WO2016097773A1 - Antagonistes des iap thérapeutiques pour traiter des troubles prolifératifs - Google Patents

Antagonistes des iap thérapeutiques pour traiter des troubles prolifératifs Download PDF

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WO2016097773A1
WO2016097773A1 PCT/GB2015/054105 GB2015054105W WO2016097773A1 WO 2016097773 A1 WO2016097773 A1 WO 2016097773A1 GB 2015054105 W GB2015054105 W GB 2015054105W WO 2016097773 A1 WO2016097773 A1 WO 2016097773A1
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jak
iap antagonist
proliferative disorder
signaling
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Richard Bryan LOCK
Jennifer RICHMOND
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Children's Cancer Institute
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    • 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
    • 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
    • A61K31/415—1,2-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
    • A61K31/495—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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • This invention is in the field of compositions and methods to treat proliferative disorders including cancers.
  • Inhibitors of Apoptosis Proteins are naturally occurring intra-cellular proteins that suppress caspase-dependent apoptosis.
  • Second mitochondria- derived activator of caspases (Smac), also known as DIABLO, is an intracellular protein that functions to antagonize, i.e., inhibit, the activity of lAPs.
  • Smac and lAPs function together to maintain the viability of healthy cells.
  • lAPs are not adequately antagonized and therefore prevent apoptosis and cause or exacerbate abnormal proliferation and survival.
  • Smac mimetics are synthetic small molecules that mimic the structure and IAP antagonist activity of the four N-terminal amino acids of Smac.
  • the Smac mimetics antagonize lAPs, causing an increase in apoptosis among abnormally proliferating cells.
  • Various Smac mimetics are in development for use in the treatment of proliferative disorders. Smac mimetics have also been shown to promote apoptosis in chronically infected cells while sparing uninfected cells and are in development for treatment of viral and other infections.
  • STATs Signal Transducer and Activator of Transcription, or Signal Transduction And Transcription.
  • Activated STATs dissociate from the receptor and translocate from the cytoplasm to the nucleus, where they regulate transcription of selected genes.
  • JAKs have been associated with certain cancers and other disorders. Approximately 50% of pediatric patients with acute lymphoblastic leukemia (ALL) and the Philadelphia chromosome (or similar translocations) harbor mutations in JAKs.
  • ALL acute lymphoblastic leukemia
  • Philadelphia chromosome or similar translocations harbor mutations in JAKs.
  • the JAK2 V617F mutation has been associated with myeloproliferative disorders, e.g., polycythemia vera (PV), primary or essential thrombocythemia (ET), and myeloid metaplasia with myelofibrosis (MMM).
  • PV polycythemia vera
  • ET primary or essential thrombocythemia
  • MMMM myeloid metaplasia with myelofibrosis
  • JAKAFI ruxolitinib phosphate
  • JAKAFI is an example of a JAK1/2 inhibitor approved in the U.S. for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera, myelofibrosis, and post-essential thrombocythemia myelofibrosis.
  • This invention in one aspect, relates to a method of treating a mammalian subject, e.g., a human, or a (companion) animal, a food animal, or a sporting animal, suffering from or having a proliferative disorder (e.g. associated with a Janus Kinase (JAK) mutation), such as by administering an IAP antagonist (to the subject).
  • a mammalian subject e.g., a human, or a (companion) animal, a food animal, or a sporting animal
  • a proliferative disorder e.g. associated with a Janus Kinase (JAK) mutation
  • aspects of the invention include, among others, treatment of proliferative disorders, such as those associated with aberrant (e.g. JAK) signaling, e.g., with one or more JAK mutations, for example with a combination of an IAP antagonist and a JAK inhibitor.
  • JAK aberrant
  • the invention includes a method of treating (a subject presenting with one or more symptoms of) a proliferative disorder associated with aberrant JAK signaling, said method comprising: (a) determining if the subject's disorder is associated with aberrant JAK signaling, such as but not limited to obtaining or having obtained a sample of abnormally proliferating cells from the subject and optionally determining or having determined if some or all of the sample of abnormally proliferating cells have a JAK mutation such as by genotyping/phenotyping (or having
  • the IAP antagonist has the following general chemical formula:
  • R5a and R5b are the same and are an alkyl, an alkyl substituted with hydroxyl, or an alkyl substituted with alkoxy; where R7a and R7b are the same and are alkyl; where R8a and R8b are the same and are selected from H, or alkyl; where R3a and R3b are the same and are selected from H, or hydroxy; where R12a, and R12b are both H; where R13a and R13b are the same and are selected from H or F; and where, R14a and R14b are both H.
  • Such compounds are described, e.g., in US7517906 and US8022230.
  • the IAP antagonist is birinapant, which has the chemical name: N- ⁇ 1 S-[2R-(6,6'-difluoro-3'- ⁇ 4S- hydroxy-1 -[2S-(2S-methylamino-propionylamino)-butyryl]-pyrrolidin-2R-ylmethyl ⁇ - 1 H, 1 'H-[2,2']biindolyl-3-ylmethyl)-4S-hydroxy-pyrrolidine-1 -carbonyl]-propyl ⁇ -2S- methylamino-propionamide and which has the chemical formula:
  • R5 is -CH2CH3, or a pharmaceutically acceptable salt thereof.
