WO2015095250A1 - Thérapie anticancéreuse combinée avec des inhibiteurs de wee1 et mtor - Google Patents

Thérapie anticancéreuse combinée avec des inhibiteurs de wee1 et mtor Download PDF

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WO2015095250A1
WO2015095250A1 PCT/US2014/070697 US2014070697W WO2015095250A1 WO 2015095250 A1 WO2015095250 A1 WO 2015095250A1 US 2014070697 W US2014070697 W US 2014070697W WO 2015095250 A1 WO2015095250 A1 WO 2015095250A1
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Prior art keywords
inhibitors
cancer
inhibitor
weel
combination
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PCT/US2014/070697
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English (en)
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Stuart SHUMWAY
Yair BENITA
Igor Feldman
Jennifer O'neil
Andrew Bloecher
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Merck Sharp & Dohme Corp.
Ariad Pharmaceuticals, Inc.
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Publication of WO2015095250A1 publication Critical patent/WO2015095250A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compositions and methods for treating cellular proliferative disorders or disorders associated with WEE1 kinase and mTor activity and for inhibiting WEE1 kinase and mTor activity.
  • PI3K phosphatidylinositol-3 -kinase
  • mTOR is a critical downstream effector molecule that regulates the production of proteins critical for cell cycle progression and many other important cellular growth processes. See, Abraham RT and Gibbons, JJ, "The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy.” Clin Cancer Res, 2007; 13(11) 3109-14.
  • Dysregulation of the PI3 kinase axis is common in human cancer due to overactive growth factor receptor signaling, activating mutations of PI3K, loss of function of the PTEN tumor suppressor, and several other mechanisms that result in activation of mTOR kinase activity.
  • Clinically, successful pharmacological inhibition of the PI3K axis has focused on the upstream growth factor receptors and the downstream effectors of PI3 kinase, such as mTOR.
  • mTOR inhibitors can provide clinical benefit to patients with advanced malignancies.
  • WEEl activity can be increased as a result of DNA damage, causing cells to arrest in G2 and allowing for repair of DNA lesions before beginning mitosis (Raleigh, J.M., and O'Connell, M.J., J. Cell Sci., 2000, 113(10): 1727-1736).
  • WEEl has been shown to be indispensible for genomic integrity specifically as cells traverse S-phase, describing a previously unrecognized role for WEEl in maintaining fidelity of DNA replication (Beck. H., et al, J. Cell Biology, 2010, 188(5):629-638).
  • Combining cancer therapeutics is one approach to circumventing some of these mechanisms with the desired outcome being improved efficacy.
  • the instant invention relates generally to methods for treating cancer by administering a therapeutically effective amount of the combination of a WEEl inhibitor and an mTor inhibitor.
  • the WEEl inhibitor is WEE 1-1 or a pharmaceutically acceptable salt thereof, or WEE 1-2 or a pharmaceutically acceptable salt thereof
  • the mTOR inhibitor is ridaforolimus, everolimus, temsirolimus, a rapamycin-analog or a pharmaceutically acceptable salt thereof.
  • FIG. 1 Synergistic interaction of WEEl- 1 and ridaforolimus in 39 solid tumor cell lines (lung (NCIH1650, A427, NCIH520, SKMES1, MSTO, NCIH460, NCIH2122, NCIH23), breast (KPL1, OCUBM, EFM192B, T47D, MDAMB436, ZR751), colon (DLD1, RKO, HT29, SW620, LOVO, SW837, COLO320DM, HCT116), ovarian (SKOV3, A2780, PA1, ES2, OVCAR3, OV90, UWB1289BRCA1, CAOV3, UWB1289, prostate (LNCAP, VCAP) or melanoma (A375, A2058, SKMEL30, UAC062, RPMI7951, HT144)).
  • lung NCIH1650, A427, NCIH520, SKMES1, MSTO, NCIH460, NCIH2122, NCIH23
  • breast KPL1,
  • vBliss is the volumetric difference between the surface of predicted combination effect and the surface of observed combination effect as illustrated in Figure 2.
  • FIG. 2A The A2780 (Fig. 2A) and SKOV-3 (Fig. 2B) ovarian cancer cell lines were used to validate the synergy observed in the screen. Eight concentrations each of WEEl-1 and Ridaoforolimus were titrated and proliferation at 72 hours was plotted as a fraction of
  • DMSO treated control cells The predicted effect on proliferation (using Bliss synergy model) is represented as the upper surface on the plot whereas the observed effect on proliferation is represented by black dots. Observed effects are connected by vertical lines to the corresponding Bliss predicted effect for those concentrations.
  • mTORi in A2780 ovarian cancer xenograft model.
  • A2780 tumor bearing mice were treated with a single dose of ridaforolimus (1 mg/kg), WEEl-1 (60 mg/kg), or both. Tumors were processed at either 4 hours or 24 hours post dose for Western blotting against phosphotyrosine 15 of Cdc2 (pCdc2-Y15), total Cdc2, phosphoserine 235/236 of ribosomal protein S6 (pS6rp), total S6rp, cleaved PARP, and GAPDH as a loading control.
