WO2017117684A1 - Composé mimétique de smac pour utilisation dans le traitement de maladies prolifératives - Google Patents

Composé mimétique de smac pour utilisation dans le traitement de maladies prolifératives Download PDF

Info

Publication number
WO2017117684A1
WO2017117684A1 PCT/CA2017/050019 CA2017050019W WO2017117684A1 WO 2017117684 A1 WO2017117684 A1 WO 2017117684A1 CA 2017050019 W CA2017050019 W CA 2017050019W WO 2017117684 A1 WO2017117684 A1 WO 2017117684A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
dosed
compound
administered
use according
Prior art date
Application number
PCT/CA2017/050019
Other languages
English (en)
Inventor
Stephen J. Morris
Original Assignee
Pharmascience Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmascience Inc. filed Critical Pharmascience Inc.
Publication of WO2017117684A1 publication Critical patent/WO2017117684A1/fr

Links

Classifications

    • 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
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3061—Blood cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • the present invention relates to SMAC mimetics, more specifically to a compound and to pharmaceutical compositions comprising it, and to their use in the treatment of proliferative disorders, comprising cancers.
  • Apoptosis typically occurs in normal development and maintenance of healthy tissues in multicellular organisms. It is a complex process which results in the removal of damaged, diseased or developmentally redundant cells. Intrinsic apoptotic pathways are known to be dysregulated, most particularly in cancer and lymphoproliferative syndromes, as well as autoimmune disorders such as multiple sclerosis, in neurodegenerative diseases and in inflammation. In cancer, failure to apoptose in response to anti-cancer therapies contributes to resistance of many cancer types to chemotherapy and biological agents.
  • the caspases are a family of proteolytic enzymes from the class of cysteine proteases which are known to initiate and execute apoptosis.
  • the caspases are present as inactive zymogens, which are catalytically activated following external signals, for example those resulting from ligand driven Death Receptor activation, such as cytokines or immunological agents, or by release of mitochondrial factors, such as cytochrome C following genotoxic, chemotoxic, or radiation-induced cellular injury.
  • the Inhibitors of Apoptosis Proteins constitute a family of proteins which are capable of binding to and inhibiting the caspases, thereby suppressing cellular apoptosis.
  • the lAPs are capable of inhibiting programmed cell death from a wide variety of triggers, which include loss of homeostatic, or endogenous cellular growth control mechanisms, as well as chemotherapeutic drugs and irradiation.
  • the lAPs contain one to three homologous structural domains known as baculovirus IAP repeat (BIR) domains. They may also contain a RING zinc finger domain at the C-terminus, with a capability of inducing ubiquitinylation of IAP-binding molecules via its E3 ligase function.
  • BIR baculovirus IAP repeat
  • the human lAPs, XIAP, clAP1 and clAP2 each have three BIR domains, and a carboxy terminal RING zinc finger.
  • Another IAP, NAIP has three BIR domains (BIR1 , BIR2 and BIR3), but no RING domain, whereas Livin, TslAP and MLIAP have a single BIR domain and a RING domain.
  • the X chromosome-linked inhibitor of apoptosis is an example of an IAP which can inhibit the initiator caspase, known as Caspase-9, and the effector caspases, Caspase-3 and Caspase- 7, by direct binding (Schimmer AD et al. Cell Death Differ. 2006 Feb; 13(2): 179-88). It can also induce the removal of caspases through the ubiquitylation-mediated proteasome pathway via the E3 ligase activity of a RING zinc finger domain. It is via the BIR3 domain that XIAP binds to and inhibits caspase-9.
  • the linker-BIR2 domain of XIAP inhibits the activity of caspases-3 and -7.
  • the lAPs thus function as a direct brake on the apoptosis cascade, by preventing the action of, or inhibiting active caspases and by re-directing cellular signaling to a pro-survival mode. Since caspase activation is a fundamental mechanism of many chemotherapeutic and anti-cancer therapies antagonism of IAP function is may amplify the effects of chemotherapy interventions (Gadducci A et al. Eur J Gynaecol Oncol. 2002;23(5):390-6). IAP family members clAP1 and clAP2 are important regulators of NfKappa B signalling in cells.
  • Loss of clAP1 or clAP2 results in transient production of tumor necrosis factor (TNF) and formation of a pro-apoptotic RIPK1 -FADD-Caspase 8 complex or a pro-necrotic RIPK1 -FADD complex (Gyrd-Hansen Nature Reviews Cancer 10, 561 -574).
  • TNF tumor necrosis factor
  • clAP1 and clAP2 negatively regulate non- canonical NfKappa B signalling through ubiquitination of NIK.
  • Loss of clAP1 and clAP2 results in NIK accumulation which then phosphorylates NfKappaB2 p100 leading to its partial degradation and activation.
  • Non-canonical NfKappa B activation can lead to up regulation of type 1 interferons which can result in anti-cancer inflammatory responses (Chesi et al Nat Med. 2016 Nov 14. doi: 10.1038/nm.4229).
  • cancer cells may avoid apoptosis by the sustained over-expression of one or more members of the IAP family of proteins, as documented in many primary tumor biopsy samples, as well as most established cancer cell lines.
  • Epidemiological studies have demonstrated that over-expression of the various lAPs is associated with poor clinical prognosis and survival. For XIAP this is shown in cancers as diverse as leukemia and ovarian cancer.
  • Over expression of clAP1 and clAP2 resulting from the frequent chromosome amplification of the 1 1 q21 - q23 region, which encompasses both, has been observed in a variety of malignancies, including medulloblastomas, renal cell carcinomas, glioblastomas, and gastric carcinomas.
  • (X)IAP negative regulatory molecules such as XAF, appear to be tumor suppressors, which are very frequently lost in clinical cancers.
  • the caspases the lAPs may directly contribute to tumor progression and resistance to pharmaceutical intervention.
  • the lAPs are antagonized by SMAC, an intracellular protein, which binds to BIR domains. SMAC binding can displace caspases from XIAP as well as activate the E3 ubiquitin ligase activities of clAP1 and clAP2.
  • SMAC binding can displace caspases from XIAP as well as activate the E3 ubiquitin ligase activities of clAP1 and clAP2.
  • activation of the E3 ligase activity can lead to protein degradation.
  • SMAC mimetic clAP1 and clAP2 when contacted by a SMAC mimetic clAP1 and clAP2 autoubiquitinate and are subsequently and rapidly degraded in target cells.
  • SMAC mimetic clAP1 and clAP2 When contacted by a SMAC mimetic clAP1 and clAP2 autoubiquitinate and are subsequently and rapidly degraded in target cells.
  • We and others have synthesized small molecule drugs that mimic the action of SMAC.
  • the Smac mimetics When administered to patients or animals suffering proliferative disorders, the Smac mimetics antagonize lAPs, causing an increase in apoptosis among abnormally proliferating cells including cancer cells.
  • Smac peptidomimetics are those disclosed in, without limitation, US 7,517,906; US 7,419,975; US 7,589,1 18; US 7,932,382; US 7,345,081 ; US 7,244,851 ; US 7,674,787; US 7,772, 177; US 7,989,441 ; US20100324083; US20100056467; US20090069294; US201 10065726; US201 10206690; WO201 1098904.
  • the present invention relates to a compound for use in a method of treating a patient suffering a proliferative disorder that comprises administering a selected dose of N1 ,N4-bis((3S,5S)-1 -((S)-3,3-dimethyl-2-((S)-2-
  • the invention in related aspects, comprises a pharmaceutical composition in a dosage unit for intravenous infusion comprising such compound in a dose as hereinafter described and a method of treating a proliferative disorder in a human or non-human mammalian subject in need thereof that comprises internally administering to the subject an pharmaceutically effective amount of said compound or a pharmaceutically acceptable salt thereof wherein the pharmaceutically effective amount is a dose as defined more fully hereinafter.
  • the invention comprises a method of potentiating apoptosis of abnormally proliferating cells in a human or non-human mammalian subject that comprises internally administering, e.g., by intravenous infusion, a hereinafter defined dose of Compound 1 .