  • Birinapant is described as Compound 15 in US Patent 8603816.
  • a method of treating a subject presenting with one or more symptoms of a proliferative disorder associated with a mutation in a Janus Kinase (JAK) gene comprising:
  • a method of inhibiting the proliferation of abnormally proliferating cells comprising treating the cells with an IAP antagonist.
  • a method for identifying a cancer in a subject comprising determining or having
  • a method of treating a cancer in a subject in which subject some or all of the cancerous cells have a mutation in one or both copies of a JAK gene, said method optionally comprising (internally) administering to the subject an effective amount of an IAP antagonist.
  • an IAP antagonist for the manufacture of a medicament for use in a method of treating a subject presenting with or having one or more symptoms of a proliferative disorder associated with aberrant JAK signaling, said method optionally comprising:
  • determining if the subject's disorder is associated with aberrant JAK signaling such as but not limited to obtaining or having obtained a sample of abnormally proliferating cells from the subject and determining or having determined if some or all of the sample of abnormally proliferating cells have a JAK mutation such as by genotyping/phenotyping (or having
  • IAP antagonist for the treatment of a proliferative disorder, e.g. associated with aberrant JAK signaling, as described above (and as further described below).
  • the IAP antagonist copmrises a Smac mimetic.
  • the Smac mimetic comprises a bivalent Smac mimetic.
  • the Smac mimetic is characterized as (i) not inhibiting XIAP E3 ubiquitin ligase activity or as only poorly inhibiting XIAP E3 ubiquitin ligase activity; (ii) not inhibiting or poorly inhibiting NOD (i.e., NOD1/2) signaling; and/ or (iii) not inhibiting or poorly inhibiting NOD-mediated NF-kB activation.
  • the Smac mimetic is birinapant.
  • the proliferative disorder is acute lymphoblastic leukemia (ALL), a
  • myeloproliferative disorder breast cancer, pancreatic cancer, and/or non-small cell lung carcinoma.
  • the proliferative disorder is Philadelphia chromosome-like ALL (Ph-like ALL) or a myeloproliferative disorder selected from chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) (also known as chronic idiopathic myelofibrosis or agnogenic myeloid metaplasia), chronic neutrophilic leukemia, and/or chronic eosinophilic leukemia.
  • CML chronic myelogenous leukemia
  • PV polycythemia vera
  • ET essential thrombocythemia
  • PMF primary myelofibrosis
  • chronic neutrophilic leukemia chronic neutrophilic leukemia
  • chronic eosinophilic leukemia chronic neutrophilic leukemia
  • the proliferative disorder is Ph-like pediatric ALL.
  • the JAK mutation is a mutation in the JAK2 gene.
  • the JAK mutation is one or more of the JAK2 V617F mutation or a JAK2 exon 12, 13, 14, or 15 mutation.
  • an initial step is determining if abnormally proliferating cells have a JAK mutation such as by use of a JAK signaling biochemical assay, by genotyping or having genotyped the cells or by sequencing or having sequenced JAK protein expressed by the cells.
  • IAP antagonists are commonly within the genus of monovalent or bivalent Smac mimetics that have the general structure:
  • a Smac mimetic may reside in the following genus of compounds of Formula I or of Formula II:
  • P3 and P3' are pyrrolidine, pyrrolidine fused to a cycloalkyi, or pyrrolidine fused to a heterocycloalkyl having a -N- heteroatom, optionally substituted in each case, and wherein the pyrrolidine of P3/P3' may be bound to P2/P2' by an amide bond;
  • variable substituents can be, for example:
  • R 1 -H or -CH3;
  • M a covalent bond, C1 -6 alkylene, substituted C1 -C6 alkylene such as but not limited to -C(O)-, or C3-C7 cycloalkyi or heterocycloalkyl, optionally substituted in each case;
  • R 7 cycloalkyi, heterocycloalkyl, cycloalkylaryl, alkylaryl, alkylheteroaryl, aryl or heteroaryl, optionally substituted in each case;
  • R 8 -H OI- C1 -6 alkyl.
  • L is a linking group or bond covalently linking [P1 - P2-P3-P4] to [P1 '-P2'-P3'-P4'].
  • Alkyl (monovalent) and “alkylene” (divalent) when alone or as part of another term (e.g., alkoxy) mean branched or unbranched, saturated aliphatic
  • hydrocarbon group having up to 12 carbon atoms unless otherwise specified.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2- methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2- methylpentyl, 2,2-dimethylbutyl, n- heptyl, 3-heptyl, 2-methylhexyl, and the like.
  • lower when used to modify alkyl, alkenyl, etc., means 1 to 4 carbon atoms, branched or linear so that, e.g. , the terms “lower alkyl”, “C r C alkyl” and “alkyl of 1 to 4 carbon atoms” are synonymous and used interchangeably to mean methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, sec-butyl or t-butyl.
  • alkylene groups include, but are not limited to, methylene, ethylene, n-propylene, n-butylene and 2-methyl- butylene.