  • FIG. 4 Kaplan-Meier plot for survival of A2780 tumor bearing mice in the study. Mice were treated until tumors reached > 1,000 mm3 at which time they were removed from the study. Mice treated with vehicle are illustrated as lines with dots. Mice treated with ridaforolimus are illustrated as lines with squares. Mice treated with WEEl-1 are illustrated as lines with triangles pointing up. Mice treated with WEEl-1 and ridaforolimus are illustrated as lines with triangles pointing down.
  • FIG. 5 Efficacy was tested for the monotherapies of WEEl-1 and ridaforolimus (mTOR-1) at their MTD as well as the drug combination in two xenograft models of ovarian cancer, A2780 ( Figure 5A) and SKOV-3 ( Figure 5B).
  • Applicants have unexpectedly found that synergistic anticancer activity can be achieved by using a WEEl inhibitor with an mTor inhibitor, specifically wherein the WEEl inhibitor is WEEl-1 or a pharmaceutically acceptable salt thereof, or WEE 1-2 or a
  • WEEl is a central regulator of CDKl/2 and prevents premature CDK activation in unperturbed DNA replication as well as in the presence of DNA damaging agents.
  • mTOR is a central mediator of the PI3K pathway and has roles in controlling cell growth and proliferation.
  • the instant invention relates to methods for treating
  • the invention also provides the combination of a WEEl inhibitor and an mTOR inhibitor for the treatment of cancer.
  • the WEEl inhibitor is WEE 1-1 or a pharmaceutically acceptable salt thereof, or WEE 1-2 or a pharmaceutically acceptable salt thereof
  • the mTOR inhibitor is ridaforolimus, everolimus, temsirolimus, a rapamycin-analog or a pharmaceutically acceptable salt thereof.
  • the instant invention also relates to methods for treating cellular proliferative disorders or disorders associated with WEEl kinase and mTor activity by administering a therapeutically effective amount of the combination of a WEEl inhibitor and an mTOR inhibitor.
  • the invention also provides the combination of a WEEl inhibitor and an mTOR inhibitor for the treatment of cellular proliferative disorders or disorders associated with WEEl kinase and mTor activity.
  • the instant invention also relates to methods for modulating the activity of WEEl kinase and mTor in a patient by administering a therapeutically effective amount of the combination of a WEEl inhibitor and an mTOR inhibitor.
  • the invention also provides the combination of a WEEl inhibitor and an mTOR inhibitor for modulating the activity of WEEl kinase and mTor.
  • the WEEl inhibitor is WEEl-1 or a pharmaceutically acceptable salt thereof.
  • the mTOR inhibitor is ridaforolimus or a pharmaceutically acceptable salt thereof.
  • the WEEl inhibitor is administered in a dose between 100 mg per day and 250 mg per day.
  • the WEE1 inhibitors may be dosed twice a day (BID) over the course of two and a half days (for a total of 5 doses) or once a day (QD) over the course of two days (for a total of 2 doses).
  • the WEE1 inhibitor is administered in a dose between 200 mg per day and 400 mg per day, and preferably 250 -350 mg per day.
  • the WEE1 inhibitors may be dosed once a day (QD) over the course of five days.
  • the mTOR inhibitor is administered in a dose between 10 mg and 40 mg.
  • the ridaforolimus is administered five times a week.
  • the WEE1 inhibitor and the mTOR inhibitor can be prepared for simultaneous, separate or successive administration.
  • Successessive as referred to in this description means that administration of one pharmaceutical preparation is followed by administration of the other pharmaceutical preparation; after administration of one pharmaceutical preparation, the second pharmaceutical preparation can be administered substantially immediately after the first pharmaceutical preparation, or the second pharmaceutical preparation can be administered after an effective time period after the first pharmaceutical preparation; and the effective time period is the amount of time given for realization of maximum benefit from the administration of the first
  • cancer as referred to in this description includes various sarcoma and carcinoma and includes solid cancer and hematological malignancy.
  • the solid cancer as referred to herein includes, for example, brain cancer, cervicocerebral cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, endometrial cancer, lung cancer, stomach cancer, gallbladder/bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterus body cancer, uterocervical cancer, renal pelvis/ureter cancer, bladder cancer, prostate cancer, penis cancer, testicles cancer, fetal cancer, Wilms' tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, and soft part sarcoma.
  • the hematological cancer includes, for example, acute leukemia, chronic lymphatic leukemia, chronic myelocytic leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma, and non- Hodgkin's lymphoma.
  • treatment of cancer means that an anticancer agent is administered to a cancer patient so as to inhibit the growth of the cancer cells in the patient.
  • the treatment results in cancer growth regression and/or a reduction in the size of a detectable tumor.
  • the treatment results in complete disappearance of cancerous tumor(s).
  • the mTOR inhibitors in current clinical development are structural analogs of rapamycin.
  • the mTOR inhibitors of the instant invention include ridaforolimus, temsirolimus, everolimus, a rapamycin-analog and combinations thereof.
  • Ridaforolimus also known as AP 23573 and deforolimus, is a unique, non- prodrug analog of rapamycin that has antiproliferative activity in a broad range of human tumor cell lines in vitro and in murine tumor xenograft models utilizing human tumor cell lines.
  • Temsirolimus also known as Torisel®, is currently marketed for the treatment of renal cell carcinoma.