  • the invention comprises the use of a SMAC mimetic for treating a proliferative disorder in a patient comprising internally administering of a SMAC mimetic compound of Formula I
  • the invention comprises a SMAC mimetic compound of Formula I
  • the invention comprises the use of a SMAC mimetic Compound 1 of Formula I
  • the invention comprises a pharmaceutical composition in a dosage unit for intravenous infusion that comprises internally administering to the patient a SMAC mimetic of Formula I.
  • the invention comprises an injectable pharmaceutical composition comprising a SMAC mimetic of Formula I
  • Formula I or a pharmaceutically acceptable salt thereof, and an aqueous solvent.
  • the invention comprises an injectable pharmaceutical composition according to claim 53, wherein Compound 1 can be formulated as a 5 mg/mL solution in sterile water for injection for further dilution prior to infusion.
  • the invention comprises an injectable pharmaceutical composition according to claim 53, wherein Compound 1 in sterile water for injection, USP (5 mg/mL) is further diluted with dextrose 5% water (D5W) to achieve the appropriate concentration of Compound 1 for IV infusion.
  • the invention comprises an injectable pharmaceutical composition according to claim 53, wherein a final concentrations range from 0.001 to 1 mg/mL or 0.005 to 0.8 mg/mL.
  • the invention comprises an injectable pharmaceutical composition according to claim 53, wherein administration is by intravenous injection, a bolus or infusion, subcutaneous, intramuscular, intraperitoneal, intrapleural, intrathecal, intraorbital, or intraarterial injection.
  • the invention comprises a method of treatment of a proliferative disorder in a patient comprising the administration of a SMAC mimetic Compound I of Formula I
  • the invention comprises a method of stimulating the degradation of both the cellular inhibitor of apoptosis 1 and 2 (clAP1 and clAP2) proteins from the cells of a patient suffering from a condition that is caused or exacerbated by abnormal regulation of apoptosis, including, for example, cancer.
  • clAP1 and clAP2 cellular inhibitor of apoptosis 1 and 2
  • the present invention includes a method of stimulating the concomitant degradation of clAP1 and clAP2 by administering the Compound 1 or a pharmaceutically acceptable salt thereof to a human or non-human mammalian subject.
  • the invention comprises any one or more of the above methods that further comprises administering a second cancer-related therapy, such as, e.g., chemotherapy, PARP Inhibitors, PI3K inhibitors, BCL-2 Inhibitors, TRAIL agonists, anti-CD20, tumor vaccine, checkpoint inhibitor, radiation, immunotherapy, and combinations thereof.
  • a second cancer-related therapy such as, e.g., chemotherapy, PARP Inhibitors, PI3K inhibitors, BCL-2 Inhibitors, TRAIL agonists, anti-CD20, tumor vaccine, checkpoint inhibitor, radiation, immunotherapy, and combinations thereof.
  • FIG. 1 The structure of Compound 1 (AEG40826).
  • Figure 4 Efficacy of Compound 1 in combination with a BCL-2 inhibitor.
  • the combination of ABT-199 (venetoclax, Venclexta®) and Compound 1 resulted in improved potency.
  • Figure 5. Efficacy of Compound 1 in combination with a PARP inhibitor (Rucaparib). The combination decreased cancer cell viability.
  • Figure 7. Efficacy of Compound 1 in combination with hypomethylating agents Decitabine and Azacytidine. The combination of Compound 1 with either decitabine or azacytidine resulted in decreased cancer cell viability compared to either agent alone.
  • Figure 8. Efficacy of Compound 1 in combination with Camptothecin, Mitomycin C or Oxaliplatin. The combination Compound 1 with either camptothecin, mitomycin C or oxaliplatin resulted in an increased anti-cancer effect compared to either agent alone.
  • Figure 10 Efficacy of Compound 1 in combination with Cisplatin in an orthotopic model of breast cancer. The combination had a synergistic effect resulting in reduced tumor growth.
  • Figure 11 Comparison of Compound 1 with other SMAC mimetics on ovarian cancer cells. Compound 1 reduced clAP2 acutely and prevented SMAC mediated up- regulation of clAP2.
  • Figure 12. Administration of Compound 1 and plasma pharmacokinetics in cancer patients.
  • Figure 13. Peripheral blood mononuclear cell levels of clAP1 and clAP2 following administration of Compound 1.
  • Compound 1 reduced clAP1 and clAP2 acutely and prevented SMAC mediated up-regulation of clAP2.
  • Samples were collected pre and post administration of Compound 1 on week 1 and week 2.
  • clAP2 levels were below the lower limit of detection post administration of 2.1 or 4.8 mg/m 2 Compound on day 8. No sample was available for detection of clAP2 post administration of 3.2mg/m 2 Compound on day 8.
  • FIG. 14 Peripheral blood mononuclear cell levels of clAP1 two weeks after the last administration of Compound 1 . Long lasting pharmacodynamic effect of compound 1 on clAPl clAP1 protein was reduced relative to pre-dose basal levels two weeks after the last dose in cycle 1 . Samples were collected pre administration of compound at the beginning of cycle 2. Patients had not received Compound 1 for 2 weeks. Data are presented as percent of cycle 1 pre-dose (basal) clAP1 . Data show that clAP1 levels were suppressed at the beginning of cycle 2, two weeks after the last administration of Compound 1 .
  • Compound 1 causes a down regulation of both clAP1 and clAP2 proteins in cells to sensitize them to cell death and provide methods of use for treatment of cancer and other diseases and disorders characterized by inappropriate apoptosis.
  • Table 1 Binding affinities of Compound 1 and other SMAC mimetics to XIAP, clAP1 and clAP2.
  • Compound 1 administered in accordance with the present invention is a SMAC mimetic that can be used in the treatment of proliferative disorders, e.g.: various benign tumors or malignant tumors (cancer), benign proliferative diseases (e.g., psoriasis, benign prostatic hypertrophy, and restenosis), or autoimmune diseases (e.g., autoimmune proliferative glomerulonephritis, lymphoproliferative autoimmune responses).
  • proliferative disorders e.g.: various benign tumors or malignant tumors (cancer), benign proliferative diseases (e.g., psoriasis, benign prostatic hypertrophy, and restenosis), or autoimmune diseases (e.g., autoimmune proliferative glomerulonephritis, lymphoproliferative autoimmune responses).
  • phrases "pharmaceutically acceptable” is employed herein to refer to those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • a pharmaceutically acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation, including the active ingredient, and not injurious or harmful to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1 ) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch, potato starch, and substituted or unsubstituted ⁇ -cyclodextrin; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (1 1 ) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl
  • pharmaceutically acceptable carrier such as water, saline, glucose solution, glucose solution analogs, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifiers, and others may be used.
  • pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate salts, and amino acid salts, and the like.
  • salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
  • suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
  • alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like ((See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1 -19).
  • pharmaceutically effective amount refers to any amount of the composition for the prevention and treatment of subjects that is effective in treating a disease or condition associated with protein kinase activity.
  • subject or "patient” means a human or an animal subject for treatment.
  • combination within the meaning of this invention includes the simultaneous, sequential or separate use of the components or ingredients.
  • treating cancer is intended to mean the administration of a pharmaceutical composition of the present invention to a subject, preferably a human, which is afflicted with cancer to cause an alleviation of the cancer by killing, inhibiting the growth, or inhibiting the metastasis of the cancer cells.
  • the term "preventing disease” is intended to mean, in the case of cancer, the post-surgical, post-chemotherapy or post-radiotherapy administration of a pharmaceutical composition of the present invention to a subject, preferably a human, which was afflicted with cancer to prevent the regrowth of the cancer by killing, inhibiting the growth, or inhibiting the metastasis of any remaining cancer cells.
