CN116850288A - 一种以CK1ε基因或蛋白为靶点治疗杜韦利西布肠道毒性的药物 - Google Patents
一种以CK1ε基因或蛋白为靶点治疗杜韦利西布肠道毒性的药物 Download PDFInfo
- Publication number
- CN116850288A CN116850288A CN202310784225.XA CN202310784225A CN116850288A CN 116850288 A CN116850288 A CN 116850288A CN 202310784225 A CN202310784225 A CN 202310784225A CN 116850288 A CN116850288 A CN 116850288A
- Authority
- CN
- China
- Prior art keywords
- epsilon
- weili
- casein kinase
- protein
- intestinal
- 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.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 46
- 230000000968 intestinal effect Effects 0.000 title claims abstract description 40
- 108090000623 proteins and genes Proteins 0.000 title abstract description 62
- 102000004169 proteins and genes Human genes 0.000 title abstract description 55
- 229940079593 drug Drugs 0.000 title abstract description 22
- 231100000419 toxicity Toxicity 0.000 title abstract description 22
- 230000001988 toxicity Effects 0.000 title abstract description 22
- 101150067056 Epsilon gene Proteins 0.000 title abstract description 14
- 230000014509 gene expression Effects 0.000 claims abstract description 23
- 238000009825 accumulation Methods 0.000 claims abstract description 14
- 230000002222 downregulating effect Effects 0.000 claims abstract description 6
- 101001026376 Homo sapiens Casein kinase I isoform epsilon Proteins 0.000 claims description 29
- UNNKKUDWEASWDN-UHFFFAOYSA-N alkannin Natural products CC(=CCC(O)c1cc(O)c2C(=O)C=CC(=O)c2c1O)C UNNKKUDWEASWDN-UHFFFAOYSA-N 0.000 claims description 27
- BATBOVZTQBLKIL-QGZVFWFLSA-N beta,beta-Dimethylacrylshikonin Chemical group C1=CC(O)=C2C(=O)C([C@H](OC(=O)C=C(C)C)CC=C(C)C)=CC(=O)C2=C1O BATBOVZTQBLKIL-QGZVFWFLSA-N 0.000 claims description 27
- 230000000694 effects Effects 0.000 claims description 27
- 102100037398 Casein kinase I isoform epsilon Human genes 0.000 claims description 22
- 230000034512 ubiquitination Effects 0.000 claims description 17
- 238000010798 ubiquitination Methods 0.000 claims description 17
- 210000002490 intestinal epithelial cell Anatomy 0.000 claims description 15
- 230000005764 inhibitory process Effects 0.000 claims description 14
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 claims description 12
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 claims description 12
- 231100000331 toxic Toxicity 0.000 claims description 12
- 230000002588 toxic effect Effects 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 8
- 108020004459 Small interfering RNA Proteins 0.000 claims description 7
- 230000000259 anti-tumor effect Effects 0.000 claims description 7
- 230000035519 G0 Phase Effects 0.000 claims description 6
- 230000010190 G1 phase Effects 0.000 claims description 6
- 230000006378 damage Effects 0.000 claims description 6
- 230000008556 epithelial cell proliferation Effects 0.000 claims description 6
