、缬沙星、表柔比星、博来霉素、普卡霉素、丝裂霉素、其药学上可接受的盐、前药及其组合。
11.根据权利要求8的用途，其中毒素是白喉毒素或其部分。
12.根据权利要求8的用途，其中放射性核素选自I-125、At-211、Lu-177、Cu-67、I-131、Sm-153、Re-186、P-32、Re-188、In-114m、Y-90及其组合。
13.根据权利要求8的用途，其中免疫调控剂选自粒细胞集落刺激因子(G-CSF)、LAG-3、IMP-321、JCAR-014、ASLAN-002(BMS-777607)、干扰素、咪喹莫特和来自细菌的细胞膜组分、IL-2、IL-7、IL-12、CCL3、CCL26、CXCL7、合成的胞嘧啶磷酸鸟苷(CpG)、免疫检查点抑制剂及其组合。
14.根据权利要求8的用途，其中放射增敏剂选自米索硝唑、甲硝唑、替拉帕明、反式丁香酸钠及其组合。
15.根据权利要求8的用途、其中激素选自前列腺素、白三烯、前列环素、血栓烷、胰淀素、抗苗勒管激素、脂联素、促肾上腺皮质激素、血管紧张素原、血管紧张素、血管加压素、心房肽、脑钠尿肽、降血钙素、胆囊收缩素、促肾上腺皮质激素释放激素、脑啡肽、内皮素、促红细胞生成素、促卵泡激素、甘丙肽、胃泌素、生长激素释放肽、胰高血糖素、促性腺激素释放激素、生长激素释放激素、人绒毛膜促性腺激素、人胎盘促泌素、生长激素、抑制素、胰岛素、生长调节素、瘦素、促脂素、促黄体生成素、黑素细胞刺激激素、胃动素、食欲素、催产素、胰多肽、甲状旁腺激素、催乳素、催乳素释放激素、松弛素、肾素、分泌素、生长抑素、血小板生成素、促甲状腺激素、睾丸酮、脱氢表雄酮、雄烯二酮、二氢睾丸酮、醛固酮、雌二醇、雌酮、雌三醇、皮质醇、孕酮、骨化三醇、骨化二醇及其组合。
16.根据权利要求8的用途，其中所述药物进一步包括他莫昔芬(Nolvadex)、阿那曲唑(Arimidex)、来曲唑(Femara)或氟司韦特(Faslodex)。
17.根据权利要求8的用途、其中抗血管生成剂选自2-甲氧基雌二醇、血管抑制素、贝伐单抗、软骨衍生的血管生成抑制因子、内皮抑素、IFN-α、IL-12、伊曲康唑、利诺米特、血小板因子4、催乳素、SU5416、苏拉明、他克莫尼、替加仑、四硫代钼酸盐、沙利度胺、血小板反应蛋白、TNP-470、齐夫-阿柏西普、其药学上可接受的盐、前药及其组合。
18.根据权利要求8的用途，其中另外的治疗剂是PI3K/Akt途径的抑制剂。
19.根据权利要求18的用途、其中PI3K/Akt途径的抑制剂选自A-674563(CAS#552325-73-2)、AGL 2263、AMG-319、AS-041164(5-苯并[1,3]二恶唑-5-基亚甲基-噻唑烷-2,4-二酮)、AS-604850(5-(2,2-二氟-苯并[1,3]二恶唑-5-基亚甲基)-噻唑烷-2,4-二酮)、AS-605240(5-喹喔啉-6-亚甲基-1,3-噻唑烷-2,4-二酮)、AT7867(CAS#857531-00-1)、苯并咪唑系列、BML-257(CAS#32387-96-5)、BVD-723、CAL-120、CAL-129、CAL-130、CAL-253、CAL-263、CAS#612847-09-3、CAS#681281-88-9、CAS#75747-14-7、CAS#925681-41-0、CAS#98510-80-6、CCT128930(CAS#885499-61-6)、CH5132799(CAS#1007207-67-1)、CHR-4432、FPA 124(CAS#902779-59-3)、GS-1101(CAL-101)、GSK 690693(CAS#937174-76-0)、H-89(CAS#127243-85-0)、Honokiol、IC87114、IPI-145、KAR-4139、KAR-4141、KIN-1、KT 5720(CAS#108068-98-0)、米替福新、MK-2206二盐酸化物(CAS#1032350-13-2)、ML-9(CAS#105637-50-1)、盐酸纳曲通、OXY-111A、perifosine、PHT-427(CAS#1191951-57-1)、PI3激酶抑制剂、pictilisib、PIK-90(CAS#677338-12-4)、SC-103980、SF-1126、SH-5、SH-6、四氢姜黄素、TG100-115、曲西瑞宾、X-339、XL-499、其药学上可接受的盐及其组合。
20.根据权利要求18的用途、其中PI3K/Akt途径的抑制剂选自PI3-α/δ抑制剂、PI3-δ抑制剂、PI3-δ/γ抑制剂或PI3-γ抑制剂。
21.根据权利要求5所述的用途，其中HDAC抑制剂选自扶林司他、帕比司他、罗米地辛、贝利司他、其药学上可接受的盐及其组合。
22.根据权利要求8所述的用途，其中抗体、其片段或其缀合物选自利妥昔单抗(Rituxan)、布伦妥昔单抗维多汀(Adcetriz)、阿多曲妥珠单抗艾坦肽(Kadcyla)、伊匹单抗(Yervoy)、纳武单抗(Opdivo)、派姆单抗(Keytruda)、阿伦单抗、 阿特朱单抗(Tecentriq)、德鲁瓦单抗(Imfinzi)、奥法木单抗、阿托珠单抗(Gazyva)、帕尼单抗(Panitumumab)及其组合。
23.根据权利要求18所述的用途，其中PI3K/Akt途径的抑制剂是BVD-723。
CN201880040655.8A 2017-05-16 2018-05-15 用于治疗具有非典型braf突变的癌症的组合物和方法 Active CN110799245B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210881186.0A CN116036278A (zh) 2017-05-16 2018-05-15 用于治疗具有非典型braf突变的癌症的组合物和方法