  • substituted alkyl refers to alkyl moieties having substituents replacing one or more hydrogens on one or more (often no more than four) carbon atoms of the hydrocarbon backbone.
  • substituents are independently selected from the group consisting of: a halogen (e.g., I, Br, CI, or F, particularly fluoro(F)), hydroxy, amino, cyano, mercapto, alkoxy (such as a C r C 6 alkoxy, or a lower (C r C ) alkoxy, e.g., methoxy or ethoxy to yield an alkoxyalkyl), aryloxy (such as phenoxy to yield an aryloxyalkyl), nitro, oxo (e.g., to form a carbonyl), carboxyl (which is actually the combination of an oxo and hydroxy substituent on a single carbon atom), carbamoyl (an aminocarbonyl such as NR 2 C(0)-, which is the
  • alkyl substituents including specifically alkoxy, cycloalkyl, aryl, heterocyclyalkyl and heteroaryl, are optionally further substituted as defined in connection with each of their respective definitions provided below.
  • certain alkyl substituent moieties result from a combination of such substitutions on a single carbon atom.
  • an ester moiety e.g., an alkoxycarbonyl such as methoxycarbonyl, or tert-butoxycarbonyl (Boc) results from such substitution.
  • an amide moiety e.g., an alkylaminocarbonyl, such as
  • Particular substituted alkyls are substituted methyl groups.
  • groups such as hydroxymethyl, protected hydroxymethyl (e.g., tetrahydropyranyl- oxymethyl), acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, carb
  • substituted alkylene refers to alkylene moieties having substituents replacing one or more hydrogens on one or more (often no more than four) carbon atoms of the hydrocarbon backbone where the alkylene is similarly substituted with groups as set forth above for alkyl.
  • Alkoxy is -O-alkyl.
  • a substituted alkoxy is -O-substituted alkyl, where the alkoxy is similarly substituted with groups as set forth above for alkyl.
  • a lower alkoxy is
  • alkenyl (monovalent) and “alkenylene” (divalent) when alone or as part of another term mean an unsaturated hydrocarbon group containing at least one carbon-carbon double bond, typically 1 or 2 carbon-carbon double bonds, which may be linear or branched and which have at least 2 and up to 12 carbon atoms unless otherwise specified.
  • Representative alkenyl groups include, by way of example, vinyl, allyl, isopropenyl, but-2-enyl, n-pent-2-enyl, and n-hex-2-enyl.
  • substituted phenyls include but are not limited to a mono-or di (halo) phenyl group such as 2-chlorophenyl, 2- bromophenyl, 4-chlorophenyl, 2,6- dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3- bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2- fluorophenyl; 3-fluorophenyl, 4-fluorophenyl, a mono-or di (hydroxy) phenyl group such as 4-hydroxyphenyl, 3- hydroxyphenyl, 2,4-dihydroxyphenyl, the protected- hydroxy derivatives thereof; a nitrophenyl group such as 3-or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono-or di (halo
  • substituents such as in a disubstituted phenyl group
  • Heterocyclic group "heterocyclic”, “heterocycle”, “heterocyclyl”,
  • heterocycloalkyl or “heterocyclo” alone and when used as a moiety in a complex group, are used interchangeably and refer to any mono-, bi-, or tricyclic, saturated or unsaturated, non-aromatic hetero-atom-containing ring system having the number of atoms designated, or if no number is specifically
  • ring atoms are carbon and at least one heteroatom and usually not more than four heteroatoms (i.e., nitrogen, sulfur or oxygen).
  • heteroatoms i.e., nitrogen, sulfur or oxygen.
  • any bicyclic groups where any of the above heterocyclic rings are fused to an aromatic ring (i.e., an aryl (e.g., benzene) or a heteroaryl ring).
  • the group incorporates 1 to 4 heteroatoms.
  • Particular unsubstituted non-aromatic heterocycles include morpholinyl (morpholino), pyrrolidinyls, oxiranyl, indolinyls, 2,3- dihydoindolyl, isoindolinyls, 2,3-dihydoisoindolyl, tetrahydroquinolinyls, tetrahydroisoquinolinyls, oxetanyl, tetrahydrofuranyls, 2,3- dihydrofuranyl, 2H- pyranyls, tetrahydropyranyls, aziridinyls, azetidinyls, l -methyl-2-pyrrolyl, piperazinyls and piperidinyls.
  • morpholinyl morpholino
  • pyrrolidinyls oxiranyl
  • indolinyls 2,3- dihydoindolyl
  • substituted heterocyclo refers to heterocyclo moieties having substituents replacing one or more hydrogens on one or more (usually no more than six) atoms of the heterocyclo backbone. Such substituents are
  • halo e.g., I, Br, CI, F
  • alkoxy such as C r C 6 alkoxy
  • substituted alkoxy aryloxy (such as phenoxy)
  • nitro carboxyl, oxo, carbamoyl, alkyl, substituted alkyl (such as trifluoromethyl), -OCF 3 , aryl, substituted aryl, alkylsulfonyl (including lower alkylsulfonyl), and arylsulfonyl.