  • the term "synergistic effect" is intended to mean that the effect achieved with the combination of the compounds of the present invention and either the chemotherapeutic agents or death receptor agonists of the invention is greater than the effect which is obtained with only one of the compounds, agents or agonists, or advantageously the effect which is obtained with the combination of the above compounds, agents or agonists is greater than the addition of the effects obtained with each of the compounds, agents or agonists used separately. Such synergy enables smaller doses to be given.
  • apoptosis or "programmed cell death” is intended to mean the regulated process of cell death wherein a dying cell displays a set of well- characterized biochemical hallmarks that include cell membrane blebbing, cell soma shrinkage, chromatin condensation, and DNA laddering, as well as any caspase- mediated cell death.
  • ⁇ is intended to mean a polypeptide or protein, or fragment thereof, encoded by an IAP gene.
  • lAPs include, but are not limited to human or mouse NAIP (Birc 1 ), HIAP-1 (clAP2, Birc 3), HIAP-2 (clAP1 , Birc 2), XIAP (Birc 4), survivin (Birc 5), livin (ML-IAP, Birc 7), ILP-2 (Birc 8) and Apollon/BRUCE (Birc 6) (see for example US Patent Numbers 6, 107,041 ; 6, 133,437; 6, 156,535; 6,541 ,457; 6,656,704; 6,689,562; Deveraux and Reed, Genes Dev.
  • enhancing apoptosis is intended to mean increasing the number of cells that apoptose in a given cell population either in vitro or in vivo.
  • cell populations include, but are not limited to, ovarian cancer cells, colon cancer cells, breast cancer cells, lung cancer cells, pancreatic cancer cells, or T cells and the like. It will be appreciated that the degree of apoptosis enhancement provided by an apoptosis-enhancing compound of the present invention in a given assay will vary, but that one skilled in the art can determine the statistically significant change in the level of apoptosis that identifies a compound that enhances apoptosis otherwise limited by an IAP.
  • enhancing apoptosis means that the increase in the number of cells undergoing apoptosis is at least 25%, more preferably the increase is 50%, and most preferably the increase is at least one-fold.
  • the sample monitored is a sample of cells that normally undergo insufficient apoptosis (i.e., cancer cells).
  • Methods for detecting the changes in the level of apoptosis are described in the Examples and include methods that quantitate the fragmentation of DNA, methods that quantitate the translocation phosphatidylserine from the cytoplasmic to the extracellular side of the membrane, determination of activation of the caspases and methods quantitate the release of cytochrome C and the apoptosis inhibitory factor into the cytoplasm by mitochondria.
  • proliferative disease or “proliferative disorder” is intended to mean a disease that is caused by or results in inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both.
  • cancers such as lymphoma, leukemia, melanoma, ovarian cancer, breast cancer, pancreatic cancer, and lung cancer, and autoimmune disorders are all examples of proliferative diseases.
  • the term "death receptor agonist” is intended to mean an agent capable of stimulating by direct or indirect contact the pro apoptotic response mediated by the death-receptors.
  • an agonist TRAIL receptor Antibody would bind to TRAIL receptor (S) and trigger an apoptotic response.
  • other agent such as interferon-a could trigger the release of endogeneous TRAIL and/or up regulate the TRAIL receptors in such a way that the cell pro- apoptotic response is amplified.
  • the compounds of the present invention, or pharmaceutically acceptable salts thereof, may also be administered simultaneously with, prior to, or after administration of one or more of the therapeutic agents described below.
  • Such combination therapy may include administration of a single pharmaceutical dosage formulation which contains a compound of the present invention and one or more additional agents given below, as well as administration of the compound of the present invention and each of additional agent in its own separate pharmaceutical dosage formulation.
  • a compound of the present invention and a chemotherapeutic agent such as taxol (paclitaxel), taxotere, etoposide, cisplatin, vincristine, vinblastine, and the like
  • a chemotherapeutic agent such as taxol (paclitaxel), taxotere, etoposide, cisplatin, vincristine, vinblastine, and the like
  • a single oral dosage composition such as a tablet or capsule
  • each agent administered in separate oral dosage formulations or via intravenous injection can be administered to the patient either together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations or via intravenous injection.
  • the compounds of the present invention and one or more additional agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.
  • these compounds may synergize with molecules that may stimulate the death receptor apoptotic pathway through a direct or indirect manner, as for example, the compounds of the present invention may be used in combination with soluble TRAIL any agent or procedures that can cause an increase in circulating level of TRAIL, such as interferon-alpha or radiation.
  • the present invention also encompasses the use of the compounds of the present invention in combination with radiation therapy or one or more additional agents such as those described in WO 03/09921 1 (PCT/US03/15861 ), which is hereby incorporated by reference.
  • additional agents include, but are not limited to the following: a) an estrogen receptor modulator,
  • a proteasome inhibitor such as Velcade and MG132 (7-Leu-Leu-aldehyde) (see He at al. in Oncogene (2004) 23, 2554-2558);
  • an HDAC inhibitor such as sodium butyrate, phenyl butyrate, hydroamic acids, cyclin tetrapeptide and the like (see Rosato et al,. Molecular Cancer Therapeutics 2003, 1273-1284);
  • a modulator of the immune system such as interferon-alpha and ionizing radiation (UVB) that can induce the release of cytokines, such as the interleukins, TNF, or induce release of Death receptor Ligands such as TRAIL;
  • UVB interferon-alpha and ionizing radiation
  • TRAIL and TRAIL agonists such as the humanized antibodies HGS-ETR1 and HGS-ETR2;
  • Additional combinations may also include agents which reduce the toxicity of the aforesaid agents, such as hepatic toxicity, neuronal toxicity, nephrotoxicity and the like.
  • co-administration of one of the compounds of Formula I of the present invention with a death receptor agonist such as TRAIL, such as a small molecule or an antibody that mimics TRAIL may cause an advantageous synergistic effect.
  • TRAIL a death receptor agonist
  • the compounds of the present invention may be used in combination with any compounds that cause an increase in circulating levels of TRAIL.
  • Vinca alkaloids that can be used in combination with the nucleobase oligomers of the invention to treat cancer and other neoplasms include vincristine, vinblastine, vindesine, vinflunine, vinorelbine, and anhydrovinblastine.
  • Dolastatins are oligopeptides that primarily interfere with tubulin at the vinca alkaloid binding domain. These compounds can also be used in combination with the compounds of the invention to treat cancer and other neoplasms. Dolastatins include dolastatin-10 (NCS 376128), dolastatin-15, ILX651 , TZT-1027, symplostatin 1 , symplostatin 3, and LU103793 (cemadotin). Additionally, the compounds may be used with antibodies conjugated to dolastatin analogues such as Brentuximab vedotin.
  • Cryptophycins bind tubulin within the vinca alkaloid-binding domain and induce G2/M arrest and apoptosis. Any of these compounds can be used in combination with the compounds of the invention to treat cancer and other neoplasms.
  • Taxanes and other microtubule stabilizing compounds are Taxanes and other microtubule stabilizing compounds.
  • Taxanes such as paclitaxel, doxetaxel, RPR 109881 A, SB-T-1213, SB-T-1250, SB- T-101 187, BMS-275183, BRT 216, DJ-927, MAC-321 , IDN5109, and IDN5390 can be used in combination with the compounds of the invention to treat cancer and other neoplasms.
  • Taxane analogs e.g., BMS-184476, BMS-188797
  • functionally related non-taxanes e.g., epothilones (e.g., epothilone A, epothilone B (EPO906), deoxyepothilone B, and epothilone B lactam (BMS-247550)