- 208000027418 Wounds and injury Diseases 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 230000001965 increasing effect Effects 0.000 claims description 5
- 208000014674 injury Diseases 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 230000004044 response Effects 0.000 claims description 4
- 230000008685 targeting Effects 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 3
- 238000004904 shortening Methods 0.000 claims description 3
- 230000008719 thickening Effects 0.000 claims description 3
- 230000001594 aberrant effect Effects 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 2
- 230000000112 colonic effect Effects 0.000 claims description 2
- 231100000249 enterotoxic Toxicity 0.000 claims description 2
- 230000002242 enterotoxic effect Effects 0.000 claims description 2
- 230000000762 glandular Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000002773 nucleotide Substances 0.000 claims description 2
- 125000003729 nucleotide group Chemical group 0.000 claims description 2
- 101710118321 Casein kinase I isoform alpha Proteins 0.000 abstract description 108
- 101001023703 Homo sapiens E3 ubiquitin-protein ligase NEDD4-like Proteins 0.000 abstract description 15
- 230000009471 action Effects 0.000 abstract description 12
- 230000002441 reversible effect Effects 0.000 abstract description 10
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- 102000044159 Ubiquitin Human genes 0.000 abstract description 5
- 108090000848 Ubiquitin Proteins 0.000 abstract description 5
- 230000006663 ubiquitin-proteasome pathway Effects 0.000 abstract description 5
- 230000005714 functional activity Effects 0.000 abstract description 2
- 230000007246 mechanism Effects 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 102100034356 Casein kinase I isoform alpha-like Human genes 0.000 abstract 6
- 102100034357 Casein kinase I isoform alpha Human genes 0.000 description 102
- 235000018102 proteins Nutrition 0.000 description 51
- 210000004027 cell Anatomy 0.000 description 19
- 210000000813 small intestine Anatomy 0.000 description 16
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 15
- 229960004425 sibutramine Drugs 0.000 description 15
- 102100035493 E3 ubiquitin-protein ligase NEDD4-like Human genes 0.000 description 14
- 210000002919 epithelial cell Anatomy 0.000 description 14
- 238000001262 western blot Methods 0.000 description 12
- 238000001514 detection method Methods 0.000 description 11
- 230000025084 cell cycle arrest Effects 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
- 230000022131 cell cycle Effects 0.000 description 8
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 7
- 102400001093 PAK-2p27 Human genes 0.000 description 7
- 238000000684 flow cytometry Methods 0.000 description 7
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 6