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201762506995P 2017-05-16 2017-05-16
US62/506,995 2017-05-16
PCT/US2018/032755 WO2018213302A1 (en) 2017-05-16 2018-05-15 Compositions and methods for treating cancer with atypical braf mutations

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN202210881186.0A Division CN116036278A (zh) 2017-05-16 2018-05-15 用于治疗具有非典型braf突变的癌症的组合物和方法

Publications (2)

Publication Number Publication Date
CN110799245A CN110799245A (zh) 2020-02-14
CN110799245B true CN110799245B (zh) 2022-08-09

Family

ID=64274828

Family Applications (2)

Application Number Title Priority Date Filing Date
CN202210881186.0A Pending CN116036278A (zh) 2017-05-16 2018-05-15 用于治疗具有非典型braf突变的癌症的组合物和方法
CN201880040655.8A Active CN110799245B (zh) 2017-05-16 2018-05-15 用于治疗具有非典型braf突变的癌症的组合物和方法

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN202210881186.0A Pending CN116036278A (zh) 2017-05-16 2018-05-15 用于治疗具有非典型braf突变的癌症的组合物和方法

Country Status (9)

Country Link
US (1) US20210085663A1 (zh)
EP (1) EP3624896A4 (zh)
JP (2) JP7405408B2 (zh)
CN (2) CN116036278A (zh)
AU (2) AU2018269982B2 (zh)
BR (1) BR112019024007A2 (zh)
CA (1) CA3063614A1 (zh)
MX (1) MX2019013634A (zh)
WO (1) WO2018213302A1 (zh)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109715163B (zh) 2016-09-19 2022-11-22 诺华股份有限公司 包含raf抑制剂和erk抑制剂的治疗组合
JP7309614B2 (ja) 2017-05-02 2023-07-18 ノバルティス アーゲー 組み合わせ療法
US20190225689A1 (en) 2018-01-22 2019-07-25 Janssen Biotech, Inc. Methods of treating cancers with antagonistic anti-pd-1 antibodies
CN109771436A (zh) * 2019-03-06 2019-05-21 康赋葆(深圳)生物医药科技有限公司 四氢姜黄素与卡培他滨联合治疗大肠癌的应用
CN113811303A (zh) * 2019-05-16 2021-12-17 伊莱利利公司 用于治疗brafv600e结直肠癌的erk1/2抑制剂与braf抑制剂和egfr抑制剂的三药组合
GB201913123D0 (en) * 2019-09-11 2019-10-23 Seald As Compositions and methods for treatment of cholangiocarcinoma
GB201913124D0 (en) * 2019-09-11 2019-10-23 Seald As Compositions and methods for treatment of cholangiocarcinoma
GB201913121D0 (en) * 2019-09-11 2019-10-23 Seald As Compositions and methods for treatment of cholangiocarcinoma
CN110538316B (zh) * 2019-10-17 2021-10-15 滨州医学院 5-fu和胰高血糖素联合用于制备治疗结直肠癌的药物的用途和药物组合物
WO2021165849A1 (en) * 2020-02-18 2021-08-26 Novartis Ag Therapeutic combinations comprising a raf inhibitor for use in treating braf mutant nsclc
WO2022179568A1 (en) * 2021-02-25 2022-09-01 Westlake Therapeutics (Hangzhou) Co., Limited Neoantigenic peptide and its use for treating braf gene mutation related diseases
US20240173329A1 (en) * 2021-03-09 2024-05-30 Genentech, Inc. Belvarafenib for use in treatment of brain cancers
WO2023049798A1 (en) * 2021-09-22 2023-03-30 Henry Ford Health System Hdac3 inhibitors for the treatment of langerhans cell histiocytosis and langerhans cell sarcoma