  • Torisel® Temsirolimus
  • Everolimus also known as Certican® or RAD001, marketed by Novartis, has greater stability and enhanced solubility in organic solvents, as well as more favorable pharmokinetics with fewer side effects, than rapamycin (sirolimus). Everolimus has been used in conjunction with microemulsion cyclosporin (Neoral®, Novartis) to increase the efficacy of the immunosuppressive regime.
  • the WEE1 inhibitor used in the methods of the instant invention is -1, the structure of which is as shown below.
  • WEEl-1 is a WEE1 inhibitor which may be useful for the treatment of cancer.
  • WEEl-1 is also known as 2-allyl-l-[6-(l-hydroxy-l-methylethyl)pyridin-2-yl]-6- ⁇ [4-(4- methylpiperazin- 1 -yl)phenyl] amino ⁇ - 1 ,2-dihydro-3H-pyrazolo[3 ,4-d]pyrimidin-3-one.
  • WEE 1-1 has been described in U.S. Patent No.7, 834,019, and in PCT International Publications
  • the WEE1 inhibitor of the instant invention is WEE 1-2, the structure of which is as shown below.
  • WEE 1-2 is a WEE1 inhibitor which may be useful for the treatment of cancer.
  • WEE1-2 is also known as 3-(2,6-dichlorophenyl)-4-imino-7-[(2'-methyl-2',3'-dihydro- H- spiro[cyclopropane-l,4'-isoquinolin]-7'-yl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(lH)- one.
  • WEE 1-2 has been described in PCT International Publication WO2008/153207 and US Publication US2011-0135601, which are incorporated by reference herein in their entirety.
  • Crystalline forms of WEE 1-2 are described in International Publication WO2009/151997 and US Publication US2011-0092520, which are incorporated by reference herein in their entirety.
  • the compounds used in the methods of the instant invention may also exist as various crystalline forms, amorphous substances, pharmaceutically acceptable salts, hydrates and solvates.
  • the compounds may be provided as prodrugs.
  • prodrugs are functional derivatives of the inhibitors used in the methods of the instant invention that can be readily converted into compounds that are needed by living bodies. Accordingly, in the methods of treatment of various cancers of the invention, the term "administration" includes not only the administration of a specific compound but also the administration of a compound which, after administered to patients, can be converted into the specific compound in the living body.
  • Metabolites of the compound may include active compounds that are produced by putting the compound in a biological environment, and are within the scope of the compounds described in the invention.
  • the compounds used in the methods of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119- 1190), and may occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, all such stereoisomers being included in the present invention.
  • the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include use of all suitable isotopic variations of the compounds disclosed herein.
  • different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Iso topically-enriched compounds disclosed herein can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. Dosing and Routes of Administration
  • mTOR inhibitors and WEE1 inhibitors used in the methods of the invention various preparation forms can be selected, and examples thereof include oral preparations such as tablets, capsules, powders, granules or liquids, or sterilized liquid parenteral preparations such as solutions or suspensions, suppositories, ointments and the like.
  • oral preparations such as tablets, capsules, powders, granules or liquids
  • sterilized liquid parenteral preparations such as solutions or suspensions, suppositories, ointments and the like.
  • the mTOR inhibitors and WEE1 inhibitors described in the present invention are prepared with
  • pharmaceutically acceptable salt means a conventional, well-known pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt when the compound has a hydroxy 1 group, or an acidic group such as a carboxyl group then it may form a base-addition salt at the hydroxyl group or the acidic group; or when the compound has an amino group or a basic heterocyclic group, then it may form an acid-addition salt at the amino group or the basic heterocyclic group.
  • the base-addition salts include, for example, alkali metal salts such as sodium salts, potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts;
  • ammonium salts and organic amine salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, and N,N'-dibenzylethylenediamine salts.
  • the acid-addition salts include, for example, inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, and perchlorates; organic acid salts such as maleates, fumarates, tartrates, citrates, ascorbates, and trifluoroacetates; and sulfonates such as methanesulfonates, isethionates, benzenesulfonates, and p-toluenesulfonates.
  • inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, and perchlorates
  • organic acid salts such as maleates, fumarates, tartrates, citrates, ascorbates, and trifluoroacetates
  • sulfonates such as methanesulfonates, isethionates, benzenesulfonates, and p-toluene
  • pharmaceutically acceptable carrier or diluent refers to excipients [e.g., fats, beeswax, semi-solid and liquid polyols, natural or hydrogenated oils, etc.]; water (e.g., distilled water, particularly distilled water for injection, etc.), physiological saline, alcohol (e.g., ethanol), glycerol, polyols, aqueous glucose solution, mannitol, plant oils, etc.); additives [e.g., extending agent, disintegrating agent, binder, lubricant, wetting agent, stabilizer, emulsifier, dispersant, preservative, sweetener, colorant, seasoning agent or aromatizer, concentrating agent, diluent, buffer substance, solvent or solubilizing agent, chemical for achieving storage effect, salt for modifying osmotic pressure, coating agent or antioxidant], and the like.
  • excipients e.g., fats, beeswax, semi-solid and
  • Solid preparations can be prepared in the forms of tablet, capsule, granule and powder without any additives, or prepared using appropriate carriers (additives).
  • carriers may include saccharides such as lactose or glucose; starch of corn, wheat or rice; fatty acids such as stearic acid; inorganic salts such as magnesium metasilicate aluminate or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycol; alcohols such as stearyl alcohol or benzyl alcohol; synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose or
  • hydroxypropylmethylcellulose hydroxypropylmethylcellulose
  • other conventionally used additives such as gelatin, talc, plant oil and gum arabic.