- 239000013642 negative control Substances 0.000 description 6
- 230000002018 overexpression Effects 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- SJVQHLPISAIATJ-ZDUSSCGKSA-N 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=CC(Cl)=C2C(=O)N1C1=CC=CC=C1 SJVQHLPISAIATJ-ZDUSSCGKSA-N 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 231100000174 enterotoxicity Toxicity 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 238000011532 immunohistochemical staining Methods 0.000 description 5
- 108050006400 Cyclin Proteins 0.000 description 4
- 102000009339 Proliferating Cell Nuclear Antigen Human genes 0.000 description 4
- 108091081021 Sense strand Proteins 0.000 description 4
- 238000003197 gene knockdown Methods 0.000 description 4
- 239000012096 transfection reagent Substances 0.000 description 4
- 108091026890 Coding region Proteins 0.000 description 3
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 229950004949 duvelisib Drugs 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000013613 expression plasmid Substances 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000000865 phosphorylative effect Effects 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 230000000306 recurrent effect Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 230000006370 G0 arrest Effects 0.000 description 2
- 230000037057 G1 phase arrest Effects 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000012828 PI3K inhibitor Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000000749 co-immunoprecipitation Methods 0.000 description 2
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000013115 immunohistochemical detection Methods 0.000 description 2
- 238000001114 immunoprecipitation Methods 0.000 description 2
- 208000037817 intestinal injury Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000009456 molecular mechanism Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 230000003827 upregulation Effects 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- NEZONWMXZKDMKF-JTQLQIEISA-N Alkannin Chemical compound C1=CC(O)=C2C(=O)C([C@@H](O)CC=C(C)C)=CC(=O)C2=C1O NEZONWMXZKDMKF-JTQLQIEISA-N 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- 201000004085 CLL/SLL Diseases 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 241001071917 Lithospermum Species 0.000 description 1
- 229930192627 Naphthoquinone Natural products 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 229940123573 Protein synthesis inhibitor Drugs 0.000 description 1