CN116570599B (zh) * 2023-07-04 2023-10-20 四川大学华西医院 Vs6766联合ly3009120的应用及药物组合物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015095842A2 (en) * 2013-12-20 2015-06-25 Biomed Valley Discoveries, Inc. Methods and compositions for treating non-erk mapk pathway inhibitor-resistant cancers
CN104780976A (zh) * 2012-08-13 2015-07-15 洛克菲勒大学 治疗和诊断黑素瘤
CN104837491A (zh) * 2012-08-09 2015-08-12 细胞基因公司 利用3-(4-((4-(吗啉代甲基)苯甲基)氧基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮治疗癌症的方法
WO2016008853A1 (en) * 2014-07-14 2016-01-21 Universität Zürich Prorektorat Mnw Means and methods for identifying a patient having a braf-positive cancer as a non-responder to a braf inhibitor and as a responder to an mapk/erk inhibitor
CN106211755A (zh) * 2013-12-20 2016-12-07 生物医学谷探索股份有限公司 使用erk和raf抑制剂的组合的癌症治疗

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2639416C (en) * 2007-09-11 2019-12-31 F. Hoffmann-La Roche Ag Diagnostic test for susceptibility to b-raf kinase inhibitors
WO2014147573A2 (en) * 2013-03-21 2014-09-25 Novartis Ag Combination therapy
BR122020006408B1 (pt) * 2013-03-29 2021-09-28 The Johns Hopkins University Dose unitária de unidades formadoras de colônia de c. novyi, composição farmacêutica e uso de c. novyi nt para tratar ou atenuar um efeito de um tumor sólido presente em um ser humano
US11007174B2 (en) * 2013-07-12 2021-05-18 Piramal Enterprises Limited Pharmaceutical combination for the treatment of melanoma
US20160310477A1 (en) * 2013-12-20 2016-10-27 Biomed Valley Discoveries, Inc. Cancer treatments using combinations of mek type 1 and erk inhibitors
AU2014368916B2 (en) * 2013-12-20 2020-04-30 Biomed Valley Discoveries, Inc. Cancer treatments using combinations of PI3K/Akt pathway and ERK inhibitors
EP3082423A4 (en) * 2013-12-20 2017-09-20 Biomed Valley Discoveries, Inc. Cancer treatments using combinations of cdk and erk inhibitors
EP4389225A3 (en) * 2013-12-20 2024-10-09 Biomed Valley Discoveries, Inc. Cancer treatments using combinations of type 2 mek and erk inhibitors
WO2015095835A1 (en) * 2013-12-20 2015-06-25 Biomed Valley Discoveries, Inc. Methods of modulating radioiodine uptake for the treatment of radioiodine-refractory cancers
WO2016025650A1 (en) * 2014-08-13 2016-02-18 Celgene Avilomics Research, Inc. Combinations of an erk inhibitor and a cdk4/6 inhibitor and related methods
ES2930050T3 (es) * 2015-06-15 2022-12-05 Asana Biosciences Llc Inhibidores heterocíclicos de ERK1 y ERK2 y su uso en el tratamiento de cáncer
WO2017007941A2 (en) * 2015-07-08 2017-01-12 Dana-Farber Cancer Institute, Inc. Compositions and methods for identification, assessment prevention, and treatment of cancer using slncr isoforms

