WO2011009059A2 - Méthode de traitement ou de prévention du cancer - Google Patents

Méthode de traitement ou de prévention du cancer Download PDF

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WO2011009059A2
WO2011009059A2 PCT/US2010/042306 US2010042306W WO2011009059A2 WO 2011009059 A2 WO2011009059 A2 WO 2011009059A2 US 2010042306 W US2010042306 W US 2010042306W WO 2011009059 A2 WO2011009059 A2 WO 2011009059A2
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compound
alkyl
carcinoma
cancer
akt
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PCT/US2010/042306
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WO2011009059A3 (fr
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Phillip A. Dennis
M. Christine Hollander
Marc Nicklaus
Megan Peach
Sherry R. Chemler
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The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
The Research Foundation Of State University Of New York
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Publication of WO2011009059A3 publication Critical patent/WO2011009059A3/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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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

Definitions

  • Cancer is a major world- wide health problem. Those afflicted with cancer suffer physically and emotionally and, unless treated in a timely manner, die an early death. There is also a tremendous burden on the families and friends of those afflicted as well as on society at large. Although many drugs are in use for cancer treatment, there is a desire for additional cancer treatment agents. In addition, there is a desire for a method to prevent cancer, delay or slow down its onset and/or progression, or to prevent the progression of precancerous lesions into cancer.
  • Akt is at the nexus of many signaling pathways and is thought to be an important target for therapeutic intervention in cancer. Activation of Akt occurs through ligand binding to growth factor receptors, activation of various oncogenes such as Ras, Egfr and Her2 or inactivation of tumor suppressor genes such as PTEN. Akt activation has been detected in a high percentage of multiple tumor types, as well as many types of premalignant lesions. Thus, enhanced activation of Akt likely contributes to the pathogenesis and/or maintenance of a wide variety of human malignancies, which is supported by the poor clinical outcomes associated with Akt activation in many of these tumors.
  • Akt is a serine/threonine kinase with diverse targets involved in protein synthesis, cell cycle progression and resistance to apoptosis. In vitro as well as clinical studies have suggested that Akt may be an important target for cancer therapy. Akt is constitutively active in NSCLC cell lines and promotes resistance to chemotherapy drugs and radiation in vitro. Activation and overexpression of Akt are often associated with resistance to chemotherapy or radiotherapy in patients as well. Phosphorylation of Akt at S473, a marker of Akt activation, has been correlated with poor clinical outcomes in many tumor types, including lung, melanoma, breast, prostate, endometrial, gastric, pancreatic, and brain cancers, as well as acute myelogenous leukemia.
  • Akt inhibition Reversal of drug resistance coupled with Akt inhibition has been demonstrated in both cell-based studies and animal models by PI3K inhibitors and by PTEN overexpression in PTEN-null cells. Dominant- negative mutants of Akt were also shown to enhance cytotoxicity by chemotherapeutic agents suggesting an important role of Akt in drug resistance. Furthermore, inhibition of receptor tyrosine kinases, such as epidermal growth factor receptor, sensitizes cells to chemotherapy or radiotherapy through downregulation of the PI3K-Akt pathway.
  • receptor tyrosine kinases such as epidermal growth factor receptor
  • the invention provides a method for inhibiting mTOR, inhibiting Akt, activating AMPK, treating or preventing development of cancer, and/or preventing progression of premalignant lesions to cancer in an animal comprising administering to the animal an effective amount of a compound as described herein in greater detail.
  • the method involves the use of these compounds as single agents or in combination with conventional cancer therapy such as chemotherapy, biological therapy, or radiation.
  • the invention further provides novel compounds and pharmaceutical compositions for use in treating or preventing development of cancer or preventing the progression of
  • the invention also provides a method of inhibiting CSFlR.
  • one or more compounds of the invention have the ability to simultaneously inhibit Akt and activate AMPK, providing profound inhibition of mTOR and/or an anti-cancer effect.
  • Fig. 1 depicts dose-dependent regulation of Akt/mTOR signaling by
  • Non-small cell lung cancer cells H1703, A549, and Hl 57 were cultured in RPMI 5% FBS and treated with vehicle or increasing doses NSC743411 (Nl 1) for 24 hours. Whole cell lysates were harvested and western blot analysis was performed.