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 230000004156 Wnt signaling pathway Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000003990 capacitor Substances 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000023738 chronic lymphocytic leukemia/small lymphocytic lymphoma Diseases 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 230000008508 epithelial proliferation Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 230000037417 hyperactivation Effects 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 101150044508 key gene Proteins 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000013227 male C57BL/6J mice Methods 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- -1 naphthoquinone compounds Chemical class 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960002450 ofatumumab Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007119 pathological manifestation Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000000007 protein synthesis inhibitor Substances 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
-
- 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
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了一种以CK1ε基因或蛋白为靶点治疗杜韦利西布肠道毒性的药物,属于医药技术领域。所述药物通过下调CK1ε基因的表达或抑制CK1ε蛋白功能活性或抑制CK1ε蛋白累积逆转杜韦利西布肠道毒性,本发明为干预杜韦利西布引起的肠道毒性提供了新的治疗药物作用靶点。本发明提出E3泛素连接酶NEDD4L可以使CK1ε泛素化进而通过泛素蛋白酶体通路发生降解,为目前寻找药物引起肠道毒性的干预策略提供了新的方向,一定程度上解决临床上可用干预药物少、机制单一的现状。干预药物通过下调CK1ε逆转杜韦利西布肠道毒性,扩大了杜韦利西布临床应用价值。
Description
技术领域
本发明涉及医药技术领域,具体涉及CK1ε基因或CK1ε蛋白作为药物靶点在制备治疗杜韦利西布肠道毒性药物中的应用。
背景技术
杜韦利西布(Duvelisib)作为PI3K抑制剂的典型代表药物,能够同时抑制PI3K-δ和PI3K-γ的活性,适用于治疗复发性或难治性慢性淋巴细胞白血病和两种惰性非霍奇金淋巴瘤,患者无进展生存期长(16.4个月vs 9.1个月),总体反应率高(73.8%vs 45.3%),展现出极好的治疗效果,具有临床不可替代性。然而杜韦利西布临床使用时广泛存在严重甚至致死的肠道毒性,77.8%患者在使用杜韦利西布后出现肠道毒性,其中3级以上不良反应的发生率高达22.2%(Patel K,et al.Duvelisib for CLL/SLL and follicular non-Hodgkin lymphoma.Blood 2019;134:1573-7.;Davids MS,et al.Efficacy and Safetyof Duvelisib Following Disease Progression on Ofatumumab in Patients withRelapsed/Refractory CLL or SLL in the DUO Crossover Extension Study.ClinCancer Res 2020;26:2096-103.),因此肠道毒性被美国FDA标记为“黑框警告”。
目前临床缺乏可干预杜韦利西布肠道毒性的有效手段,造成这一问题的主要原因在于杜韦利西布引起肠道毒性的分子机制尚未完全阐明。鉴于该药物在临床治疗上对于复发性或难治性血液肿瘤患者具有重要且不可替代的作用,深入研究杜韦利西布引起肠道毒性的分子机制,发现可干预的靶点,寻找有效的干预策略,对于杜韦利西布等PI3K抑制剂的临床应用具有重要意义。
酪蛋白激酶1ε(Casein Kinase 1ε,CK1ε)可通过磷酸化多种蛋白质底物调节各种生理和病理状态下的细胞过程,在细胞周期调控中具有多重功能。CK1ε可通过磷酸化Disheveled(DVL)进而稳定β-连环蛋白,并以此激活经典Wnt信号通路,促进细胞增殖相关基因转录(Janovska P,et al.Targeting Casein Kinase 1(CK1)in HematologicalCancers.Int J Mol Sci2020;21.)。CK1ε还能通过磷酸化多个抑制性位点促进细胞周期正性调节蛋白cdc25A与SCF/β-TrCP结合,诱导其发生泛素蛋白酶体通路降解,进而抑制细胞周期进程(Piao S,et al.CK1 epsilon targets Cdc25A for ubiquitin-mediatedproteolysis under normal conditions and in response to checkpointactivation.Cell Cycle 2011;10:531-7.)。但目前CK1ε蛋白与杜韦利西布肠道毒性之间的关系尚无文献报道,有待进一步研究。
β,β-二甲基丙烯酰基紫草素(ALCAP2)是紫草素根中主要的活性成分,属于萘醌类化合物。现有的研究表明,β,β-二甲基丙烯酰基紫草素具有抗肿瘤作用。但目前尚无β,β-二甲基丙烯酰基紫草素治疗CK1ε相关疾病或损伤的报道。
发明内容
本发明的目的在于通过探究与杜韦利西布诱发肠道毒副作用相关的基因/蛋白,以此作为预防和治疗杜韦利西布肠道毒性的作用靶点,筛选用于治疗杜韦利西布肠道毒性副反应的药物,解决杜韦利西布用药存在的肠道毒副作用,扩大杜韦利西布的临床应用价值。
为实现上述目的,本发明采用如下技术方案:
本发明提供了以酪蛋白激酶1ε基因(CK1ε)或酪蛋白激酶1ε(CK1ε)为靶点在制备治疗杜韦利西布引发的肠道毒副作用的药物中的应用,所述杜韦利西布引发的肠道毒副作用表现包括小肠上皮细胞发生G0/G1期阻滞,所述药物为下调酪蛋白激酶1ε基因表达或靶向抑制酪蛋白激酶1ε功能或抑制酪蛋白激酶1ε累积的药物。
