Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
  • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
  • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
  • C07K14/4702—Regulators; Modulating activity
  • C07K14/4705—Regulators; Modulating activity stimulating, promoting or activating activity
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• This invention relates to stabilized polypeptides and methods of treating a disease, disorder, or condition such as cancer.
• an alkyl group has 1 to 4 carbon atoms (“Ci_ 4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1 -2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”).
• alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents. In certain embodiments, the alkyl group is an unsubstituted Ci-10 alkyl (e.g., -CH 3 ). In certain embodiments, the alkyl group is a substituted Ci_io alkyl.
• each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents.
• the heteroalkyl group is an unsubstituted heteroCno alkyl.
• the heteroalkyl group is a substituted heteroCi_io alkyl.
• an alkenyl group has 2 to 5 carbon atoms ("C 2 _5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2 ⁇ t alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2 _ 3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms ("C 2 alkenyl”).
• the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1- butenyl).
• a heteroaikenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC? ⁇ alkenyl"). In some embodiments, a heteroaikenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroCi-s alkenyl"). In some embodiments, a heteroaikenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -7 alkenyl").
• Carbocyclyl or “carbocyclic” refers to a radical of a non- aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C3-10
• each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents.
• the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
• a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl").
• a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
• the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
• aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14 aryl”).
• an aryl group has 6 ring carbon atoms ("Ce aryl”; e.g., phenyl).
• 5- membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
• Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
• Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
• substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
• the present invention contemplates any and ail such combinations in order to arrive at a stable compound.
• heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
• thiol refers to the group -SH.
• amino refers to the group -NH 2 .
• substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino, as defined herein. In certain embodiments, the "substituted amino” is a monosubstituted amino or a disubstituted amino group.
• nitrogen protecting groups include, but are not limited to, phenothiazinyl- (lO)-acyl derivative, N'- )-toluenesulfonylaminoacyl derivative, N -phenyiaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl- 3-oxazolin-2-one, N-phthalimide, A ⁇ dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1 , 1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l ,3-dimethyl-l ,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl- l,3,5-triazacyclohexan
• Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
• oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butyithiomethyl,
• alkanesulfonyloxy arenesulfonyloxy, alkyi-carbonyloxy (e.g. , acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,0-dimethylhydroxylamino, pixyl, haloformates, -NO?,
• amino acid refers to a molecule containing both an amino group and a carboxvl group.
• Amino acids include alpha-amino acids and beta-amino acids, the structures of which are depicted b s an alpha amino acid.
• Suitable amino acids include, without limitation, natural alpha-amino acids such as D- and L-isomers of the 20 common naturally occurring alpha-amino acids found in peptides (e.g., A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V, as provided in Table 1 depicted below), unnatural alpha-amino acids (as depicted in Tables 2 and 3 below), natural beta-amino acids (e.g., beta-alanine), and unnnatural beta-amino acids.
• natural alpha-amino acids such as D- and L-isomers of the 20 common naturally occurring alpha-amino acids found in peptides (e.g., A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V, as provided in Table 1 depicted below
• Amino acids used in the construction of peptides of the present invention may be prepared by organic synthesis, or obtained by other routes, such as, for example, degradation of or isolation from a natural source.
• the formula -[XAA]- corresponds to the natural and/or unnatural amino acids having the following formulae:
• Exemplary unnatural alpha-amino acids R and R' are equal to:
• Peptide stapling refers to cross-linking side chains of a polypeptide chain by covalently joining olefin moieties (i.e.., "stapled together") using a ring-closing metathesis (RCM) reaction.
• RCM ring-closing metathesis
• Peptide stitching encompasses multiple “staples” in a single polypeptide chain to provide a multiply stapled (also known as "stitched") polypeptide (see U.S. Patents 7,192,713 and 7,786,072, and International PCT Publications WO2008/121767 and
• Suitable olefin metathesis catalyst include, but are not limited to, Schrock catalyst, Grubbs Catalyst 1st generation, or benzylidene- bis(tricyclohexylphosphine)dichlororuthenium, Grubbs Catalyst 2nd Generation, or benzylidene[l,3-bis(2,4,6-tiimethylphenyl)-2-midazolidinylidene]dichloro- (tricyclohexylphosphine)ruthenium, and Hoveyda-Grubbs Catalyst 2nd Generation, or 1,3 - bis-(2,4,6-trimethylphenyl)-2-imidazoiidinylidene)dichloro(o-isopropoxyp- phenylmethylene)ruthenium.
• inhibitors refer to the ability of a polypeptide to reduce, slow, halt, or prevent the activity of a particular biological process involving STAT in a cell relative to vehicle.