  • epothilones e.g., epothilone A, epothilone B (EPO906), deoxyepothilone B, and epothilone B lactam (BMS-247550)
  • eleutherobin discodermolide, 2-epi-discodermolide, 2-des-methyldiscodermolide, 5- hydroxymethyldiscoder- molide, 19-des-aminocarbonyldiscodermolide, 9(13)- cyclodiscodermolide, and laulimalide
  • Other chemotherapeutic agents that may be administered with
  • BNP-1350 (BioNumerik) teniposide or mitoxantrone rebeccamycin analogue
  • doxorubicin (adriamycin)
  • BMS 247550 (BMS) mivobulin (Warner-Lambert)
  • BMS dolastatin-10
  • BASF cemadotin
  • glufosfamide (Baxter International) 06 benzyl guanine (Paligent) thymectacin (NewBiotics) apaziquone (Spectrum edotreotide (Novartis) Pharmaceuticals)
  • Histone tacedinaline Pfizer
  • Depsi peptide Fujisawa
  • acetyltransferas pivaloyloxymethyl butyrate Tian
  • TNF alpha virulizin (Lorus Therapeutics) revimid CDC-394 (Celgene) agonists/antago (Celgene)
  • SR-27897 (CCK A inhibitor, Sanofi- (Vasogen) Synthelabo)
  • ranpirnase ribonuclease stimulant, Alfacell
  • alvocidib CDK inhibitor, Aventis
  • N-acetylcysteine (reducing agent, Zambon) CapCellTM (CYP450 stimulant, Bavarian Nordic)
  • GCS-100 gal3 antagonist, GlycoGenesys
  • 3CPA NF-kappaB inhibitor, Active Biotech
  • G17DT immunogen (gastrin inhibitor, Aphton)
  • efaproxiral oxygenator, Alios Therapeutics
  • PI-88 heparanase inhibitor, Progen
  • ODC inhibitor eflornithine
  • tesmilifene histamine antagonist, YM Biosciences
  • minodronic acid osteoclast inhibitor, Yamanouchi
  • histamine histamine H2 receptor agonist, Maxim
  • SR-31747 (IL-1 antagonist, Sanofi- Synthelabo) gemtuzumab (CD33 antibody, Wyeth Ayerst)
  • PG2 hematopoiesis enhancer, Pharmagenesis
  • CP-461 PDE V inhibitor, Cell Pathways
  • triacetyluridine uridine prodrug, Wellstat
  • PCK-3145 apoptosis promotor, Procyon
  • bortezomib proteasome inhibitor, Millennium
  • doranidazole apoptosis promotor, Pola
  • SRL-172 T cell stimulant, SR Pharma
  • CHS-828 cytotoxic agent, Leo
  • TLK-286 glutthione S transferase inhibitor, Telik
  • trans-retinoic acid differentiated by NIH
  • PT-100 growth factor agonist, Point Therapeutics
  • MX6 apoptosis promotor, MAXIA
  • PLC inhibitor PLC inhibitor, Novartis
  • apomine apoptosis promotor, ILEX Oncology
  • bryostatin-1 PLC stimulant, GPC Biotech
  • urocidin apoptosis promotor, Bioniche
  • CDA-II apoptosis promotor, Everlife
  • SDX-101 apoptosis promotor, Salmedix
  • brostallicin apoptosis promotor, Pharmacia
  • ceflatonin apoptosis promotor, ChemGenex
  • ChemGenex apoptosis promotor, ChemGenex
  • CTP-37 A VI BioPharma
  • IMC-1 C1 1 (ImClone) trastuzumab (Genentech)
  • BCX-1777 PNP inhibitor, BioCryst
  • CCI-779 mTOR kinase tocladesine (cyclic AMP agonist, inhibitor, Wyeth)
  • PG2 hematopoiesis ranpirnase (ribonuclease stimulant, enhancer, Pharmagenesis)
  • ImmunolTM galarubicin RNA synthesis inhibitor, (triclosan oral rinse, Endo)
  • GCS-100 gal3 antagonist, PBI-1402 (PMN stimulant,
  • G17DT immunogen (gastrin promotor, Procyon) bortezomib inhibitor, Aphton) (proteasome inhibitor,
  • SRL-172 T cell stimulant, SR
  • YM Biosciences (differentiator, NIH) minodronic acid (osteoclast inhibitor, PT-100 (growth factor agonist,
  • histamine histamine H2 receptor MX6 (apoptosis promotor
  • apomine apoptosis promotor, tiazofurin (IMPDH inhibitor, ILEX Oncology)
  • CDA-II apoptosis promotor
  • SR-31747 (IL-1 antagonist, Sanofi- promotor, La Roche) Synthelabo)
  • ceflatonin apoptosis promotor
  • Additional combinations may also include agents which reduce the toxicity of the aforesaid agents, such as hepatic toxicity, neuronal toxicity, nephrotoxicity and the like.
  • Compound 1 administration to humans unexpectedly results in loss of its target clAP1 from cells and tissues for longer than 1 week after administration. Additionally, it has been found as an aspect of this invention that Compound 1 results in loss of both clAP1 and clAP2 in contrast to other SMAC mimetics in development that only cause loss of clAP1 in select cell types. Compound 1 can therefore be administered less frequently than other SMAC mimetics, some of which are dosed daily. Additionally, loss of both clAP1 and clAP2 contributes to enhanced cellular potency of Compound 1 relative to other compounds that affect only clAP1 .
  • An embodiment of the present invention includes a method of stimulating the concomitant degradation of clAP1 and clAP2 by administering the Compound 1 or a pharmaceutically acceptable salt thereof to a human or non-human mammalian subject.
  • the concomitant degradation of clAP1 and clAP2 upon the administration of Compound 1 or a pharmaceutically acceptable salt thereof to a human or non-human mammalian subject occurs in less than 24 hours after administration.
  • the concomitant degradation of clAP1 and clAP2 upon the administration of Compound 1 or a pharmaceutically acceptable salt thereof to a human or non-human mammalian subject occurs in less than 12 hours after administration.
  • the concomitant degradation of clAP1 and clAP2 upon the administration of Compound 1 or a pharmaceutically acceptable salt thereof to a human or non-human mammalian subject occurs within 2 hours of administration.
  • Compound 1 and/or pharmaceutically acceptable salts thereof may be used in the treatment or prevention of proliferative, inflammatory or autoimmune disease; optionally wherein the proliferative disease is cancer; or is an autoimmune disease, inflammatory disorder, or state characterized by inflammation or cell proliferation; or treating or prevention or arthritis, or immune hypersensitivity; of infectious diseases, or inflammation; for use in preventing or treatment of thrombosis, heart attacks, or stroke.
  • the use of the SMAC mimetic compound of Formula I that further comprising the administration of a therapeutically effective amount of at least one additional active pharmaceutical ingredient for the treatment of cancer, in combination therapy.
  • the SMAC mimetic may be pre-dosed, co-dosed or post-dosed relative to the other therapeutic.
  • the SMAC mimetic compound of Formula I in combination therapy, wherein the additional pharmaceutical acceptable active ingredient is a BCL2 antagonist.
  • the BCL2 antagonist is ABT-199 (venetoclax known under the trade name Venclexta®) and it can be administered in an amount ranging from about 20 mg/day to about 400 mg/day.
  • the SMAC mimetic can be administered in an amount ranging from 0.1 mg/m 2 to 4.8 mg/m 2 once weekly or less frequently.
  • the SMAC mimetic may be pre-dosed, co- dosed or post-dosed relative to the other therapeutic.
  • the SMAC mimetic compound of Formula I in combination therapy, wherein the additional pharmaceutical acceptable active ingredient is a PARP inhibitor.
  • the PARP inhibitor is selected from rucaparib, olaparib, veliparib, talazoparib, iniparib, MK4827 (niraparib), and BBG290. More preferably the PARP inhibitor is rucaparib, and it can be administered in an amount ranging from about 300 mg/day to 600 mg/day.
  • the SMAC mimetic can be administered in an amount ranging from 0.1 mg/m 2 to 4.8 mg/m 2 once weekly or less frequently.
  • the SMAC mimetic may be pre-dosed, co-dosed or post- dosed relative to the other therapeutic.
  • the additional pharmaceutical acceptable active ingredient is a PI3K inhibitor.
  • the PI3K inhibitor is selected from idelalisib, perifosine, buparlisib, duvelisib, alpelisib, PX-866, copanlisib, Bez235, TGR1202, SF1 126, and PQR309, and LY294002.
  • the SMAC mimetic can be administered in an amount ranging from 0.1 mg/m 2 to 4.8 mg/m 2 once weekly or less frequently.
  • the SMAC mimetic may be pre-dosed, co-dosed or post-dosed relative to the other therapeutic.
  • Another embodiment of the present invention discloses the use of the SMAC mimetic compound of Formula I in combination therapy, wherein the additional pharmaceutical acceptable active ingredient is a taxane.
  • the taxane is docetaxel.
  • the SMAC mimetic can be administered in an amount ranging from 0.1 mg/m 2 to 4.8 mg/m 2 once weekly or less frequently.
  • the SMAC mimetic may be pre-dosed, co- dosed or post-dosed relative to the other therapeutic.
  • the present invention includes the use of the SMAC mimetic compound of Formula I in combination therapy, wherein the additional pharmaceutical acceptable active ingredients are a taxane and a platinum containing drug.
  • the taxane is docetaxel or paclitaxel. More preferably the taxane is docetaxel.