所述杜韦利西布引发的肠道毒副作用的病理表现还包括:肠上皮细胞增殖抑制、小肠绒毛缩短,排列紊乱、结肠腺体间距增加、基底部增厚。
具体的,人源酪蛋白激酶1ε基因的核苷酸序列如SEQ ID No.1所示,酪蛋白激酶1ε的氨基酸序列如SEQ ID No.2所示。
本发明研究发现,杜韦利西布会抑制小肠上皮细胞中CK1ε蛋白的降解,导致CK1ε蛋白在小肠上皮细胞中累积,且杜韦利西布作用与过表达CK1ε均会导致小肠上皮细胞发生G0/G1期阻滞,提示CK1ε蛋白的累积是杜韦利西布诱发肠道毒性的关键原因,CK1ε可能是预防或治疗杜韦利西布诱发肠道毒性的潜在药物作用靶点。因此,可将抑制CK1ε基因表达或靶向抑制CK1ε功能或抑制CK1ε蛋白累积作为干预杜韦利西布肠道毒性的手段。
本发明研究中采用RNA干扰技术下调小肠上皮细胞中CK1ε蛋白水平,进而逆转杜韦利西布引起的小肠上皮细胞G0/G1期阻滞,具体表现为使用siRNA后,显著下调杜韦利西布引起的小肠上皮细胞G0/G1期细胞比例升高、细胞周期阻滞相关蛋白p27升高,揭示了CK1ε基因是杜韦利西布导致肠道损伤的关键基因。因此,本发明为干预杜韦利西布引起的肠道毒性提供了新的药物作用靶点。
针对CK1ε基因开发相应的敲低该基因表达的药物制剂,所述药物通过下调CK1ε基因的表达实现治疗杜韦利西布引起肠道毒性副反应的目的。
优选的,所述药物包括靶向酪蛋白激酶1ε基因的siRNA。针对CK1ε基因的siRNA能够抑制CK1ε的表达,进而逆转杜韦利西布诱发的肠道毒性。
本发明还提供了CK1ε基因或CK1ε蛋白作为药物作用靶点在筛选治疗杜韦利西布肠道毒性药物中的应用。
具体的,利用细胞或动物模型筛选促进CK1ε降解的药物或靶向抑制CK1ε功能的药物,通过测定CK1ε蛋白活性或表达水平来评判待测药物活性。
本发明研究发现,合用CK1ε抑制剂或CK1ε泛素化促进剂可以显著下调由杜韦利西布引起的CK1ε累积并逆转杜韦利西布引起的小肠上皮细胞的细胞周期阻滞。因此,本发明提供了CK1ε抑制剂或CK1ε泛素化促进剂在干预杜韦利西布引起的肠毒性方面的新用途。
具体的,所述药物包括酪蛋白激酶1ε抑制剂或酪蛋白激酶1ε泛素化促进剂。靶向抑制CK1ε或CK1ε泛素化促进剂可显著降低杜韦利西布引起的小肠上皮细胞中CK1ε功能的过度激活。
优选的,所述CK1ε抑制剂为PF-4800567。
优选的,所述酪蛋白激酶1ε泛素化促进剂为NEDD4样E3泛素连接酶(NEDD4L)或NEDD4L促进剂。本发明研究发现NEDD4L是CK1ε的E3泛素连接酶,使CK1ε泛素化进而通过泛素蛋白酶体通路发生降解,从而降低CK1ε蛋白的累积,实现治疗杜韦利西布引起肠毒性副反应的目的。
本发明的另一个目的是提供NEDD4样E3泛素连接酶或NEDD4样E3泛素连接酶促进剂在制备治疗酪蛋白激酶1ε蛋白异常表达引起的疾病或损伤的药物中的应用,所述NEDD4样E3泛素连接酶或其促进剂促进酪蛋白激酶1ε泛素化从而降低酪蛋白激酶1ε的累积。
进一步的,所述疾病或损伤为杜韦利西布诱发的肠道毒性反应。所述NEDD4L促进剂可以通过与杜韦利西布联合用药下调杜韦利西布引起的CK1ε蛋白累积。
优选的,所述NEDD4L促进剂可以为但不限于β,β-二甲基丙烯酰基紫草素或其药学上可接受的盐。
本发明针对杜韦利西布引发的肠道毒性,提供了一种有效的治疗药物。动物实验结果表明,与杜韦利西布单用组相比,合用β,β-二甲基丙烯酰基紫草素可以逆转杜韦利西布引起的肠上皮细胞中NEDD4L蛋白水平下调以及CK1ε、p27的表达上调和G0/G1细胞周期阻滞,肠道损伤得以恢复。
优选的,所述药物中β,β-二甲基丙烯酰基紫草素与杜韦利西布的质量比为1.5-3:1。
所述药物还包括药学上可接受的辅料,包括填充剂、润湿剂、粘合剂、崩解剂或润滑剂。所述药物的制剂形式可以为固体制剂或液体制剂。优选的,所述药物的制剂形式为口服制剂。
本发明还提供了一种抗肿瘤联合用药物组合物,包括杜韦利西布和药学上可接受的载体形成的第一制剂,以及β,β-二甲基丙烯酰基紫草素或其盐和药学上可接受的载体形成的第二制剂。
本发明研究表明,β,β-二甲基丙烯酰基紫草素或其盐与杜韦利西布联用生物安全性好,不仅可以逆转杜韦利西布引起的肠道毒性,还可以增强杜韦利西布的抗肿瘤作用。
本发明还提供了所述的药物组合物在制备治疗淋巴瘤药物中的应用。所述淋巴瘤可以为但不限于:复发性或难治性慢性淋巴细胞白血病(CLL)和小淋巴细胞淋巴瘤(SLL)。
本发明具备的有益效果:
(1)本发明提供了CK1ε基因或CK1ε蛋白作为药物靶点在制备治疗杜韦利西布肠道毒性药物中的应用,所述药物通过下调CK1ε基因的表达或抑制CK1ε蛋白功能活性或抑制CK1ε蛋白累积逆转杜韦利西布肠道毒性。本发明为干预杜韦利西布引起的肠道毒性提供了新的治疗药物作用靶点。
(2)本发明首次提出了NEDD4L是CK1ε的E3泛素连接酶,使CK1ε泛素化进而通过泛素蛋白酶体通路发生降解,为目前寻找药物引起肠道毒性的干预策略提供了新的方向,一定程度上解决临床上可用干预药物少、机制单一的现状。
附图说明
图1为杜韦利西布和CK1ε过表达质粒对CK1ε蛋白和肠上皮细胞IEC-6的影响,其中A为流式细胞术检测杜韦利西布在不同作用浓度和作用时间下的细胞周期;B为westernblot检测CK1ε蛋白表达水平;C为western blot检测CK1ε过表达质粒的影响。
图2为CK1ε基因特异性敲低对杜韦利西布导致肠上皮细胞IEC-6增殖抑制的影响,其中A为western blot检测CK1ε蛋白和p27表达水平;B为流式细胞术检测细胞周期阻滞;C为免疫组化染色检测体内特异性敲低CK1ε对杜韦利西布导致肠上皮细胞增殖抑制的影响。
图3为CK1ε抑制剂对杜韦利西布导致肠上皮细胞增殖抑制的影响。
图4为杜韦利西布对肠上皮细胞CK1ε转录水平、蛋白水平和泛素化水平的影响,其中A为转录水平,B为蛋白水平,C为泛素化水平。
图5为NEDD4L对CK1ε蛋白表达水平的影响,其中A为western blot检测CK1ε蛋白和p27表达水平;B为免疫共沉淀实验检测泛素化水平。
图6为合用CK1ε泛素化促进剂β,β-二甲基丙烯酰基紫草素对杜韦利西布导致肠上皮细胞IEC-6细胞周期阻滞的影响,其中A为western blot检测CK1ε蛋白和p27表达水平;B为流式细胞术检测细胞周期阻滞。
图7为合用CK1ε泛素化促进剂β,β-二甲基丙烯酰基紫草素对杜韦利西布诱导小鼠肠道损伤的影响。
图8为肠道切片免疫组织化学染色法检测合用β,β-二甲基丙烯酰基紫草素对肠上皮细胞增殖、CK1ε蛋白累积的影响,其中A为免疫组化检测PCNA表达水平,B为免疫组化检测CK1ε蛋白表达水平。