  • oxadiazinyls dithiazinyls, dioxazinyls, oxathiazinyls, tetrazinyls, thiatriazinyls, oxatriazinyls, dithiadiazinyls, imidazolinyls, dihydropyrimidyls,
  • tetrahydropyrimidyls tetrazolo [1 , 5-b] pyridazinyl and purinyls
  • benzo- fused derivatives for example benzoxazolyls, benzofuryls, benzothienyls, benzothiazolyls, benzothiadiazolyl, benzotriazolyls, benzoimidazolyls, isoindolyls, indazolyls, indolizinyls, indolyls, naphthyridines, pyridopyrimidines, phthalazinyls, quinolyls, isoquinolyls and quinazolinyls.
  • heteroaryls include; 1 H- pyrrolo[2,3-£>]pyridine, 1 , 3-thiazol-2-yl, 4- (carboxymethyl)-5-methyl-1 , 3- thiazol- 2-yl, 1 ,2,4-thiadiazol-5-yl, 3- methyl-1 , 2,4-thiadiazol-5-yl, 1 ,3,4-triazol-5-yl, 2- methyl-1 ,3,4-triazol-5-yl, 2-hydroxy-1 ,3,4- triazol-5-yl, 2-carboxy-4-methyl-1 ,3,4- triazol-5-yl , 1 , 3-oxazol-2-yl, 1 , 3,4-oxadiazol-5-yl, 2-methyl-1 , 3,4-oxadiazol-5-yl, 2- (hydroxymethyl)- 1 , 3,4-oxadiazol-5-yl, 1 , 2,4-oxadiazol-5-yl
  • heteroaryl includes: 5-methyl-2-phenyl-2H-pyrazol-3-yl, 4- (carboxymethyl)-5-methyl-1 , 3-thiazol-2-yl, 1 , 3,4-triazol-5-yl, 2-methyl-l , 3,4-triazol-5-yl, 1 H-tetrazol-5-yl, 1 -methyl-1 H- tetrazol-5-yl, 1 -(1 -(dimethylamino) eth-2 -y I) -I H -tetrazo l-5-y I , l-(carboxymethyl)- 1 H-tetrazol-5-yl, 1 - (methylsulfonic acid)-IH- tetrazol-5-yl, 1 , 2,3-triazol-5-yl, 1 ,4, 5,6- tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1
  • L are a single or double covalent bond, C1 -12 alkylene, substituted C1 -12 alkylene, C1 -12 alkenylene, substituted C1 -12 alkenylene, C1 -12 alkynylene, substituted C1 -12 alkynylene, X n -phenyl-Y n , or X n -(phenyl) 2 -Yn, wherein X and Y are independently C1 -6 alkylene, substituted C1 -6 alkylene, C1 - 6 alkenylene, substituted C1 -6 alkenylene, C1 -6 alkynylene, substituted C1 -6 alkynylene, or S(0) 2 .
  • heterocycloalkyi substituted heterocycloalkyi, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
  • R 4 , R 5 , and R 12 are, independently, -H, -OH, C1 -6 alkyl, 01 -6 heteroalkyl, 01 -6 alkoxy, aryloxy, cycloalkyi, heterocycloalkyi, aryl, 01 -6 alkyl aryl, or heteroaryl, or 01 -6 alkyl heteroaryl, optionally substituted in each case except when R 4 is -H or -OH.
  • Compound 15 i.e., birinapant
  • Smac mimetic a specific Smac mimetic.
  • Other illustrative examples are:
  • the selected Smac mimetic does not inhibit XIAP E3 ligase activity by more than 50%, or even 35%, relative to untreated cells when applied in the same concentrations at which they inhibit clAP1 activity, e.g., up to 10 uM.
  • the Smac mimetic is selected and administered to a patient if it does not inhibit either or both of (i) XIAP-dependent NOD1/2 signaling or (ii) XIAP-dependent inhibition of pro-IL-1 -beta processing by more than 50% at concentrations up to 10 uM, or even 100 nM, in the case of XIAP-NOD1/2 signaling or 1 uM, or even 500 nM, in the case of pro-IL-1 -beta processing. See, e.g., US20140303090.
  • a selected Smac mimetic derepresses XIAP- mediated caspase-3 repression and/or degrades clAP-1 not bound to TRAF2 (non TRAF2-bound, e.g., "cytoplasmic" clAP-1 or “free” clAP-1 ) as well as clAP1 bound to TRAF2 and/or degrades clAP-2 bound to TRAF2 but does not degrade clAP-2 not bound to TRAF2 or weakly degrades clAP-2 not bound to TRAF2 relative to degradation of clAP-2 bound to TRAF2. See, e.g., US20140303090.
  • IAP antagonists also include, e.g., compounds disclosed in US8889712,
  • IAP antagonists also include molecules that reduce the expression of an IAP gene, such as clAP1 or clAP2. Suitable antagonists that are capable of reducing the expression of an IAP gene would be known to persons skilled in the art. Examples include nucleic acid molecules, such as RNA or DNA molecules (including double-stranded or single-stranded), and peptides, such as antisense peptide nucleic acids, that interfere with the expression of the target gene.
  • Useful DNA molecules include antisense, as well as sense (e.g. coding and/or regulatory) DNA molecules.