  • the platinum containing drug is cisplatin or oxaliplatin. More preferably the platinum containing drug is cisplatin.
  • the SMAC mimetic can be administered in an amount ranging from 0.1 mg/m 2 to 4.8 mg/m 2 once weekly or less frequently.
  • the SMAC mimetic may be pre-dosed, co-dosed or post-dosed relative to the other therapeutic.
  • the docetaxel can be administered in an amount ranging from 50 mg/m 2 to 75 mg/m 2 once weekly or less frequently.
  • the cisplatin can be administered in an amount ranging from 50 mg/m 2 to 75 mg/m 2 once weekly or less frequently.
  • Further embodiment of the present invention discloses the use of the SMAC mimetic compound of Formula I in combination therapy, wherein the additional pharmaceutical acceptable active ingredient is a camptothecin.
  • the SMAC mimetic can be administered in an amount ranging from 0.1 mg/m 2 to 4.8 mg/m 2 once weekly or less frequently.
  • the SMAC mimetic may be pre-dosed, co-dosed or post-dosed relative to the other therapeutic.
  • Another embodiment of the present invention discloses the use of the SMAC mimetic compound of Formula I in combination therapy, wherein the additional pharmaceutical acceptable active ingredient is a hypomethylating agent.
  • the hypomethylating agent is decitabine or azacytadine.
  • the SMAC mimetic compound of Formula I is administered in an amount ranging from 0.1 mg/m 2 to 4.8 mg/m 2 once weekly or less frequently.
  • the SMAC mimetic compound of Formula I is administered in an amount ranging from 0.1 mg/m 2 to 4.8 mg/m 2 once weekly or less frequently in combination with the hypomethylating agent azacytidine.
  • the SMAC mimetic may be pre-dosed, co-dosed or post-dosed relative to the other therapeutic.
  • SMAC mimetic compound of Formula I in combination therapy, wherein the additional pharmaceutical acceptable active ingredient is a platinum containing drug, preferably cisplatin or oxaliplatin. More preferably the SMAC mimetic compound of Formula I is administered in an amount ranging from about 0.1 mg/m 2 to 4.8 mg/m 2 once weekly or less frequently in com bination with cisplatin.
  • the SMAC mimetic compound of Formula I is administered in an amount ranging from about 0.1 mg/m 2 to 4.8 mg/m 2 once weekly or less frequently in combination with the platinum containing drug oxaliplatin.
  • the SMAC mimetic may be pre-dosed, co- dosed or post-dosed relative to the other therapeutic.
  • Another embodiment of the present invention discloses the use of the SMAC mimetic compound of Formula I in combination therapy, wherein the additional pharmaceutical acceptable active ingredient is a mitomycin C.
  • the SMAC mimetic compound of Formula I is administered in anamount ranging from about 0.1 mg/m 2 to 4.8 mg/m 2 once weekly or less frequently in combination with mitomyin C.
  • the SMAC mimetic may be pre-dosed, co-dosed or post-dosed relative to the other therapeutic.
  • SMAC mimetic compound of Formula I in combination therapy, wherein the additional pharmaceutical acceptable active ingredient is a TRAIL receptor agonist.
  • the TRAIL receptor agonist is selected from the group consisting of DS-8273a, mapatumumab, lexatumumab, conatumumab, APG880 and combinations thereof.
  • the SMAC mimetic compound of Formula I is administered in an amount ranging from 0.1 mg/m 2 to 4.8 mg/m 2 once weekly or less frequently in combination with a TRAIL receptor agonist.
  • the SMAC mimetic may be pre-dosed, co-dosed or post-dosed relative to the other therapeutic.
  • Another embodiment of the present invention discloses the use of the SMAC mimetic compound of Formula I in combination therapy, wherein the additional pharmaceutical acceptable active ingredient is an anti-CD20 antibody.
  • the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab IGN-002, AME-133, PR0131921 , GA101 and combinations thereof. More preferably the anti-CD20 antibody is rituximab.
  • the SMAC mimetic compound of Formula I is administered in an amount ranging from about 0.1 mg/m 2 to 4.8 mg/m 2 once weekly or less frequently in combination with an anti-CD 20 antibody.
  • the SMAC mimetic may be pre-dosed, co-dosed or post-dosed relative to the other therapeutic.
  • the present invention discloses a method of treatment that includes the administration to a subject in need thereof of a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of Compound 1 , or a pharmaceutically acceptable salt thereof.
  • Compound 1 , compositions and methods of the present invention are useful for the treatment of any cancer negatively affected by the concomitant degradation of clAP1 and clAP2, including solid tumors such as skin, breast, brain, lung, testicular carcinomas, and the like.
  • Cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to the following (Table 3):
  • osteogenic sarcoma osteogenic sarcoma (osteosarcoma), fibrosarcoma,
  • fibrous histiocytoma chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma,
  • osteochronfroma osteocartilaginous exostoses
  • benign chondroma chondroblastoma
  • chondromyxofibroma osteoid
  • sarcoma angiosarcoma, fibrosarcoma,
  • liposarcoma myxoma, rhabdomyoma, fibroma, lipoma and teratoma
  • Gastrointestinal esophagus squamous cell carcinoma, adenocarcinoma, Table 3.
  • adenocarcinoma ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma
  • small bowel adenocarcinoma, lymphoma, carcinoid
  • neurofibroma neurofibroma, fibroma), large bowel (adenocarcinoma, tubular
  • Genitourinary kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], tract lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,
  • Gynecological uterus endometrial carcinoma
  • cervix cervical carcinoma, pre-tumor cervical dysplasia
  • ovaries ovarian carcinoma
  • Leydig cell tumors Leydig cell tumors, dysgerminoma, malignant teratoma), vulva
  • squamous cell carcinoma intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma
  • vagina vagina
  • carcinoma squamous cell carcinoma, botryoid sarcoma
  • Hematologic blood myeloid leukemia [acute and chronic], acute
  • lymphoblastic leukemia chronic lymphocytic leukemia
  • myeloproliferative diseases multiple myeloma
  • myelodysplastic leukemia myelodysplastic leukemia
  • Liver hepatoma hepatocellular carcinoma
  • cholangiocarcinoma hepatoblastoma
  • angiosarcoma hepatocellular adenoma
  • hemangioma hepatocellular adenoma
  • meninges meningioma, meningiosarcoma, gliomatosis
  • brain astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform
  • oligodendroglioma oligodendroglioma, schwannoma, retinoblastoma, congenital
  • the methods of the invention can include administration of Compound 1 or a pharmaceutically acceptable salt thereof alone or in combination with one or more additional chemotherapeutic agents. Administration of multiple agents can be simultaneous or sequential.
  • Useful chemotherapeutic agents include, but are not limited to, alkylating agents (e.g., cyclophosphamide, mechlorethamine, chlorambucil, melphalan), anthracyclines (e.g., daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin), cytoskeletal disruptors (e.g., paclitaxel, docetaxel), epothilones (e.g., epothilone A, epothilone B, epothilone D), inhibitors of topoisomerase I and II (e.g., irinotecan, topotecan, etoposide, teniposide,
  • chemotherapeutic agents include fludarabine, doxorubicin, paclitaxel, docetaxel, camptothecin, etoposide, topotecan, irinotecan, cisplatin, carboplatin, oxaliplatin, amsacrine, mitoxantrone, 5-fluoro-uracil, or gemcitabine.
  • Compound 1 may be used in combination with TRAIL receptor antagonists such as DS-8273a, mapatumumab, lexatumumab, conatumumab, or APG880.
  • Compound 1 may be used in combination with BCL-2 inhibitors such as ABT-199 ((venetoclax), PARP inhibitors such as rucaparib, olaparib, veliparib, taiazoparib, iniparib, MK4827(niraparib), and BBG290 as well as PI3K inhibitors such as idelalisib, perifosine, buparlisib, duvelisib, alpelisib, PX-866, copanlisib, Bez235, TGR1202, SF1 126, and PQR309, and LY294002.
  • ABT-199 (venetoclax)
  • PARP inhibitors such as rucaparib, olaparib, veliparib, taiazoparib, iniparib, MK4827(niraparib)
  • BBG290 as well as PI3K inhibitors such as idelalisib, perif
  • the patient can be treated with the Compound 1 and/or pharmaceutically acceptable salts thereof disclosed herein in any combination with one or more checkpoint inhibitors including but not limited to PD-1 or PDL-1 antibodies such as: pembrolizumab, nivolumab, pidilizumab, BMS 936559, MPDL328OA and fragments, derivatives, conjugates, variants, radioisotope-labeled complexes, biosimilars and combinations thereof.