• R X! is hydrogen, a leaving group, or -OR X2 , wherein R X2 is hydrogen; optionally substituted alkyl; optionally substituted alkyl; optionally substituted alkenyi; optionally substituted alkynyl; optionally substituted carbocvclyl; optionally substituted heterocvclyl; optionally substituted aryl; optionally substituted heteroaryl; an oxygen protecting group;
• each instance of R b is, independently, a suitable amino acid side chain; hydrogen; cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; cyclic or acyclic, substituted or unsubstituted acyl; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; cyano; isocyano; halo; or nitro;
• each instance of R c is, independently, -R E , -OR E , -N(R E ) 2 , or -SR E , wherein each instance of R E is, independently, hydrogen, cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; a resin; a suitable hydroxyl, amino, or thiol protecting group; or two R E groups together form a substituted or unsubstituted 5- to 6- membered heterocyclic or heteroaromatic ring;
• W is O, S, or NR Wi ;
• R W2 is hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyi; optionally substituted carbocyclyl; optionally substituted heterocyclvl; optionally substituted aryl; optionally substituted heteroaryl, or two R 3 ⁇ 4 ' 2 groups are joined to form an optionally substituted cyclic moiety;
• each instance of zl and z2 is, independently, an integer between 2 to 30;
• each instance of j is, independently, an integer between 1 to 10;
• each instance of s and t is, independently, an integer between 0 and 100;
• the invention provides a stabilized polypeptide precursor of Formula (II):
• each instance of R b is, independently, a suitable amino acid side chain; hydrogen; cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; cyclic or acyclic, substituted or unsubstituted acyl; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; cyano; isocyano; halo; or nitro;
• each instance of R c is, independently, hydrogen; cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; cyclic or acyclic, substituted or unsubstituted acyl; substituted or unsubstituted hydroxy!; substituted or unsubstituted thiol; substituted or unsubstituted amino; cyano; isocyano; halo; or nitro;
• each instance of R e is, independently, -R E , -OR E , -N(R E ) 2 , or -SR E , wherein each instance of R E is, independently, hydrogen, cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; a resin; a suitable hydroxyl, amino or thiol protecting group; or two R E groups together form a substituted or unsubstituted 5- to 6- membered heterocyclic or heteroaromatic ring;
• each instance of R f is, independently, hydrogen, cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; a resin; a suitable amino protecting group; a label optionally joined by a linker, wherein the linker is selected from cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkenylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkynylene; cyclic or acyclic, branched or unbranched,
• R 3 ⁇ 4 2 is hydrogen, optionally substituted alkyl; optionally substituted alkenyl;
• each instance of XAA is, independently, a natural or unnatural amino acid
• each instance of y and z are, independently, an integer between 2 to 8;
• each instance of zl and z2 is, independently, an integer between 2 to 30;
• j is, independently, an integer between 1 to 10;
• p is an integer between 0 to 10;
• the stabilized polypeptide formed by RCM and/or click chemistry reaction from the precursor of Formula (II) is of Formula (III):
• each instance of K, L s , L 2 , and M is, independently, a bond, cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkenylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkynylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroalkylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroalkenylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroalkynyiene; substituted or unsubstituted arylene; substituted or unsubstituted heteroarylene; or substituted or unsubstituted acy
• each instance of R e is, independently, -R E , -OR E , -N(R E ) 2 , or -SR E , wherein each instance of R E is, independently, hydrogen, cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; a resin; a suitable hydroxyl, amino, or thiol protecting group; or two R E groups together form a substituted or unsubstituted 5- to 6- membered heterocyclic or heteroaromatic ring;
• each instance of XAA is, independently, a natural or unnatural amino acid
• each instance of y and z is, independently, an integer between 2 to 8;
• each instance of zl and z2 is, independently, an integer between 2 to 30;
• each instance of p is, independently, an integer between 0 to 10;
• R 3 ⁇ 4 ⁇ is hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyi; optionally substituted carbocyclyl; optionally substituted heterocyclyl; optionally substituted aryl; optionally substituted heteroaryl, or two R 3 ⁇ 4'2 groups are joined to form a optionally substituted cyclic moiety.
• R ft is hydrogen.
• R 3 ⁇ 4 2 is halogen.
• R 3 ⁇ 4 2 is F.
• R 3 ⁇ 42 is CI.
• R 3 ⁇ 4 ⁇ is Br.
• R W2 is I.
• A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
• H mZ corresponds to a triple bond.
• u, v and q are, independently, 0, 1, 2, 3, or 4.
• each instance of K, Li, L 2 , and M independently, correponds to a bond, cyclic or acyclic, branched or unbranched, substituted or unsubstituted Ci-20 alkylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted Ci -2 o alkenylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted Ci-20 alkynvlene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted C 1-2 o heteroalkylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted Ci-2 0 heteroaikenylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted Q.
• heteroaikenylene cyclic or acyclic, branched or unbranched, substituted or unsubstituted Ci-15 heteroaikynylene; substituted or unsubstituted C MS arylene; substituted or unsubstituted CMS heteroarylene; or substituted or unsubstituted C MS acylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted CMO alkylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted CMO alkenylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted CMO alkynylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted CMO heteroalkylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted C MO heteroaikenylene;
• M is acyclic. In certain embodiments, M is unbranched. In certain embodiments, M is unsubstituted. In certain embodiments, M is a bond. In certain embodiments, M is not a bond.
• K and Li are the same. In certain embodiments, K and Lj are different. In certain embodiments, K and L 2 are the same. In certain embodiments, K and L 2 are different.