  • Antisense DNA molecules include short
  • RNA molecules capable of reducing the expression of an IAP gene also referred to herein as RNA interference molecules, include siRNA, dsRNA, stRNA, shRNA, and miRNA (e.g., short temporal RNAs and small modulatory RNAs) and ribozymes.
  • RNA interference is particularly useful for specifically inhibiting the production of a particular protein.
  • RNAi RNA interference
  • Waterhouse et al. 1998 have provided a model for the mechanism by which dsRNA can be used to reduce protein production.
  • This technology relies on the presence of dsRNA molecules that contain a sequence that is essentially identical to the mRNA of the gene of interest or part thereof, in this case an mRNA encoding a polypeptide according to the invention.
  • the length of the sense and antisense sequences that hybridize should each be at least 19 contiguous nucleotides, preferably at least 30 or 50 nucleotides, and more preferably at least 100, 200, 500 or 1000 nucleotides.
  • the full-length sequence corresponding to the entire gene transcript may be used. The lengths are most preferably 100-2000 nucleotides.
  • the degree of identity of the sense and antisense sequences to the targeted transcript should be at least 85%, preferably at least 90% and more preferably 95-100%.
  • the RNA molecule may of course comprise unrelated sequences which may function to stabilize the molecule.
  • the RNA molecule may be expressed under the control of a RNA polymerase II or RNA polymerase III promoter. Examples of the latter include tRNA or snRNA promoters.
  • RNAi molecules suitable for use with present invention can be effected by first scanning the mRNA sequence of the target downstream of the AUG start codon for AA dinucleotide sequences. Occurrence of each AA and the 3' adjacent 19 nucleotides is recorded as potential siRNA target sites.
  • Potential target sites are compared to an appropriate genomic database using any sequence alignment software, such as BLAST. Putative target sites which exhibit significant homology to other coding sequences are filtered out. Qualifying target sequences are selected as template for siRNA synthesis.
  • DNAzymes are single-stranded polynucleotides which are capable of cleaving single and double stranded polynucleotides which are capable of cleaving both single and double stranded target sequences (Breaker, R. R. and Joyce, G. Chemistry and Biology 1995; 2:655; Santoro, S. W. & Joyce, G. F. Proc. Natl, Acad. Sci. USA 1997; 943:4262) A general model (the "10-23" model) for the DNAzyme has been proposed.
  • DNAzymes have a catalytic domain of 15 deoxynbonucleotides, flanked by two substrate-recognition domains of seven to nine deoxynbonucleotides each.
  • This type of DNAzyme can effectively cleave its substrate RNA at purine:pyrimidine junctions (Santoro, S. W. & Joyce, G. F. supra; for rev of DNAzymes see Khachigian, L M. Curr Opin Mol Ther 4: 1 19-21 (2002).
  • RNA interference molecules include unmodified and modified double stranded (ds) RNA molecules including, short-temporal RNA (stRNA), small interfering RNA (siRNA), short-hairpin RNA (shRNA), microRNA (miRNA) and double-stranded RNA (dsRNA).
  • dsRNA molecules e.g. siRNA
  • the dsRNA molecules also may contain 3' overhangs, such as 3'UU or 3TT overhangs.
  • the siRNA molecules of the present invention have a double stranded structure.
  • the siRNA molecules of the present invention are double stranded for more than about 25%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90% of their length.
  • suitable modified residues include aminoallyl UTP, pseudo-UTP, 5-l-UTP, 5-I- CTP, 5-Br-UTP, alpha-S ATP, alpha-S CTP, alpha-S GTP, alpha-S UTP, 4-thio UTP, 2-thio-CTP, 2'NH 2 UTP, 2'NH 2 CTP, and 2'F. UTP.
  • Suitable modified nucleotides also include aminoallyl uridine, pseudo-uridine, 5-l-uridine, 5-I- cytidine, 5-Br-uridine, alpha-S adenosine, alpha-S cytidine, alpha-S guanosine, alpha-S uridine, 4-thio uridine, 2-thio-cytidine, 2'NH 2 uridine, 2'NH 2 cytidine, and 2'F uridine, including the free pho (NTP) RNA molecules, as well as all other useful forms of the nucleotides.
  • NTP free pho
  • RNA interference molecules may also contain modifications in the ribose sugars, as well as modifications in the phosphate backbone of the nucleotide chain.
  • siRNA or miRNA molecules containing a-D-arabinofuranosyl structures in place of the naturally-occurring a-D-ribonucleosides found in RNA can be used as RNA interference molecules according to the present invention.
  • shRNAs comprises short, e.g. about 19 to about 25 nucleotide, antisense strand, followed by a nucleotide loop of about 5 to about 9 nucleotides, and the analogous sense strand.
  • the sense strand may precede the nucleotide loop structure and the antisense strand may follow.
  • the siRNA, shRNA or miRNA is targeted against a sequence selected from the group consisting of NCBI Reference Sequence: NM_001 166.4, NCBI Reference Sequence: NM_001256163.1 , NCBI Reference Sequence: NM_001256166.1 , GenBank: DQ068066.1 , NCBI Reference Sequence:
  • NCBI Reference Sequence NM_001 167.3
  • NCBI Reference Sequence NM_001204401.1
  • NCBI Reference Sequence NR_037916.1
  • NCBI Reference Sequence NG_007264.1.