图9为合用β,β-二甲基丙烯酰基紫草素对小鼠体重的影响。
图10为合用β,β-二甲基丙烯酰基紫草素对杜韦利西布抗肿瘤作用的影响。
具体实施方式
下面结合具体实施例对本发明做进一步说明。以下实施例仅用于说明本发明,不用来限制本发明的适用范围。在不背离本发明精神和本质的情况下,对本发明方法、步骤或条件所做的修改或替换,均属于本发明的范围。
下述实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,为可从商业途径得到的试剂和材料。
C57BL/6J小鼠购买自北京维通利华实验动物技术有限公司;2-羟丙基-β-环糊精购买自上海阿拉丁生化科技股份有限公司;大鼠小肠上皮细胞(IEC-6)购买自中国医学科学院基础医学研究所;CK1ε抗体购自Origene公司;GAPDH抗体购自杭州戴格生物技术有限公司;p27抗体购自Santa Cruz Biotechnology公司;PCNA抗体购买自杭州华安生物技术有限公司;siRNA购自上海吉玛制药有限公司,negative control(NC)正义链序列为5’-ACGUGACACGUUCGGAGAATT-3’;siCK1ε正义链5’-GCUAUGUGC UCAUGUACUUTT-3’和5’-GCAAUCUGGUAUACAUCAUTT-3’;转染试剂购自Polyplus Transfection公司;AAV9-NC和AAV9-sh CK1ε购买自上海吉凯基因科技有限公司。
杜韦利西布,CAS号1201438-56-3,化学名为(S)-3-(1-((9H-嘌呤-6-基)氨基)乙基)-8-氯-2-苯基-1(2H)-异喹啉酮,分子式为C22H17ClN6O,分子量为416.86,购买自上海皓元生物医药科技有限公司,结构式如下:
β,β-二甲基丙烯酰基紫草素(ALCAP2),CAS号为24502-79-2,分子式为C21H22O6,分子量为370.396,购买自南通经纬生物科技有限公司,结构式如下:
PF-4800567,CAS号为1188296-52-7,分子式为C17H18ClN5O2,分子量为359.81,购买自上海皓元生物医药科技有限公司,结构式如下:
实施例1
将大鼠小肠上皮细胞IEC-6以8万/孔的密度接种于12孔板中,24h稳定贴壁后,给与浓度梯度的杜韦利西布(0、2、4、8和16μM)作用24h或8μM杜韦利西布作用不同时间(0、3、6、9、12和24h),收取细胞,使用PI染色结合流式细胞术检测细胞周期。提取蛋白并定量,随后用western blot进行蛋白水平检测。
将大鼠小肠上皮细胞IEC-6以12万/孔的密度接种于12孔板中,24h稳定贴壁后,将CK1ε过表达质粒(原始载体:pCDNA3.0-3’HA,CK1ε编码序列的Gene ID:58822),以及阴性对照vector,通过jetPRIME转染试剂将其导入IEC-6细胞中,24h后收取细胞,提取蛋白并定量,随后用western blot进行蛋白水平检测。
结果如图1所示,流式细胞术结果说明相较于对照组,随着杜韦利西布作用浓度和时间的增加,会显著增加G0/G1期细胞比例(图1A)。用western blot进行蛋白水平检测,与对照组相比,随着作用浓度和时间增加,杜韦利西布会显著上调IEC-6中CK1ε蛋白水平(图1B),提示杜韦利西布会引起细胞周期阻滞和CK1ε蛋白累积。在细胞内过表达CK1ε后,细胞周期阻滞相关蛋白p27水平显著增加(图1C),提示CK1ε可能是杜韦利西布引起细胞周期阻滞的关键蛋白。
实施例2
大鼠小肠上皮细胞IEC-6以8万/孔的密度接种于12孔板中,24h稳定贴壁后,将靶向CK1ε的siRNA(正义链为5’-GCUAUGUGCUCAUGUA CUUTT-3’,5’-GCAAUCUGGUAUACAUCAUTT-3’)以及阴性对照NC(正义链为5’-ACGUGACACGUUCGGAGAATT-3’),利用jetPRIME转染试剂将其导入IEC-6细胞中,表达稳定后,给予8μM杜韦利西布作用24h后收取细胞,使用PI染色结合流式细胞术检测细胞周期;提取蛋白并定量,随后用western blot进行蛋白水平检测。
20只C57BL/6雄性小鼠分为AAV9-NC组和AAV9-sh CK1ε组,每组10只,通过灌肠方式给予每只小鼠1×1011v.g病毒量,体积为100μL。小鼠经3周稳定培养后,将AAV9-NC组和AAV9-sh CK1ε组两组小鼠再次随机分组为:AAV9-NC-vehicle组;AAV9-NC-duvelisib组;AAV9-sh CK1ε-vechile组;AAV9-sh CK1ε-duvelisib组。每组5只小鼠。给药组每日灌胃给予10mg/kg的杜韦利西布,对照组每日灌胃给予10μL/g标准的20%环糊精,持续8周。解剖取肠道组织,通过免疫组化染色检测PCNA表达水平。
如图2所示,在IEC-6细胞中敲低CK1ε后再给予杜韦利西布可以逆转药物引起的p27和CK1ε蛋白水平上升(图2A),G0/G1细胞周期阻滞(图2B),说明靶向CK1ε的siRNA可以通过逆转杜韦利西布引起的CK1ε蛋白累积从而缓解细胞周期阻滞。在小鼠肠道特异性敲低CK1ε后再给予杜韦利西布可以逆转药物引起的肠上皮细胞增殖抑制(图2C)。
实施例3
大鼠小肠上皮细胞IEC-6以8万/孔的密度接种于12孔板中,24h稳定贴壁后,合用CK1ε抑制剂PF-4800567(0.5μM)和杜韦利西布(8μM)共同作用24h后收取细胞,提取蛋白并定量,随后用western blot进行蛋白水平检测。
如图3所示,CK1ε抑制剂PF-4800567可以逆转杜韦利西布引起的细胞周期阻滞相关蛋白p27水平的上升。
实施例4
大鼠小肠上皮细胞IEC-6以16万/孔的密度接种于6孔板中,24h稳定贴壁后,给与浓度梯度的杜韦利西布(0、2、4、8和16μM)作用24h后,收取细胞提取RNA,随后用qRT-PCR进行转录水平检测。
人胚肾细胞293T以200万/皿的密度接种于细胞培养皿中,24h稳定贴壁后,外源性过表达CK1ε和泛素(原始载体:pCDNA3.0-3'His,Ubc编码序列的Gene ID:50522)后,经杜韦利西布作用后,通过免疫沉淀富集CK1ε,检测CK1ε泛素化情况。
如图4所示,IEC-6细胞中CK1ε转录水平没有显著差异(图4A),在蛋白合成抑制剂放线菌酮的作用下,发现杜韦利西布可延长CK1ε的半衰期(图4B),提示杜韦利西布可以抑制CK1ε的降解。免疫共沉淀结果说明杜韦利西布可以显著降低CK1ε的泛素化水平(图4C)。以上结果提示杜韦利西布可能通过抑制CK1ε发生泛素蛋白酶体通路降解进而上调CK1ε的蛋白水平。