• all of K, Li, L 2 , and M are the same. In certain embodiments, all of K, Li, L 2 , and M are different.
• R k is unsubstituted alkyl; Li is straight chain unsubstituted alkylene; and R c is straight chain unsubstituted alkyl (e.g. methyl or ethyl).
• Lj is straight chain unsubstituted CMO alkylene.
• Li is straight chain unsubstituted C2-1 0 alkylene.
• L] is straight chain unsubstituted Cs-io alkylene.
• Li is straight chain unsubstituted C4-10 alkylene.
• a polypeptide having a stabilized alpha helix and a stabilized beta hairpin comprising the steps of:
• methionine (M), alanine (A), leucine (L), glutamate (E), and lysine (K) all have especially high alpha-helix forming propensities.
• proline (P) and glycine (G) are alpha-helix disruptors.
• the coupling step further comprises a suitable base.
• suitable bases include, but are not limited to, potassium carbonate, potassium hydroxide, sodium hydroxide, tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, triethylbenzylammonium hydroxide, 1 ,1,3,3-tetramethylguanidine, 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine, diisopropylethylamine (DIPEA), tetramethylethylenediamine (TMEDA), pyridine (Py), 1,4- diazabicyclo[2.2.2]octane (DABCO), N,N-dimethylamino pyridine (DMAP), or triethylamine (NEt 3 ).
• DIPEA diisopropylethylamine
• TEDA tetramethylethylenediamine
• DMAP 1,4- diazabic
• the coupling step is carried out in a suitable medium.
• a suitable medium is a solvent or a solvent mixture that, in combination with the combined reacting partners and reagents, facilitates the progress of the reaction therebetween.
• a suitable solvent may solubilize one or more of the reaction components, or, alternatively, the suitable solvent may facilitate the suspension of one or more of the reaction components; see generally, March 's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M.B. Smith and J. March, 5 th Edition, John Wiley & Sons, 2001 , and Comprehensive Organic Transformations, R.C. Larock, 2 nd Edition, John Wiley & Sons, 1999, the entire contents of each of which are incorporated herein by reference.
• the coupling step is conducted at suitable temperature, such as between about 0 °C and about 100 °C.
• RCM catalysts in addition to RCM catalysts, other reagents capable of promoting carbon-carbon bond formation can also be utilized.
• other reactions that can be utilized include, but are not limited to palladium coupling reactions, transition metal catalyzed cross coupling reactions, pinacol couplings (terminal aldehydes), hydrozirconation (terminal alkynes), nucleophilic addition reactions, and NHK (Nozaki- Hiyama-Kishi (Furstner et al., J. Am. Chem. Soc. 1996, 118, 12349)) coupling reactions.
• the appropriate reactive moieties are first incorporated into desired amino acids or unnatural amino acids, and then the peptide is subjected to reaction conditions to effect "stitching" and subsequent stabilization of a desired secondary structure.
• compositions comprising a polypeptide as described herein, and optionally a pharmaceutically acceptable carrier.
• compositions comprise compositions for therapeutic use as well as cosmetic compositions. Such compositions may optionally comprise one or more additional therapeutically active agents.
• a method of administering a pharmaceutical composition comprising an inventive pharmaceutical composition to a subject in need thereof is provided. In some embodiments, the inventive composition is administered to humans.
• the present invention provides a method of inducing apoptosis of a cell in a biological sample, the method comprising administering, contacting, or applying an effective amount of a provided polypeptide, or pharmaceutical composition thereof, to the biological sample.
• cystadenocarcinoma medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicular cancer, small cell lung carcinoma, non-small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, meduiloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, and Kaposi's sarcoma.
• Exemplary hematopoietic neoplastic disorders include, but are not limited to, disorders involving hyperplastic/neoplastic cells of hematopoietic origin, e.g., arising from myeloid, lymphoid or erythroid lineages, or precursor cells thereof.
• the disorders arise from poorly differentiated acute leukemias, e.g., erythroblastic leukemia and acute megakaryoblastic leukemia.
• malignant lymphomas include, but are not limited to non-Hodgkin lymphoma and variants thereof, peripheral T-ceil lymphomas, adult T cell leukemia/lymphoma (ATL), cutaneous T- cell lymphoma (CTCL), large granular lymphocytic leukemia (LGF), Hodgkin's disease, and eed-Stemberg disease.
• Exemplary proliferative disorders of the colon include, but are not limited to, nonneoplastic polyps, adenomas, familial syndromes, colorectal carcinogenesis, colorectal carcinoma, and carcinoid tumors.
• Exemplary proliferative disorders of the ovary include, but are not limited to, ovarian tumors such as, tumors of coelomic epithelium, serous tumors, mucinous tumors, endometeriod tumors, clear cell adenocarcinoma, cystadenofibroma, brenner tumor, surface epithelial tumors; germ cell tumors such as mature (benign) teratomas, monodermal teratomas, immature malignant teratomas, dysgenninoma, endodermal sinus tumor, choriocarcinoma; sex cord-stomai tumors such as, granulosa-theca ceil tumors,

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• 2014
  • 2014-10-01 EP EP14850442.6A patent/EP3052520A4/en not_active Withdrawn
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