  • Gene therapy techniques may also be used to antagonize lAPs by introducing coding sequences for Smac and thereby amplifying expression of endogenous Smac, e.g., full or partial Smac cDNA molecules.
  • An illustrative example of an IAP antagonist that employs gene therapy is the recombinant vaccinia virus carrying a partial Smac gene disclosed in Pan et al., "SMAC-armed vaccinia virus induced both apoptosis and necroptosis and synergizes the efficiency of vinblastine in HCC," Hum Cell. 2014 Oct; 27(4): 162-71 . doi: 10.1007/s13577- 014-0093-z. Epub 2014 Apr 26.
  • Some embodiments of the invention include co-administering to the subject one or more second therapy(ies) selected from radiation, chemotherapy (which includes biological therapy), immunotherapy, photodynamic therapy, targeted therapies such as JAKAFI (ruxolitinib phosphate), and combinations thereof.
  • second therapy selected from radiation, chemotherapy (which includes biological therapy), immunotherapy, photodynamic therapy, targeted therapies such as JAKAFI (ruxolitinib phosphate), and combinations thereof.
  • coadministering and “coadministration,” are not limited to simultaneous coadministration but more generally refer to a treatment regimen that comprises administration of an IAP antagonist and at least a second therapy sequentially or simultaneously.
  • Biological or chemotherapeutic agents include but are not limited to the chemotherapeutic agents described in "Modern Pharmacology with Clinical Applications", Sixth Edition, Craig & Stitzel, Chpt. 56, pg 639-656 (2004).
  • the chemotherapeutic agent can be, but is not limited to, alkylating agents, antimetabolites, anti-tumor antibiotics, plant-derived products such as taxanes, enzymes, hormonal agents, miscellaneous agents such as cisplatin, monoclonal antibodies, glucocorticoids, mitotic inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, immunomodulating agents such as interferons, cellular growth factors, cytokines, and nonsteroidal anti-inflammatory compounds (NSAID), cellular growth factors and kinase inhibitors.
  • NSAID nonsteroidal anti-inflammatory compounds
  • classifications for chemotherapeutic agents include mitotic inhibitors, and antiestrogenic agents.
  • suitable biological and chemotherapeutic agents include nitrogen mustards such as cyclophosphamide, alkyl sulfonates, nitrosoureas, ethylenimines, triazenes, folate antagonists, purine analogs, pyrimidine analogs, anthracyclines, bleomycins, mitomycins, dactinomycins, plicamycin, vinca alkaloids, epipodophyllotoxins, taxanes, glucocorticoids, L- asparaginase, estrogens, androgens, progestins, luteinizing hormones, octreotide actetate, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, carboplatin, mitoxantrone, monoclonal antibodies, levamisole, interferons, interleukins, filgrastim and sargramostim.
  • nitrogen mustards such as cyclophosphamide
  • a TRAIL receptor agonist, or TRAIL agonist is an agent that binds to a TRAIL receptor, such as TRAIL receptor 1 (TRAIL R1 , also known as “death receptor 4" or DR4), TRAIL receptor 2 (TRAIL R2, also known as “death receptor 5" or DR5), or both DR4 and DR5, and leads to apoptosis in at least one mammalian (e.g., human) cell type (such as a TRAIL-sensitive tumor cell line) when used in an amount effective to induce apoptosis under physiological conditions.
  • TRAIL receptor agonists used in the present invention preferably do not bind to TRAIL decoy receptors.
  • TRAIL has received considerable attention recently because of the finding that many cancer cell types are sensitive to TRAIL-induced apoptosis, while most normal cells appear to be resistant to this action of TRAIL.
  • TRAIL-resistant cells may arise by a variety of different mechanisms including loss of the receptor, presence of decoy receptors, or overexpression of FLIP which competes for zymogen caspase-8 binding during DISC formation.
  • the compounds or compositions that are used in the method of the present invention may increase tumor cell sensitivity to TRAIL leading to enhanced cell death, the clinical correlations of which are expected to be increased apoptotic activity in TRAIL resistant tumors, improved clinical response, increased response duration, and ultimately, enhanced patient survival rate.
  • the antibody can be a DR4 antibody, a DR5 antibody, or a DR4/5 antibody, i.e., an antibody that binds to both DR4 and DR5.
  • the TRAIL receptor agonist is recombinant human TRAIL or a soluble TRAIL polypeptide or a Fc-TRAIL fusion peptidobody.
  • Fc-TRAIL fusion proteins are disclosed, e.g., in US20130064838.
  • TRAIL fusion proteins comprising a collectin trimerization domain are disclosed, e.g., in US20130064838.
  • TRAIL agonists include those disclosed in, e.g., US6284236; US69981 16; US7915245.
  • antibody includes reference to isolated forms of both glycosylated and non-glycosylated immunoglobulins of any isotype or subclass, including any combination of: 1 ) human (e.g., CDR-grafted), humanized, and chimeric antibodies, 2) monospecific (e.g., DR5) or multi-specific antibodies (e.g., DR4/5), and 3) monoclonal, polyclonal, or single chain (scFv) antibodies, irrespective of whether such antibodies are produced, in whole or in part, via immunization, through recombinant technology, by way of in vitro synthetic means, or otherwise.