实施例5
大鼠小肠上皮细胞IEC-6以12万/孔的密度接种于12孔板中,24h稳定贴壁后,将NEDD4L(原始载体:pCDNA3.0-3'Flag,NEDD4L编码序列的Gene ID:291553)过表达质粒以及阴性对照vector,通过jetPRIME转染试剂将其导入IEC-6细胞中,24h后收取细胞,提取蛋白并定量,随后用western blot进行蛋白水平检测。
采用脂质体转染技术,构建NEDD4L,泛素以及CK1ε过表达的293T细胞,通过免疫共沉淀实验检测二者的相互结合作用及CK1ε的泛素化水平变化。
如图5所示,IEC-6细胞中过表达NEDD4L可缓解杜韦利西布所导致的p27和CK1ε蛋白水平的增加。免疫共沉淀的结果显示CK1ε的多聚泛素化在NEDD4L存在的情况下得到了增强。上述研究共同说明NEDD4L可以促进CK1ε的多聚泛素化并使其发生降解。
实施例6
大鼠小肠上皮细胞IEC-6以8万/孔的密度接种于12孔板中,24h稳定贴壁后,β,β-二甲基丙烯酰基紫草素(1、2μM)和杜韦利西布(8μM)共同作用24h后收取细胞,使用PI染色结合流式细胞术检测细胞周期;提取蛋白并定量,随后用western blot进行蛋白水平检测。
60只雄性C57BL/6J小鼠,随机分为对照组、杜韦利西布组,低剂量β,β-二甲基丙烯酰基紫草素组,杜韦利西布+低剂量β,β-二甲基丙烯酰基紫草素组,高剂量β,β-二甲基丙烯酰基紫草素组,杜韦利西布+高剂量β,β-二甲基丙烯酰基紫草素组,每组1只,通过灌胃的方式给药。杜韦利西布的剂量为10mg/kg/day,低剂量β,β-二甲基丙烯酰基紫草素的剂量为15mg/kg/day,高剂量β,β-二甲基丙烯酰基紫草素的剂量为30mg/kg/day,对照组给予20%的环糊精溶剂,连续给药8周。称量小鼠体重,剖取小肠和结肠组织,测量长度,并对小肠及结肠组织进行包埋、切片、HE染色和免疫组化染色。
如图6所示,β,β-二甲基丙烯酰基紫草素可以逆转杜韦利西布引起的NEDD4L蛋白水平下调,以及CK1ε、p27的表达上调。流式细胞术数据显示,β,β-二甲基丙烯酰基紫草素可以逆转杜韦利西布引起的G0/G1细胞周期阻滞。
如图7所示,对肠道组织进行HE染色,给予杜韦利西布引起小鼠小肠绒毛缩短、排列紊乱,结肠腺体间距增加、基底部增厚的损伤在合用β,β-二甲基丙烯酰基紫草素后得以恢复正常。
如图8所示,对肠道组织切片通过免疫组化检测PCNA表达,给予杜韦利西布所引起的肠上皮细胞增殖抑制在合用β,β-二甲基丙烯酰基紫草素后得到明显改善(图8A)。对肠道切片进行免疫组织化学染色,检测CK1ε蛋白水平的变化。合用β,β-二甲基丙烯酰基紫草素可以显著降低杜韦利西布引起的CK1ε蛋白水平增加(图8B)。
如图9所示,合用β,β-二甲基丙烯酰基紫草素对小鼠的体重无明显影响。
实施例7
人慢性淋巴B细胞白血病细胞MEC-1以8000/孔的密度接种于96孔板中,24h稳定后,给予β,β-二甲基丙烯酰基紫草素(1、2μM)和杜韦利西布(4μM)共同作用48h后,每孔加入20μL的CCK-8试剂,孵育2-3h后,在450nm下检测吸光度,计算细胞存活率。
如图10所示,合用1μM的β,β-二甲基丙烯酰基紫草素对杜韦利西布的抗肿瘤作用无影响,合用2μM的β,β-二甲基丙烯酰基紫草素可以增强杜韦利西布的抗肿瘤作用。
Claims (10)
1.以酪蛋白激酶1ε基因或酪蛋白激酶1ε为靶点在制备治疗杜韦利西布引发的肠道毒副作用的药物中的应用,其特征在于,所述杜韦利西布引发的肠道毒副作用表现包括小肠上皮细胞发生G0/G1期阻滞,所述药物为下调酪蛋白激酶1ε基因表达或靶向抑制酪蛋白激酶1ε功能或抑制酪蛋白激酶1ε累积的药物。
2.如权利要求1所述的应用,其特征在于,所述杜韦利西布引发的肠道毒副作用表现还包括肠上皮细胞增殖抑制、小肠绒毛缩短,排列紊乱、结肠腺体间距增加、基底部增厚。
3.如权利要求1所述的应用,其特征在于,所述酪蛋白激酶1ε基因的核苷酸序列如SEQID No.1所示,所述酪蛋白激酶1ε的氨基酸序列如SEQ ID No.2所示。
4.如权利要求3所述的应用,其特征在于,所述药物为靶向酪蛋白激酶1ε基因的siRNA或酪蛋白激酶1ε抑制剂或酪蛋白激酶1ε泛素化促进剂。
5.如权利要求4所述的应用,其特征在于,所述酪蛋白激酶1ε泛素化促进剂为NEDD4样E3泛素连接酶或NEDD4样E3泛素连接酶促进剂。
6.NEDD4样E3泛素连接酶或NEDD4样E3泛素连接酶促进剂在制备治疗酪蛋白激酶1ε蛋白异常表达引起的疾病或损伤的药物中的应用,其特征在于,所述NEDD4样E3泛素连接酶或其促进剂促进酪蛋白激酶1ε泛素化从而降低酪蛋白激酶1ε的累积。
7.如权利要求6所述的应用,其特征在于,所述疾病或损伤为杜韦利西布诱发的肠道毒性反应。
8.如权利要求6所述的应用,其特征在于,所述NEDD4样E3泛素连接酶促进剂为β,β-二甲基丙烯酰基紫草素或其药学上可接受的盐。
9.一种抗肿瘤联合用药物组合物,其特征在于,包括杜韦利西布和药学上可接受的载体形成的第一制剂,以及β,β-二甲基丙烯酰基紫草素或其盐和药学上可接受的载体形成的第二制剂。
10.如权利要求9所述的药物组合物在制备治疗淋巴瘤药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310784225.XA CN116850288A (zh) | 2023-06-29 | 2023-06-29 | 一种以CK1ε基因或蛋白为靶点治疗杜韦利西布肠道毒性的药物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310784225.XA CN116850288A (zh) | 2023-06-29 | 2023-06-29 | 一种以CK1ε基因或蛋白为靶点治疗杜韦利西布肠道毒性的药物 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116850288A true CN116850288A (zh) | 2023-10-10 |
Family
ID=88224394
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310784225.XA Pending CN116850288A (zh) | 2023-06-29 | 2023-06-29 | 一种以CK1ε基因或蛋白为靶点治疗杜韦利西布肠道毒性的药物 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116850288A (zh) |