  • PD-1 or PDL-1 antibodies such as: pembrolizumab, nivolumab, pidilizumab, BMS 936559, MPDL328OA and fragments, derivatives, conjugates, variants, radioisotope-labeled complexes, biosimilars and combinations thereof.
  • anti-CD20 antibodies including rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, IGN-002, ocrelizumab, AME-133, PRO131921 , GA101 and fragments, derivatives, conjugates, variants, radioisotope-labeled complexes and bio
  • Compound 1 is used in combination with an anticancer vaccine, or TLR agonist to treat cancer.
  • Compound 1 or a pharmaceutically acceptable salt thereof, 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 pharmaceutically acceptable excipient, e.g., a carrier or diluent.
  • Administration is normally by intravenous injection, either as a bolus or infusion, but other routes of administration are not precluded including, e.g., subcutaneous, intramuscular, intraperitoneal, intrapleural, intrathecal, intraorbital, or intraarterial injection.
  • compositions of the present invention may be obtained by conventional procedures using conventional pharmaceutically acceptable excipients, well known in the art.
  • compositions of the present invention may be prepared as sterile injectable solutions by incorporating the Compound 1 and/or salts thereof of the present invention in the required amount in an appropriate solvent alone or with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient alone or with any additional desired ingredient from a previously sterile-filtered solution thereof.
  • an agent of the invention as described above may be formulated with one or more additional compounds that enhance the solubility of these agents. The invention also extends to such derivatives of such agents of the invention.
  • compositions of the present invention may be presented in unit- dose or multi-dose containers, such as sealed ampoules or vials. Such containers are typically sealed in such a way to preserve the sterility and stability of the formulation until use.
  • formulations may be stored as suspensions, solutions or emulsions in oily or aqueous vehicles, as indicated above.
  • a pharmaceutical composition may be stored in a freeze-dried condition requiring only the addition of a sterile liquid carrier immediately prior to use.
  • the pharmaceutical composition of the invention is a composition in which the active pharmaceutical ingredient, i.e., Compound 1 or a pharmaceutically acceptable salt thereof, is pure enough, and the composition is otherwise suitable, for internal administration to a human or other mammal. It can be prepared in unit dose form, i.e., a form suitable for single administration to a subject such as by infusion.
  • a pharmaceutical composition in intravenous unit dose form may comprise a vial or pre- filled syringe, or an infusion bag or device, each comprising a pharmaceutically effective amount of Compound 1 to supply the desired dose (or a convenient fraction of such dose), as described hereinafter, such that the contents of one vial or syringe (or a small number of multiple vials, depending upon the fraction of dose in each) are administered at a time.
  • Compound 1 is prepared in a form suitable for administration by intravenous injection.
  • Compound 1 forms an undesirable gel in the presence of saline or at basic pH.
  • Compound 1 can be supplied in solution without physiological sodium chloride, or in ethanol or other non-aqueous solution such that the formation of an undesirable gel is avoided.
  • Compound 1 can be formulated as a 5 mg/ml_ solution in sterile water for injection for further dilution prior to infusion.
  • Compound 1 in sterile water for injection, USP (5 mg/mL) will be further diluted with dextrose 5% water (D5W) to achieve the appropriate concentration of Compound 1 for IV infusion.
  • D5W dextrose 5% water
  • Compound 1 After dilution in D5W to final concentrations range from 0.001 to 1 mg/mL, or 0.005 to 0.8 mg/mL, preferably from 0.006 to 0.768 mg/mL.
  • Compound 1 can be prepared as a sterile solid powder for reconstitution in solution without physiological sodium chloride and at acidic pH such that the formation of an undesirable gel is avoided.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered by intravenous infusion, including, e.g., by infusion over an infusion period of about 1 to about 120 minutes, or 1 to about 60 minutes, e.g., about 15 minutes.
  • a dosing regimen can be, once or repeated daily, weekly, bi-weekly, monthly, twice- weekly, or three times weekly (i.e., thrice weekly) intravenous injections, or, e.g., once weekly injections in cycles of three weeks on and one week off, every week, or less frequently, for as long as the treatment is effective, e.g., until disease progresses or the drug is not tolerated.
  • the pharmaceutically effective amount administered in each injection is an amount that is effective and tolerated.
  • An effective dose is one that over the course of therapy, which may be, e.g., one or more weeks 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.
  • Doses employed in the practice of this invention can be effective in potentiating apoptosis of abnormally proliferating cells in a patient suffering a proliferative disorder such as cancer or autoimmune disease or certain other disorders, e.g., viral infection.
  • a proliferative disorder such as cancer or autoimmune disease or certain other disorders, e.g., viral infection.
  • Compound 1 can be administered intravenously, e.g., by infusion, at a dose of 0.
  • BSA patient body surface area
  • 0.05 to 5, 0.05 to 3, 0.05 to 1 , 0.1 to 5, 0.1 to 3, 0.1 to 1 , 0.2 to 1 .4 mg/m 2 administered, e.g., by infusion over about 1 to about 120 minutes, e.g., about 15 minutes.
  • the dose in most cases will be more than 0.05 mg/m 2 .
  • Current clinical studies employ about 0.1 mg/m 2 to about 5 mg/m 2 , specifically, 0.1 to 4.8 mg/m 2 .
  • compositions of the instant invention refer to compositions suitable for administration in a medical use, i.e., internal administration to a patient.
  • Compositions suitable for infusion in accordance with the method of this invention conveniently comprise a sterile aqueous preparation of Compound 1 , which is preferably isotonic with the blood of the recipient.
  • This aqueous preparation may be formulated according to known methods using suitable carriers or diluents which may include a buffer.
  • this invention comprises a pharmaceutical dosage unit comprising Compound 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients in an aqueous solvent for use in intravenous or subcutaneous administration for the treatment of a cancer or an autoimmune disorder.
  • Compound 1 or a pharmaceutically acceptable salt thereof can occur simultaneous with, subsequent to, or prior to the combination therapy, such as chemotherapy or radiation, so long the target cells are sensitized to the chemotherapeutic agent or radiation by the method and compositions of the present invention or vice versa.
  • Compound 1 and/or pharmaceutically acceptable salts thereof of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of the present disclosure or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound and/or pharmaceutically acceptable salt thereof of the present disclosure is possible.
  • the combination therapy may also include therapies in which Compound 1 and/or pharmaceutically acceptable salts thereof of the present disclosure and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds and/or pharmaceutically acceptable salts thereof of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other pharmaceutically acceptable active ingredients, in addition to Compound 1 and/or pharmaceutically acceptable salts thereof of the present disclosure.
  • the above combinations include combinations of Compound 1 of the present disclosure not only with one other pharmaceutically acceptable active compound, but also with two or more other pharmaceutically acceptable active compounds.
  • Compound 1 and/or pharmaceutically acceptable salts thereof of the present disclosure may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present disclosure are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefore by those skilled in the art, contemporaneously or sequentially with a compound and/or pharmaceutically acceptable salt thereof of the present disclosure.