  • the term “antibody” is inclusive of those that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic for human
  • antibodies isolated from a host cell transfected to express the antibody e.g., from a transfectoma
  • antibodies isolated from a recombinant, combinatorial antibody library e.g., antibodies prepared, expressed, created or isolated by any other means that involve splicing of immunoglobulin gene sequences to other DNA sequences.
  • the antibodies of the present invention are monoclonal antibodies, such as humanized or fully-human monoclonal antibodies.
  • TRAIL agonist activity may be fragments of antibodies, peptides, recombinant forms of the endogenous TRAIL, or small molecules, that effectively engage the receptor and thereby trigger TRAIL-receptor signaling. Accordingly, in addition to recombinant antibodies, new classes of therapeutic proteins are being developed and include
  • recombinant protein scaffolds e.g. DARPINs, anticalins, affibodies, fibronectin domains
  • binding is mediated by surface diversity that interacts with targets which include TRAIL receptors DR4 and DR5 (e.g. Veesler, D., et al., J. Biol. Chem. 284(44):30718-30726, (2009).
  • a Smac mimetic is co-administered with GM-CSF, as disclosed, e.g., in WO2014022612.
  • a Smac mimetic is co-administered with an NSAID, as disclosed, e.g., in PCT/GB2015/053533.
  • JAK inhibitors i.e., inhibitors of one or more of JAK1 , JAK2, JAK3, and TYK2
  • JAK inhibitors include, without limitation, ruxolitinib, tofacitinib, baricitinib, CYT387, GLPG0634, GSK2586184, lestaurtinib, pacritinib, and TG101348.
  • Fedratinib is a JAK2 inhibitor that is theoretically useful but clinical studies with this agent were terminated due to safety reasons.
  • compositions comprising an IAP antagonist, alone or in combination with one or more other active pharmaceutical ingredients, are administered to a human or veterinary subject.
  • the pharmaceutical compositions typically comprise at least one
  • compositions can be administered in the conventional manner by routes including systemic, subcutaneous, topical, or oral routes. Administration may be by intravenous injection, either as a bolus or infusion, but other routes of administration, including, among others, subcutaneous or oral administration, are not precluded.
  • An intravenous formulation can contain, e.g., from 1 mg/mL up to and including 5 mg/mL of the IAP antagonist, such as specifically Compound 15 (birinapant), in sterile 0.05M citrate buffered PBS, pH 5. Formulation may be by immediate release or prolonged release. Specific modes of administration and formulation will depend on the indication and other factors including the particular compound being administered.
  • the amount of compound to be administered is that amount which is therapeutically effective, i.e., the amount that ameliorates the disease symptoms, i.e., that slows cancer progression or causes regression, without serious adverse effects relative to the disease being treated or causes improvement of the infectious disease or the autoimmune disease.
  • an effective dose is one that over the course of therapy, which may be, e.g., 1 or more weeks, e.g., multiple courses of 3 weeks on/1 week off, results in treatment of the proliferative disorder, i.e., a decrease in the rate of disease progression, termination of disease progression, or regression or remission, or results in a decrease in infectious burden or resolution of symptoms of an infectious or autoimmune disease.
  • composition refers to a composition suitable for administration in medical use.
  • the dosage to be administered will depend on the characteristics of the subject being treated, e.g., the particular patient treated, age, weight, health, types of concurrent treatment, if any and the specific disease or disorder that is being treated. Frequency of treatments can be easily determined by one of skill in the art (e.g., by the clinician).
  • a second or further agent e.g., a TRAIL agonist, GM-CSF, an NSAID (e.g., celecoxib), a JAK inhibitor, or 5-azacitidine
  • a second or further agent e.g., a TRAIL agonist, GM-CSF, an NSAID (e.g., celecoxib), a JAK inhibitor, or 5-azacitidine
  • an IAP antagonist e.g., celecoxib
  • 5-azacitidine e.g., 5-azacitidine
  • the dose of the other agent(s) or the dose of the Smac mimetic required when used together or in combination may be less than the dose of either agent when used alone.
  • an IAP antagonist and a second agent into a single dosage unit, e.g., a sterile solution for intravenous administration
  • compositions to be used comprise a therapeutically effective amount of the active pharmaceutical ingredients as described above with one or more pharmaceutically acceptable excipients.
  • pharmaceutical composition refers to a composition suitable for administration in medical or veterinary use. It should be appreciated that the determinations of proper dosage forms, dosage amounts, and routes of administration for a particular patient are within the level of ordinary skill in the pharmaceutical and medical arts.
  • compositions suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active pharmaceutical ingredients, which is preferably isotonic with the blood of the recipient.
  • This aqueous preparation may be formulated according to known methods using suitable dispersing or wetting agents, emulsifying and suspending agents.
  • suitable dispersing or wetting agents emulsifying and suspending agents.
  • Various antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, and sorbic acid also may be included.
  • the sterile injectable preparation also may be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 ,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or di-glycerides.