  • These solid preparations such as tablets, capsules, granules and powders may generally contain, for example, 0.1 to 100% by weight, and preferably 5 to 98%> by weight, of the inhibitor, based on the total weight of each preparation.
  • Liquid preparations are produced in the forms of suspension, syrup, injection and drip infusion (intravenous fluid) using appropriate additives that are conventionally used in liquid preparations, such as water, alcohol or a plant-derived oil such as soybean oil, peanut oil and sesame oil.
  • appropriate solvent or diluent may be exemplified by distilled water for injection, an aqueous solution of lidocaine hydrochloride (for intramuscular injection), physiological saline, aqueous glucose solution, ethanol, polyethylene glycol, propylene glycol, liquid for intravenous injection (e.g., an aqueous solution of citric acid, sodium citrate and the like) or an electrolytic solution (for intravenous drip infusion and intravenous injection), or a mixed solution thereof.
  • distilled water for injection an aqueous solution of lidocaine hydrochloride (for intramuscular injection), physiological saline, aqueous glucose solution, ethanol, polyethylene glycol, propylene glycol, liquid for intravenous injection (e.g., an aqueous solution of citric acid, sodium citrate and the like) or an electrolytic solution (for intravenous drip infusion and intravenous injection), or a mixed solution thereof.
  • Such injection may be in a form of a preliminarily dissolved solution, or in a form of powder per se or powder associated with a suitable carrier (additive) which is dissolved at the time of use.
  • the injection liquid may contain, for example, 0.1 to 10% by weight of an active ingredient based on the total weight of each preparation.
  • Liquid preparations such as suspension or syrup for oral administration may contain, for example, 0.1 to 10% by weight of an active ingredient based on the total weight of each preparation.
  • Each preparation in the invention can be prepared by a person having ordinary skill in the art according to conventional methods or common techniques.
  • a preparation can be carried out, if the preparation is an oral preparation, for example, by mixing an appropriate amount of the compound of the invention with an appropriate amount of lactose and filling this mixture into hard gelatin capsules which are suitable for oral administration.
  • preparation can be carried out, if the preparation containing the compound of the invention is an injection, for example, by mixing an appropriate amount of the compound of the invention with an appropriate amount of 0.9% physiological saline and filling this mixture in vials for injection.
  • the components of this invention may be administered to mammals, including humans, either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the components can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • Suitable dosages are known to medical practitioners and will, of course, depend upon the particular disease state, specific activity of the composition being administered, and the particular patient undergoing treatment. In some instances, to achieve the desired therapeutic amount, it can be necessary to provide for repeated administration, i.e., repeated individual administrations of a particular monitored or metered dose, where the individual administrations are repeated until the desired daily dose or effect is achieved. Further information about suitable dosages is provided below.
  • administration and variants thereof (e.g., “administering” a compound) in reference to a component of the invention means introducing the component or a prodrug of the component into the system of the animal in need of treatment.
  • a component of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., the mTOR inhibitor)
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the component or prodrug thereof and other agents.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • a suitable amount of an mTOR inhibitor is administered to a patient undergoing treatment for cancer.
  • the mTOR inhibitor is administered in doses from about 10 mg - 40 mg per day.
  • the mTOR inhibitor is administered in a dose of 10 mg per day.
  • the mTOR inhibitor is administered in a dose of 20 mg per day.
  • the mTOR inhibitor is administered in a dose of 30 mg per day.
  • the mTOR inhibitor is administered in a dose of 40 mg per day.
  • the mTOR inhibitor can be administered 5 times per week. For example, ridaforolimus is started on Day 1, and continued at the specified dosing level for five consecutive days, followed by two days of no ridaforolimus treatment. Ridaforolimus is then continued on this daily X 5 schedule each week.
  • a suitable amount of a WEEl inhibitor is administered to a patient undergoing treatment for cancer.
  • the WEEl inhibitor is administered in a dose between 100 mg per day and 250 mg per day.
  • the WEEl inhibitors may be dosed twice a day (BID) over the course of two and a half days (for a total of 5 doses) or once a day (QD) over the course of two days (for a total of 2 doses).
  • the WEEl inhibitor is administered in a dose between 200 mg per day and 400 mg per day, and preferably 250 -350 mg per day.
  • the WEEl inhibitors may be dosed once a day (QD) over the course of five days.
  • the combination therapeutic comprising the WEEl inhibitors and mTOR inhibitors of the invention are administered to a human patient, in accord with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerebrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, or inhalation routes.
  • known methods such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerebrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, or inhalation routes.
  • compositions of the present invention are administered in a therapeutically effective or synergistic amount.
  • a therapeutically effective or synergistic amount As used herein, a
  • therapeutically effective amount is such that co-administration of a WEEl inhibitor and an mTor inhibitor, or administration of a composition of the present invention, results in reduction or inhibition of the targeting disease or condition.
  • a therapeutically synergistic amount is that amount of WEEl inhibitor and mTOR inhibitor necessary to synergistically or significantly reduce or eliminate conditions or symptoms associated with a particular disease.
  • the treatment of the present invention involves the combined administration of a WEEl inhibitor and an mTOR inhibitor.
  • the combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities.