-
2023
- 2023-06-29 CN CN202310784225.XA patent/CN116850288A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20220143064A1 (en) | Tau antisense oligomers and uses thereof | |
US10201556B2 (en) | Combination for use in treating diseases or conditions associated with melanoma, or treating diseases or conditions associated with activated B-raf pathway | |
Mao et al. | Neddylation inhibitor MLN4924 suppresses cilia formation by modulating AKT1 | |
ITMI952539A1 (it) | Classe di oligonucleotidi fosfodiesterici ad attivita' citotossica composizioni farmaceutiche che li contengono e loro uso | |
Morihiro et al. | Floxuridine oligomers activated under hypoxic environment | |
CN109646680B (zh) | 一种治疗kras突变型肠癌的联合用药物 | |
US8026225B2 (en) | Short nucleic acid molecule-mediated modulation of Aurora B kinase expression and combinations for use in anticancer therapy | |
US8748592B1 (en) | siRNA for inhibition of OTUB1 expression and pharmaceutical composition containing the same | |
Dai et al. | MicroRNA-22 regulates thyroid cell growth and lipid accumulation via IL6R | |
EP2742950B1 (en) | Pharmaceutical composition containing fibulin-3 protein as an active ingredient for inhibiting the growth of cancer stem cells | |
CN116850288A (zh) | 一种以CK1ε基因或蛋白为靶点治疗杜韦利西布肠道毒性的药物 | |
KR101541974B1 (ko) | miR29b를 포함하는 신경줄기세포의 신경세포로의 분화 촉진용 조성물 및 방법 | |
KR101413581B1 (ko) | miR-186, miR-216b, miR-337-3p 및 miR-760를 유효성분으로 포함하는 암의 예방 또는 치료용 조성물 | |
Cellai et al. | Specific PAF antagonist WEB‐2086 induces terminal differentiation of murine and human leukemia cells | |
KR20150137473A (ko) | USP15의 발현을 저해하는 siRNA 및 이를 포함하는 약제학적 조성물 | |
Li et al. | The optimal outcome of suppressing Ewing sarcoma growth in vivo with biocompatible bioengineered miR-34a-5p prodrug | |
Ozkurt et al. | miR663 Prevents Epo Inhibition Caused by TNF‐Alpha in Normoxia and Hypoxia | |
KR102591642B1 (ko) | 종양 전이의 약물 치료를 위한 표적 및 이의 응용 | |
US20190015473A1 (en) | Targeting the hdac2-sp3 complex to enhance synaptic funcation | |
Wu et al. | Adiponectin signals through Adiponectin Receptor 1 to reverse imatinib resistance in K562 human chronic myeloid leukemia cells | |
Wang et al. | Inhibition of the miR-155 and protein prenylation feedback loop alleviated acute graft-versus-host disease through regulating the balance between T helper 17 and Treg cells | |
EP3101133B1 (en) | Sirna in tandem expression and uses thereof in treating chronic lymphocytic leukemia | |
CN110420328B (zh) | Syt14抑制剂在制备肺癌治疗药物中的用途 | |
US10117903B1 (en) | Method for regulating cancer stem cell growth by inhibiting phosphorylation of 120th threonine residue of TSPYL5 protein, a composition containing the peptide sequence functioning to inhibit the phosphorylation and a use thereof | |
CN115261469B (zh) | Brd9在慢性淋巴细胞白血病诊治中的应用 |
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 |