  • fatty acids such as oleic acid may be used in the preparation of injectables. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Carrier formulation suitable for subcutaneous, intravenous, intramuscular, etc. administrations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.
  • a pharmaceutical composition in intravenous unit dose form may comprise, e.g., a vial or pre-filled syringe, or an infusion bag or device, each comprising an effective amount or a convenient fraction of an effective amount such that the contents of one vial or syringe are administered at a time.
  • An effective dose is one that over the course of therapy, which may be, e.g., 1 or more weeks, e.g., multiple courses of 3 weeks on/1 week off, results in treatment of the disorder, e.g., a decrease in the rate of disease progression, termination of disease progression, or regression or remission.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the compounds (TRAIL agonist and IAP antagonist) are admixed with at least one inert pharmaceutically acceptable excipient such as (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example,
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules also can be prepared with coatings and shells, such as enteric coatings and others well known in the art.
  • the solid dosage form also may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Such solid dosage forms may generally contain from 1 % to 95% (w/w) of the active compounds. In certain embodiments, the active compounds generally range from 5% to 70% (w/w).
  • kits comprises two separate pharmaceutical compositions: one composition contains the IAP antagonist used in the method of the present invention, and a second composition contains the second agent.
  • the kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, e.g., pre-filled syringes, boxes and bags.
  • the kit comprises directions for the use of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g. , oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician or veterinarian.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc . . . Second Week, Monday, Tuesday, . . . " etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a substance of the present invention can consist of one tablet or capsule, while a daily dose of the second substance can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this variety and aid in correct administration of the active agents.
  • a dispenser designed to dispense the daily doses one at a time in the order of their intended use.
  • the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
  • a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed.
  • a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances.
  • the composition can also include adjuvants, such as we
  • the compounds and compositions used in the method of the present invention also may benefit from a variety of delivery systems, including time-released, delayed release or sustained release delivery systems. Such option may be particularly beneficial when the compounds and composition are used in conjunction with other treatment protocols as described in more detail below.
  • controlled release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No. 5,075, 109.
  • Delivery systems also include non-polymer systems that are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-di-and tri-glycerides; hydrogel release systems; sylastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like.
  • lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-di-and tri-glycerides
  • hydrogel release systems such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-di-and tri-glycerides
  • sylastic systems such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-di-and tri-glycerides
  • peptide based systems such as mono-di-and tri-glycerides
  • wax coatings such as those described in U.S. Pat. Nos.
  • Long-term sustained release means that the implant is constructed and arranged to deliver therapeutic levels of the active compounds for at least 30 days, and preferably 60 days.
  • Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.
  • the compounds used in the method of the present invention and pharmaceutical compositions comprising compounds used in the method of the present invention can be administered to a subject suffering from cancer, an autoimmune disease or another disorder where a defect in apoptosis is implicated.
  • the patient can be treated prophylactically, acutely, or chronically using the compounds and compositions used in connection with the method of the present invention, depending on the nature of the disease.
  • the host or subject in each of these methods is human, although other mammals may also benefit from the present invention.
  • Methodologies for determining if a subject is suffering from aberrant JAK signaling are known. These include biochemical assays for analyzing JAK- mediated phosphorylation, genotyping for presence of a mutation in one or both copies of a JAK gene, e.g., in the JH2 domain, and phenotyping to identify mutant amino acid sequence(s) in a JAK gene such as by protein sequencing or antibody binding assays.
  • PDX cells were pre-incubated with the pan-caspase inhibitor QVD or the RIPK1 inhibitor Nec-1 prior to birinapant treatment.
  • QVD significantly attenuated birinapant-induced apoptosis in 3/4 sensitive PDXs, while Nec-1 caused significant inhibition in 2/4 PDXs.
  • Nec-1 caused significant inhibition in 2/4 PDXs.
  • birinapant resistance in BCP-ALL PDXs was not due to failure of target degradation
  • the levels of lAPs and other relevant proteins were assessed after birinapant treatment.
  • the cleaved (activated) forms of both caspase-3 and caspase-8 were markedly upregulated in sensitive PDXs within 6 h of birinapant treatment in contrast to the resistant PDXs, indicating that resistance occurred downstream of clAP1/2 degradation.
  • birinapant also caused rapid (within 6 h) degradation of clAP1 in vivo regardless of the PDX response, despite clear differences in caspase-3, -7, -8, and -9 activation between a sensitive (ALL-2) and resistant (ALL-7) PDX.
  • Birinapant induced a CR in a Ph-like PDX at a dose 1/8th (3.8 mg/kg) of its maximum tolerated dose (30 mg/kg).
  • Birinapant also significantly enhanced the anti-leukemic activity of an induction- type regimen of vincristine, dexamethasone and L-asparaginase (VXL) in vivo. These findings support further evaluation of birinapant in the treatment of Ph-like ALL.

Abstract

Des antagonistes des IAP sont utiles dans le traitement de troubles prolifératifs associés à une signalisation JAK aberrante.
PCT/GB2015/054105 2014-12-19 2015-12-21 Antagonistes des iap thérapeutiques pour traiter des troubles prolifératifs WO2016097773A1 (fr)

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