  • Preparation and dosing schedules for such chemotherapeutic agents may be used according to manufacturers' instructions or as determined empirically by the skilled practitioner. Preparation and dosing schedules for chemotherapy are also described in Chemotherapy Service Ed., M. C. Perry, Williams & Wilkins, Baltimore, Md. (1992).
  • the mTOR inhibitor may precede or follow administration of the WEE1 inhibitor or may be given simultaneously therewith.
  • the clinical dosing of therapeutic combination of the present invention could be affected by the extent of adverse reactions.
  • An mTOR inhibitor and WEE1 inhibitor combination of the instant invention may also be useful in combination with additional therapeutic, chemotherapeutic and anti-cancer agents. Further combinations of an mTOR inhibitor and WEE1 inhibitor combination of the instant invention with therapeutic, chemotherapeutic and anti-cancer agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Such additional agents include the following: estrogen receptor modulators, programmed cell death protein 1 (PD-1) inhibitors, programmed death-ligand 1 (PD- Ll) inhibitors, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, ⁇ -secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and agents that interfere with cell cycle checkpoints.
  • the mTOR inhibitor and WEE1 inhibitor combination of the instant invention may be particularly useful when co- administered with radiation therapy.
  • PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab and
  • Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381,
  • LY117081 toremifene, fulvestrant, 4-[7-(2,2-dimethyl-l-oxopropoxy-4-methyl-2-[4-[2-(l- piperidinyl)ethoxy]phenyl]-2H-l-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4'- dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.
  • “Androgen receptor modulators” refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5a-reductase inhibitors, nilutamide, fiutamide, bicalutamide, liarozole, and abiraterone acetate.
  • Retinoid receptor modulators refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, a- difluoromethylornithine, ILX23-7553, trans-N-(4'-hydroxyphenyl) retinamide, and N-4- carboxyphenyl retinamide.
  • Cytotoxic/cytostatic agents refer to compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins, histone deacetylase inhibitors, inhibitors of kinases involved in mitotic progression, inhibitors of kinases involved in growth factor and cytokine signal transduction pathways, antimetabolites, biological response modifiers, hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteosome inhibitors, ubiquitin ligase inhibitors, and aurora kinase inhibitors.
  • cytotoxic/cytostatic agents include, but are not limited to, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2- methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu- (hexane-l,6-d
  • hypoxia activatable compound is tirapazamine.
  • proteosome inhibitors include but are not limited to lactacystin and MLN-341 (Velcade).
  • microtubule inhibitors/microtubule-stabilising agents include paclitaxel, vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS 184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L- proline-t-butylamide, TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and 6,288,237)
  • topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3',4'-0-exo-benzylidene-chartreusin, 9-methoxy-N,N- dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, l-amino-9-ethyl-5-fluoro-2,3- dihydro-9-hydroxy-4-methyl-lH,12H-benzo[de]pyrano[3',4' :b,7]-indolizino[l,2b]quinoline- 10, 13(9H, 15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP 1350, BNPI1100, BN80915, BN80942, etoposide phosphat
  • inhibitors of mitotic kinesins are described in PCT International Publications WO03/039460, WO03/050064, WO03/050122, WO03/049527, WO03/049679, WO03/049678, WO04/039774, WO03/079973, WO03/099211, WO03/105855, WO03/106417, WO04/037171, WO04/058148, WO04/058700, WO04/126699, WO05/018638, WO05/019206, WO05/019205, WO05/018547, WO05/017190, and US Publication No.
  • inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E, inhibitors of MCAK and inhibitors of Rab6-KIFL.
  • histone deacetylase inhibitors include, but are not limited to, SAHA, TSA, oxamflatin, PXD101, MG98 and scriptaid. Further reference to other histone deacetylase inhibitors may be found in the following manuscript; Miller, T.A. et al. J. Med. Chem. 46(24):5097-5116 (2003).
  • “Inhibitors of kinases involved in mitotic progression” include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub- 1 and inhibitors of bub-Rl .
  • An example of an "aurora kinase inhibitor” is VX-680.
  • Antiproliferative agents includes antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 , and INX3001 , and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'- fluoromethylene-2 ' -deoxycytidine, N- [5 -(2,3 -dihydro-benzofuryl)sulfonyl] -N ' -(3
  • monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar.
  • HMG-CoA reductase inhibitors refers to inhibitors of 3-hydroxy-3- methylglutaryl-CoA reductase.
  • HMG-CoA reductase inhibitors include, but are not limited to, lovastatin (MEVACOR®; see U.S. Patent Nos. 4,231,938,
  • simvastatin ZOCOR®; see U.S. Patent Nos. 4,444,784, 4,820,850 and 4,916,239)
  • pravastatin PRAVACHOL®; see U.S. Patent Nos. 4,346,227, 4,537,859,
  • HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
  • Prenyl-protein transferase inhibitor refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and
  • GGPTase-II geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
  • prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Patent No. 5,420,245, U.S. Patent No. 5,523,430, U.S. Patent No. 5,532,359, U.S. Patent No. 5,510,510, U.S. Patent No. 5,589,485, U.S. Patent No. 5,602,098, European Patent Publ. 0 618 221, European Patent Publ. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ. 0 696 593, WO 94/19357, WO
  • Angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-l/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon- ⁇ , interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib (PNAS, Vol. 89, p. 7384 (1992);
  • NSAIDs nonsteroidal anti-inflamm
  • steroidal anti-inflammatories such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone
  • carboxyamidotriazole combretastatin A-4, squalamine, 6-0-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin- 1, angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med. 105: 141-145 (1985)), and antibodies to VEGF (see, Nature Biotechnology, Vol. 17, pp.963-968 (October 1999); Kim et al, Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).
  • agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the instant invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. 38:679-692 (2000)).
  • agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost. 80:10-23 (1998)), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101 :329-354 (2001)).
  • Agents that interfere with cell cycle checkpoints refer to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents.
  • agents include inhibitors of ATR, ATM, the CHK11 and CHK12 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7- hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
  • agents that interfere with receptor tyrosine kinases refer to compounds that inhibit RTKs and therefore mechanisms involved in oncogenesis and tumor progression.
  • agents include inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met.
  • Further agents include inhibitors of RTKs as described by Bume- Jensen and Hunter, Nature, 411 :355-365, 2001.
  • inhibitors of cell proliferation and survival signaling pathway refer to compounds that inhibit signal transduction cascades downstream of cell surface receptors.
  • Such agents include inhibitors of serine/threonine kinases (including but not limited to, inhibitors of Akt such as described in the following patents and publications: WO 02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US 2004-0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO 03/086403, WO 2004/041162, WO
  • angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]- l-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-l-[[3,5-dichloro-4- (4-chlorobenzoyl)phenyl]methyl] - 1 H- 1 ,2,3 -triazole-4-carboxamide,CM 101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl- bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(
  • integral blockers refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ ⁇ ⁇ 3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ 5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the ⁇ ⁇ ⁇ 3 integrin and the ⁇ ⁇ ⁇ 5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the ⁇ ⁇ ⁇ 6 ? ⁇ ⁇ ⁇ 8 ?
  • ⁇ - ⁇ , ⁇ 2 ⁇ , 5 ⁇ , ⁇ 6 ⁇ and ⁇ 6 ⁇ 4 integrins refers to antagonists of any combination of ⁇ ⁇ ⁇ 3, ⁇ ⁇ ⁇ 5, ⁇ ⁇ ⁇ 6> ⁇ ⁇ ⁇ 8> ⁇ ⁇ > ⁇ 2 ⁇ , ⁇ 5 ⁇ , ⁇ 6 ⁇ and ⁇ 6 ⁇ 4 integrins.
  • tyrosine kinase inhibitors include N- (trifluoromethylphenyl)-5 -methylisoxazol-4-carboxamide, 3 - [(2,4-dimethylpyrrol-5 - yl)methylidenyl)indolin-2-one, 17-(allylamino)-17-demethoxygeldanamycin, 4-(3-chloro-4- fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline, N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12- hexahydro- 10-(hydroxymethyl)- 10-hydroxy-9-methyl-9, 12-epoxy- lH-diindolo[ 1 ,2,3 -fg: 3 ' ,2', 1 '-
  • Combinations with compounds other than anti-cancer compounds are also encompassed in the instant methods.
  • combinations of the mTOR inhibitor and WEE1 inhibitor combination of the instant invention with PPAR- ⁇ (i.e., PPAR-gamma) agonists and PPAR- ⁇ (i.e., PPAR-delta) agonists may be useful in the treatment of certain malingnancies.
  • PPAR- ⁇ and PPAR- ⁇ are the nuclear peroxisome proliferator-activated receptors ⁇ and ⁇ .
  • the expression of PPAR- ⁇ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmacol. 1998; 31 :909-913; J. Biol. Chem.
  • PPAR- ⁇ agonists and PPAR- ⁇ / ⁇ agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR- H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-l,2- benzisoxazol-6-yl)oxy]-2-methylpropionic acid (disclosed in USSN 09/782,856), and 2(R)-7-(3- (2-chloro-4-(4-fluorophenoxy)
  • Another embodiment of the instant invention is the use of the presently disclosed compounds in combination with gene therapy for the treatment of cancer.
  • Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Patent No.
  • a uPA/uPAR antagonist (Adenovirus-Mediated Delivery of a uPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August 1998;5(8): 1105-13), and interferon gamma (J. Immunol.
  • the compounds used in the methods of the instant invention may also be administered in combination with an inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins.
  • MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar).
  • P-gp p-glycoprotein
  • the compounds described in the present invention may be employed in conjunction with anti-emetic agents to treat nausea or emesis, including acute, delayed, late- phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy.
  • a compound described in the present invention may be used in conjunction with other anti-emetic agents, especially neurokinin- 1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S.Patent Nos.
  • neurokinin- 1 receptor antagonists especially 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S.Patent
  • an antidopaminergic such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and
  • conjunctive therapy with an anti-emesis agent selected from a neurokinin- 1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosed for the treatment or prevention of emesis that may result upon administration of the instant compounds.
  • Neurokinin- 1 receptor antagonists of use in conjunction with the compounds of the present invention are fully described, for example, in U.S. Patent Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147;
  • the neurokinin- 1 receptor antagonist for use in conjunction with the compounds of the present invention is selected from: 2-(R)-(l-(R)-(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-lH,4H-l,2,4- triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Patent No. 5,719,147.