  • compositions of the present disclosure also include those that also contain one or more other pharmaceutically acceptable active ingredients, in addition to Compound 1 and/or pharmaceutically acceptable salts thereof of the present disclosure.
  • the weight ratio of the compound and/or pharmaceutically acceptable salt thereof of the present disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, a pharmaceutically acceptable effective dose of each will be used.
  • Compound 1 and/or pharmaceutically acceptable salts thereof may also be administered simultaneously with, prior to, or after administration of one or more of the therapeutic agents described above.
  • Such combination therapy may include administration of a single pharmaceutical dosage formulation which contains a compound of the present invention and one or more additional agents given below, as well as administration of the compound of the present invention and each of additional agent in its own separate pharmaceutical dosage formulation.
  • the present invention includes combinations of Compound 1 and/or pharmaceutically acceptable salts thereof and anti-CD20 antibodies selected from rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab IGN-002, AME- 133, PR0131921 , GA101 and combinations thereof.
  • anti-CD20 antibodies selected from rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab IGN-002, AME- 133, PR0131921 , GA101 and combinations thereof.
  • the Compound and/or pharmaceutically acceptable salts thereof of the present invention, and one or more additional agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.
  • the present invention includes combinations of Compound 1 and/or pharmaceutically acceptable salts thereof and TRAIL receptor antagonists selected from DS-8273a, mapatumumab, lexatumumab, conatumumab, APG880 and combinations thereof.
  • TRAIL receptor antagonists selected from DS-8273a, mapatumumab, lexatumumab, conatumumab, APG880 and combinations thereof.
  • the Compound 1 and/or pharmaceutically acceptable salts thereof of the present invention and one or more additional agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.
  • Compound 1 also known as AEG40826 or HGS1029 are provided in the following Examples.
  • Example 1 Efficacy of Compound 1 in combination with Rituximab (Anti-CD20) treatment in a mouse model of lymphoma.
  • the effect of combining Compound 1 with Rituximab was examined in a mouse model of Burkitt's lymphoma ( Figure 2).
  • Ramos cells were injected into the flank of female SCID mice and allowed to grow to an average size of 330mm 3 .
  • Compound 1 (AEG40826) was administered once weekly at a dose of 5 mg/kg by intravenous bolus tail vein injection.
  • Rituximab (Rituxan®) was administered once weekly at a dose of 10 mg/kg by intravenous bolus tail vein injection. Tumor sizes were measured by caliper. Data indicate that Compound 1 has some single agent activity against the lymphoma cancer cells and that the combination of Compound 1 and Rituximab resulted in strong anti-cancer efficacy.
  • Human HCT-1 1 16 colorectal tumor cells were treated with SMAC mimetics for 72 hours in the presence of 10ng/mL recombinant human TRAIL (Figure 3). Cellular viability was measured by Cell Titre Glo (Promega). Data indicates that Compound 1 is approximately 4 fold more potent than birinapant.
  • Example 3 Efficacy of Compound 1 in combination with BCL-2 inhibition.
  • Human A2780 ovarian carcinoma cells grown in monolayer culture were treated with 5 uM BCL2 inhibitor ABT-199 ((Venetoclax known as Venclexta®) for 72 hours in the presence of a concentration curve of Compound 1 (Figure 4).
  • Cellular viability was measured by Cell Titre Glo (Promega). Data indicate that the BCL2 inhibitor had less than 20% effect on cell viability and that addition of Compound 1 resulted in improved potency.
  • Example 5 Efficacy of Compound 1 in combination with PI3K inhibition Human MV41 1 leukemia cells grown in culture were treated with 750 nM PI3K inhibitor LY294002 for 72 hours in the presence of a concentration curve of Compound 1 (Figure 6). Cellular viability was measured by Cell Titre Glo (Promega). Data indicate that the PI3K inhibitor had less approximately 20% effect on cell viability and that addition of Compound 1 resulted in decreased cancer cell viability.
  • Example 7 Efficacy of Compound 1 in combination with Camptothecin, Mitomycin C or Oxaliplatin.
  • HCT1 16 colorectal tumor cells were grown in monolayer culture and were treated for 72 hours with 10nM or 10OnM Compound 1 alone or in the presence of camptothecin, mitomycin C or oxaliplatin. Cell viability was measured using MTT reagent (Promega). Data ( Figure 8) show that Compound 1 did not affect the viability of the tumor cells as a single agent. Camptothecin, mitomycin C and oxaliplatin treatment resulted in reduced cellular viability. Addition of Compound 1 to either camptothecin, mitomycin C or oxaliplatin resulted in increased anti-cancer effect.
  • Platinum compounds including cisplatin are a mainstay of current cancer therapy.
  • Compound 1 sensitizes an orthotopic breast tumor model to cisplatin.
  • Compound 1 was dosed five days per week from day 23 to day 49.
  • Cisplatin was given on days 15 and 22. Neither 5 mg/kg cisplatin nor 0.3 mg/kg Compound 1 significantly affected tumor growth as single agents. When co-dosed, Compound 1 synergized with cisplatin to produce a reduction in tumor growth (Figure 10).
  • Example 10 Compound 1 causes degradation of clAP1 and clAP2 in tumor cells Hey ovarian cancer cells were treated with the following Smac mimetics: Compound (AEG40286), birinapant and LCL-161 . Cell proteins were harvested after 3 or 18 hours of treatment. clAPI levels were detected and quantified in cell lysates by clAPI specific ELISA. clAP2 levels were detected by western blot and quantified using a Licor Odyssey scanner. Data show that Compound 1 more potently causes reduction of clAPI than either LCL-161 or birinapant at either 3 or 18 hours of treatment (Figure 1 1 ). Compound 1 results in loss of clAP2 at 3 hours.
  • Compound 1 does not cause an increase in clAP2 levels at 18 hours in contrast to LCL-161 and birinapant which increase clAP2 levels to approximately 140 and 180 percent of control, respectively. These results are consistent with enhanced efficacy of Compound 1 .
  • Example 11 Administration of Compound 1 and pharmacokinetics in cancer patients. Plasma exposure of Compound 1 was measured in cancer patients treated with Compound 1 in a clinical trial (NCT00708006). Compound 1 in water at a
  • Example 12 Peripheral blood mononuclear cell levels of clAPI and clAP2 following administration of Compound 1.
  • Peripheral blood samples were obtained from patients immediately prior to administration of Compound 1 and 2 hours post-administration. Cells were lysed and clAP1 and clAP2 levels were detected by quantitative ELISA. Samples were collected on day 1 pre and post infusion as well as one week later pre and post infusion and on subsequent week. Data indicates that administration of Compound 1 resulted in profound loss of clAP1 which was maintained for at least one week at doses of 0.2 mg/m 2 and higher ( Figure 13).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Hematology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Biomedical Technology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un composé mimétique de SMAC et des compositions pharmaceutiques de celui-ci, plus spécifiquement, la présente invention concerne un composé 1 ayant la structure suivante : (I) des sels pharmaceutiquement acceptable de celui-ci et des compositions pharmaceutiques comprenant celui-ci, et leur utilisation seuls ou en combinaison dans le traitement de troubles prolifératifs, comprenant des cancers. La présente invention concerne en outre une composition pharmaceutique dans une dose unitaire pour perfusion intraveineuse qui comprend l'administration interne au patient d'un mimétique de SMAC, leurs régimes et posologie pour traiter un trouble prolifératif chez un patient. L'invention comprend en outre la stimulation de la dégradation concomitante de cIAP1 et cIAP2 dans des cellules cancéreuses.
PCT/CA2017/050019 2016-01-08 2017-01-06 Composé mimétique de smac pour utilisation dans le traitement de maladies prolifératives WO2017117684A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CA2.916.970 2016-01-08
CA2916970A CA2916970A1 (fr) 2016-01-08 2016-01-08 Un compose mimetique smac destine au traitement des maladies proliferatives