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104837491A (zh) * 2012-08-09 2015-08-12 细胞基因公司 利用3-(4-((4-(吗啉代甲基)苯甲基)氧基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮治疗癌症的方法
CN104780976A (zh) * 2012-08-13 2015-07-15 洛克菲勒大学 治疗和诊断黑素瘤
WO2015095842A2 (en) * 2013-12-20 2015-06-25 Biomed Valley Discoveries, Inc. Methods and compositions for treating non-erk mapk pathway inhibitor-resistant cancers
CN106211755A (zh) * 2013-12-20 2016-12-07 生物医学谷探索股份有限公司 使用erk和raf抑制剂的组合的癌症治疗
WO2016008853A1 (en) * 2014-07-14 2016-01-21 Universität Zürich Prorektorat Mnw Means and methods for identifying a patient having a braf-positive cancer as a non-responder to a braf inhibitor and as a responder to an mapk/erk inhibitor

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Abstract 4693: The selective ERK inhibitor BVD-523 is active in models of MAPK pathway-dependent cancers, including those with intrinsic and acquired drug resistance;Ursula Germann，等;《ArticleInfo & MetricsProceedings: AACR 106th Annual Meeting》;20150831;第479-484页 *
Abstract LB-B15: A novel PI3K gamma isoform selective small molecule kinase inhibitor demonstrates single agent anti-tumor activity and enhanced combination activity with checkpoint blockade in syngeneic mouse models of cancer;Saurabh Saha，等;《AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics》;20151231;第1页 *
Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma;Alan E Siroy，等;《J Invest Dermatol》;20140822;第135卷(第2期);第508-515页 *
CHRISTINA S. BAIK，等.Targeting BRAF-Mutant Non-Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy.《The Oncologist》.2017,第22卷第794页正文左栏倒数第4段-左栏最后一段. *
Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors;Kevin J Basile，等;《Pigment Cell Melanoma Res.》;20140531;第27卷(第3期);第479-484页 *
Targeting BRAF-Mutant Non-Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy;CHRISTINA S. BAIK，等;《The Oncologist》;20170509;第22卷;第794页正文左栏倒数第4段-左栏最后一段 1-87、123-125、128-132 *

Also Published As

Publication number Publication date
AU2018269982A1 (en) 2020-01-02
US20210085663A1 (en) 2021-03-25
BR112019024007A2 (pt) 2020-07-07
JP2020519660A (ja) 2020-07-02
MX2019013634A (es) 2020-01-21
AU2018269982B2 (en) 2024-06-13
CA3063614A1 (en) 2018-11-22
CN110799245A (zh) 2020-02-14
RU2019141300A3 (zh) 2022-02-25
JP2022176316A (ja) 2022-11-25
EP3624896A1 (en) 2020-03-25
WO2018213302A1 (en) 2018-11-22
CN116036278A (zh) 2023-05-02
JP7405408B2 (ja) 2023-12-26
AU2024219529A1 (en) 2024-10-03
EP3624896A4 (en) 2021-03-31
RU2019141300A (ru) 2021-06-16

Similar Documents

Publication Publication Date Title
CN110799245B (zh) 用于治疗具有非典型braf突变的癌症的组合物和方法
RU2722784C2 (ru) Лечение злокачественных опухолей с применением комбинаций ингибиторов erk и raf
AU2023204587A1 (en) Methods and compositions for treating non-ERK MAPK pathway inhibitor-resistant cancers
AU2014368927B2 (en) Cancer treatments using combinations of CDK and ERK inhibitors
JP6678583B2 (ja) ２型ｍｅｋ阻害剤およびｅｒｋ阻害剤の組み合わせを用いるがん処置
KR20130116291A (ko) Braf 억제제를 이용한 치료 방법
CA3218575A1 (en) Sotorasib dosing regimen
RU2812706C2 (ru) Композиции и способы для лечения злокачественной опухоли с атипичными мутациями braf
US20210324478A1 (en) Compositions and methods for identification assessment, prevention, and treatment of ewing sarcoma using tp53 dependency biomarkers and modulators
CN118576712A (zh) PLEKHA1-TACC2在提高EphA2抑制剂抗肿瘤疗效中的应用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40022785

Country of ref document: HK

GR01 Patent grant
GR01 Patent grant