  • the mTOR inhibitor and WEE1 inhibitor combination of the instant invention may also be administered with an agent useful in the treatment of anemia.
  • an anemia treatment agent is, for example, a continuous eythropoiesis receptor activator (such as epoetin alfa).
  • the mTOR inhibitor and WEE1 inhibitor combination of the instant invention may also be administered with an agent useful in the treatment of neutropenia.
  • a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF).
  • G-CSF human granulocyte colony stimulating factor
  • Examples of a G-CSF include filgrastim.
  • the mTOR inhibitor and WEE1 inhibitor combination of the instant invention may also be administered with an immunologic-enhancing drug, such as levamisole, isoprinosine and Zadaxin.
  • an immunologic-enhancing drug such as levamisole, isoprinosine and Zadaxin.
  • the mTOR inhibitor and WEE1 inhibitor combination of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids).
  • bisphosphonates include, but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate, including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.
  • the mTOR inhibitor and WEE1 inhibitor combination of the instant invention may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors.
  • aromatase inhibitors include but are not limited to: anastrozole, letrozole and exemestane.
  • RNA interference molecules e.g., siRNA
  • the mTOR inhibitor and WEE1 inhibitor combination of the instant invention may also be administered in combination with ⁇ -secretase inhibitors and/or inhibitors of NOTCH signaling.
  • Such inhibitors include compounds described in, but not limited to the following pulications: WO 01/90084, WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO 03/093264, WO 03/093251, WO 03/093253, WO 2004/039800, WO 01/90084, WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO 03/093264, WO 03/093251, WO 03/093253, WO 2004/039800, WO
  • the mTOR inhibitor and WEE1 inhibitor combination of the instant invention may also be useful for treating or preventing cancer in combination with inhibitors of Akt.
  • Such inhibitors include compounds described in, but not limited to, the following publications: WO 02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US 2004- 0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO 03/086403, WO 2004/041162, WO 2004/096131, WO 2004/096129, WO 2004/096135, WO 2004/096130, WO 2005/100356, WO 2005/100344, US 2005/029941, US 2005/44294, and US 2005/43361.
  • the mTOR inhibitor and WEE1 inhibitor combination of the instant invention may also be useful for treating or preventing cancer in combination with PARP inhibitors.
  • Radiation therapy itself means an ordinary method in the field of treatment of cancer.
  • employable are various radiations such as X-ray, ⁇ -ray, neutron ray, electron beam, proton beam; and radiation sources.
  • a linear accelerator is used for irradiation with external radiations to produce ⁇ -ray.
  • the mTOR inhibitor and WEE1 inhibitor combination of the instant invention may also be useful for treating cancer in further combination with the following therapeutic agents: pembrolizumab (Keytruda®), abarelix (Plenaxis depot®); prokine (Leukine®);
  • calusterone Methosarb®
  • capecitabine Xeloda®
  • carboplatin Paraplatin®
  • carmustine BCNU®, BiCNU®
  • carmustine Gliadel®
  • carmustine with Polifeprosan 20 Implant Gliadel Wafer®
  • celecoxib Cibrex®
  • cetuximab Erbitux®
  • chlorambucil Leukeran®
  • cisplatin Platinum
  • cladribine Leustatin®, 2-CdA®
  • clofarabine Clolar®
  • Cytoxan®, Neosar® cyclophosphamide
  • Cytoxan Injection® cyclophosphamide
  • Cytoxan Tablet® cyclophosphamide
  • Cytoxan Tablet® cytarabine
  • Cytosar-U® cytarabine liposomal
  • DepoCyt® dacarbazine
  • DTIC- Dome® dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®)
  • daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin (Daunorubicin®);
  • daunorubicin daunomycin
  • Cirubidine® Denileukin diftitox
  • Ontak® Denileukin diftitox
  • Neat® floxuridine (intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelin implant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan
  • Valin® idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®);
  • meclorethamine nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L- PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex tabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin- 50®); nelarabine (Arranon®); Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles
  • Sargramostim Prokine®
  • sorafenib Nexavar®
  • streptozocin Zanosar®
  • sunitinib maleate Sutent®
  • talc Sclerosol®
  • tamoxifen Nolvadex®
  • temozolomide Temodar®
  • teniposide VM-26 (Vumon®)
  • testolactone Teslac®
  • thioguanine, 6-TG Thioguanine®
  • thiotepa Thioplex®
  • topotecan Hycamtin®
  • toremifene Fareston®
  • Tositumomab Bexxar®
  • Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); and zoledronate (Zometa®).
  • the WEE1 inhibitor and mTOR inhibitor combination may be useful for the treatment of the following cancers: cardiac: sarcoma (angiosarcoma, fibrosarcoma,
  • rhabdomyosarcoma liposarcoma
  • myxoma rhabdomyoma, fibroma, lipoma and teratoma
  • Lung bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma
  • gastrointestinal esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymph
  • meninges meningioma, meningiosarcoma, gliomatosis
  • brain astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous
  • cystadenocarcinoma mucinous cystadenocarcinoma, unclassified carcinoma] granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal
  • rhabdomyosarcoma fallopian tubes (carcinoma); hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplasia syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; and skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma.
  • cancerous cell includes a cell afflicted by any one of the above-identified conditions.
  • a method of treating or preventing a disease in which angiogenesis is implicated which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of the combination of the present invention.