Publications (1)

Publication Number Publication Date
WO2017117684A1 true WO2017117684A1 (fr) 2017-07-13

Family

ID=59270788

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2017/050019 WO2017117684A1 (fr) 2016-01-08 2017-01-06 Composé mimétique de smac pour utilisation dans le traitement de maladies prolifératives

Country Status (2)

Country Link
CA (1) CA2916970A1 (fr)
WO (1) WO2017117684A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020109328A1 (fr) 2018-11-26 2020-06-04 Debiopharm International S.A. Traitement combiné d'infections au vih
CN111918667A (zh) * 2018-02-05 2020-11-10 特沙诺有限公司 儿科尼拉帕尼配制剂和儿科治疗方法
WO2021058794A1 (fr) 2019-09-25 2021-04-01 Debiopharm International S.A. Schémas posologiques pour le traitement de patients présentant un carcinome localement avancé des cellules squameuses
WO2023239422A2 (fr) 2021-10-22 2023-12-14 University Of Houston System Méthodes et compositions pour traiter une lésion inflammatoire chronique, une métaplasie, une dysplasie et des cancers des tissus épithéliaux

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112425560A (zh) * 2020-10-27 2021-03-02 纳肽得有限公司 皮肤增生性瘢痕动物模型及其构建方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7579320B2 (en) * 2006-03-16 2009-08-25 Aegera Therapeutics, Inc. IAP BIR domain binding compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7579320B2 (en) * 2006-03-16 2009-08-25 Aegera Therapeutics, Inc. IAP BIR domain binding compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FULDA, S .: "Molecular Pathways: Targeting Inhibitor of Apoptosis Proteins in Cancer-From Molecular Mechanism to Therapeutic Application", CLIN. CANCER RES., vol. 20, no. 2, 22 November 2013 (2013-11-22), pages 289 - 295, XP055397815, ISSN: 1078-1032 *
FULDA, S.: "Promises and Challenges of Smac Mimetics as Cancer Therapeutics", CLIN. CANCER RES., vol. 21, no. 22, 25 November 2015 (2015-11-25), pages 5030 - 5036, XP055397813, ISSN: 1078-1032 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111918667A (zh) * 2018-02-05 2020-11-10 特沙诺有限公司 儿科尼拉帕尼配制剂和儿科治疗方法
WO2020109328A1 (fr) 2018-11-26 2020-06-04 Debiopharm International S.A. Traitement combiné d'infections au vih
WO2021058794A1 (fr) 2019-09-25 2021-04-01 Debiopharm International S.A. Schémas posologiques pour le traitement de patients présentant un carcinome localement avancé des cellules squameuses
WO2023239422A2 (fr) 2021-10-22 2023-12-14 University Of Houston System Méthodes et compositions pour traiter une lésion inflammatoire chronique, une métaplasie, une dysplasie et des cancers des tissus épithéliaux

Also Published As

Publication number Publication date
CA2916970A1 (fr) 2017-07-08

Similar Documents

Publication Publication Date Title
US9365614B2 (en) IAP BIR domain binding compounds
US7795298B2 (en) IAP BIR domain binding compounds
US20070099905A1 (en) Combinations of drugs for the treatment of neoplasms
US8648094B2 (en) IAP BIR domain binding compounds
US11191854B2 (en) Pharmacokinetic enhancements of bifunctional chelates and uses thereof
WO2017117684A1 (fr) Composé mimétique de smac pour utilisation dans le traitement de maladies prolifératives
US20210290788A1 (en) Radioimmunoconjugates and dna damage and repair inhibitor combination therapy
US20110117081A1 (en) Functionalized pyrrolidines and use thereof as iap inhibitors
US20050054708A1 (en) Combinations of drugs for the treatment of neoplasms
US20110177060A1 (en) Iap bir domain binding compounds
WO2004007676A2 (fr) Therapie combinee servant a traiter des tumeurs
TW202317204A (zh) 放射免疫結合物及檢查點抑制劑組合療法
CN101360728A (zh) Iap bir结构域结合化合物
TW202337451A (zh) Ｎｔｓｒ１靶向放射性藥物及ｄｎａ損傷反應抑制劑之組合療法
TW202337450A (zh) Ｎｔｓｒ１靶向放射性藥物及檢查點抑制劑之組合療法
US20120141496A1 (en) Iap bir domain binding compounds
WO2005117847A2 (fr) Methodes et composes de traitement de neoplasmes

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17735794

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17735794

Country of ref document: EP

Kind code of ref document: A1