  • Ocular neovascular diseases are an example of conditions where much of the resulting tissue damage can be attributed to aberrant infiltration of blood vessels in the eye (see WO 2000/30651, published 2 June 2000).
  • the undesirable infiltration can be triggered by ischemic retinopathy, such as that resulting from diabetic retinopathy, retinopathy of prematurity, retinal vein occlusions, etc., or by degenerative diseases, such as the choroidal
  • neovascularization observed in age-related macular degeneration Inhibiting the growth of blood vessels by administration of the present compounds would therefore prevent the infiltration of blood vessels and prevent or treat diseases where angiogenesis is implicated, such as ocular diseases like retinal vascularization, diabetic retinopathy, age-related macular degeneration, and the like.
  • a method of treating or preventing a non-malignant disease in which angiogenesis is implicated including but not limited to: ocular diseases (such as, retinal vascularization, diabetic retinopathy and age-related macular degeneration), atherosclerosis, arthritis, psoriasis, obesity and Alzheimer's disease (Dredge, et al., Expert Opin. Biol. Ther., 2002, 2(8):953-966).
  • a method of treating or preventing a disease in which angiogenesis is implicated includes: ocular diseases (such as, retinal vascularization, diabetic retinopathy and age-related macular degeneration), atherosclerosis, arthritis and psoriasis.
  • Cells were plated in 96 well plates at 3500 cells/well. Cells were then treated with an eight by eight matrix of concentrations of WEEl-1 inhibitor and ridaforolimus. 96 hours later, cell viability was measured using cell titer glo (Promega).
  • CD1 nu/nu mice Six to eight- week-old female athymic (CD1 nu/nu) mice from Charles River Laboratories (Wilmington, MA) were housed under pathogen-free conditions in microisolator cages with laboratory chow and water ad libitum.
  • WEEl-1 was prepared in 0.5% Methylcellulose. It was administered p.o. at 5 per gram of body weight (5 days on/2 days off). Ridaforolimus was prepared in 10%> DMA ( ⁇ , ⁇ -Dimethyl Acetamide), 10% Tween-80, 40% PEG-400 and 40% water. It was administered i.p. at 5 per gram of body weight (5 days on/2 days off.
  • SK-OV-3 mice were treated for 28 days (4 cycles) for the tumor growth experiment while the mice received only 1 treatment for the mechanism of action study. A2780 mice were treated until individual tumor reached 1000 mm 3 for the tumor growth experiment while the mice received only 1 treatment for the mechanism of action study. After treatment, mice were sacrificed with C0 2 . The tumors were then removed (mechanism of action study) and frozen in liquid nitrogen for future analysis.
  • pS6 ribosomal protein levels were reduced in tumors from mice treated with ridaforolimus, both four and twenty four hours after treatment. Decreased levels of pCdc2 were observed in tumors from mice treated with WEEl-1 at 4 hours post treatment. However, pCdc2 levels were not decreased in mice treated with WEEl-1 but sacrificed 24 hours after treatment, supporting a BID dosing of WEEl-1 in mice to achieve continuous target engagement.
  • mice treated with the ridaforolimus and WEEl-1 combination the tumor pS6 ribosomal protein levels were even lower than in mice treated with ridaforolimus alone. These results suggest a previously unknown interaction between the mTOR and WEEl signaling pathways. In addition, the tumor pCdc2 levels were even lower in mice treated with the combination than in mice treated with WEEl-1 monotherapy at the 4 hour timepoint.
  • the WEEl-1 and ridaforolimus combination was significantly better in inhibiting tumor growth than either monotherapy. After the two week dosing period, mice were monitored for an additional period of one week.
  • Efficacy was tested for the monotherapies of WEEl-1 and ridaforolimus at their MTD as well as the drug combination in two xenograft models of ovarian cancer, A2780 ( Figure 5 A) and SKOV-3 ( Figure 5B).
  • 10 tumor bearing mice were treated per cohort. Mice were treated with the WEE 1-1 inhibitor at 60 mg/kg twice daily (5 days on, 2 days off), ridaforolimus at 1 mg/kg once daily (5 days on, 2 days off), or the combination of the WEEl-1 and ridaforolimus at the same doses and schedules.
  • the A2780 tumor bearing mice were dosed for two weeks and the SKOV-3 tumor bearing mice were dosed for three weeks. The mean tumor volume -/+ SEM was plotted.
  • TGI Tumor Growth Inhibition
  • TGI Tumor growth inhibition
  • TGI Tumor growth inhibition

Abstract

La présente invention concerne des procédés de traitement du cancer par administration d'une combinaison d'un inhibiteur de WEE1 et d'un inhibiteur de mTOR. Dans un mode de réalisation, l'inhibiteur de WEE1 est WEE1-1 ou l'un des ses sels pharmaceutiquement acceptables ou WEE1-2 ou l'un des ses sels pharmaceutiquement acceptables, et l'inhibiteur de mTOR est l'idaforolimus, l'évérolimus, le temsirolimus, un analogue de rapamycine ou un sel pharmaceutiquement acceptable de ceux-ci.
PCT/US2014/070697 2013-12-20 2014-12-17 Thérapie anticancéreuse combinée avec des inhibiteurs de wee1 et mtor WO2015095250A1 (fr)

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