  • Fig. 2 depicts time-dependent regulation of Akt/mTOR signaling by
  • H1703 and Hl 155 (LKBl wild-type NSCLC cells) were cultured in RPMI 5% FBS and treated with vehicle or Nl 1 at indicated time points. Whole cell lysates were harvested and western blot analysis was performed. [0009] Fig. 3 follows protein levels over time in the presence of DMSO or
  • NSC743411 H157 and A549 (LKBl -deficient NSCLC cells) were cultured in RPMI 5% FBS and treated with vehicle or Nl 1 at indicated time points. Whole cell lysates were harvested and western blot analysis was performed.
  • FIG. 4 depicts biomarker analysis of aNSC743411 -treated H1703 xenograft. Xenograft tumors were harvested and frozen in liquid nitrogen. Samples were
  • the numbers 1071, 1074, 1069, 1078, 1073, 1072, 1077, and 1079 are mouse identification numbers.
  • Fig. 5 depicts the NCI 60 toxicity screen for NSC 743411, also known as Nl 1, a compound in accordance with the invention, showing growth inhibition at micro-molar concentrations in a broad range of cell lines and cell killing at micro-molar concentrations in many cell lines.
  • Fig. 5A depicts the screen for leukemia.
  • Fig. 5B depicts the screen for colon cancer.
  • Fig. 5C depicts the screen for ovarian cancer.
  • Fig. 5D depicts the screen for non-small cell lung cancer.
  • Fig. 5E depicts the screen for CNS cancer.
  • Fig. 5F depicts the screen for renal cancer.
  • Fig. 5G depicts the screen for breast cancer.
  • Fig. 5H depicts the screen for melanoma.
  • Fig. 51 depicts the screen for prostate cancer.
  • Fig. 6 A depicts cell death induced by NSC 743411 in H 1703 as assessed by propidium iodide uptake in accordance with an embodiment of the invention.
  • Fig. 6B depicts minimal apoptosis is induced by NSC 743411 in Hl 703 as assessed by sub Gl cellular DNA content measured by flow cytometry.
  • Fig. 6 C depicts the morphology of Hl 703 cells with 24 h treatment of NSC 743411 in accordance with an embodiment of the invention.
  • Western blots of crude WBC lysates were prepared 4 h after IP injection of 3 mice with 25 mg/kg NSC 743411 and 3 mice with vehicle only.
  • Fig. 8 depicts the fold change of tumor volume in mice after implantation of H 1703 cells and injection of NSC 743411, in accordance with an embodiment of the invention. Data is reported as fold change in tumor volume relative to first day of dosing. Note that after Day 31, only odd-numbered days were monitored.
  • Fig. 9 depicts the percent change in body weight in mice after implantation of H1703 cells and injection of NSC 743411, in accordance with an embodiment of the invention. Data is reported as % change in body weight relative to first day of dosing. Note that after Day 31, only odd-numbered days were monitored.
  • Fig. 10 depicts the cell morphology change of A549 or Hl 703 cells by sulfonamide-2 in accordance with an embodiment of the invention.
  • Fig. 1OA depicts H1703 cells treated with DMSO only.
  • Fig. 1OB depicts the morphology of H1703 cells treated with sulfonamide-2.
  • Fig. 1OC depicts the morphology of A549 cells treated with DMSO only.
  • Fig. 1OD depicts the morphology of A549 cells treated with sulfonamide-2.
  • Fig. 11 depicts the GI50 values for cell growth inhibition by sulfonamide-2 as a function of compound concentration in ⁇ M, in accordance with an embodiment of the invention.
  • Fig. 1 IA depicts growth inhibition of A549 cells as a function of concentration of sulfonamide-2.
  • Fig. 1 IB depicts growth inhibition of H 1703 cells as a function of concentration of sulfonamide-2.
  • Fig. 12 depicts that sulfonamide-2 arrests the G2/M phase of cell growth, in accordance with an embodiment of the invention.
  • Fig. 12A depicts the percentage of Hl 703 cells in G2/M cell cycle phase as a function of time.
  • Fig. 12B and Fig. 12C depict the number of H1703 cells vs. fluorescence in the presence of DMSO or sulfonamide-2, respectively.
  • Fig. 12D depicts the percentage of survival of A549 cells as a function of time.
  • Fig. 12E and Fig. 12F depict the number of A549 cells vs. fluorescence in the presence of DMSO or sulfonamide-2, respectively.
  • Fig. 13 depicts that sulfonamide-2 causes G2/M phase arrest and increases acetylated tubulin expression of A549 cells, in accordance with an embodiment of the invention.
  • Fig. 13A depicts the morphology of A549 cells treated with DMSO only.
  • Fig. 13B depicts the morphology of the cells treated with sulfonamide-2.
  • Fig. 14 depicts the percentage of viable cells of H 1703 cells as a function of time. Cell death caused by sulfonamide-2 is shown by Trypan Blue staining, in accordance with an embodiment of the invention.
  • Fig. 15A depicts the number of viable H1703 cells treated with sulfonamide-2 on day 5 in full serum condition as a function of its fluorescence and Fig. 15B depicts the morphology of the cells, in accordance with an embodiment of the invention.
  • Fig. 16 depicts the percentage of nonapoptotic cell death of A549 cells with or without SiRNA, in accordance with an embodiment of the invention.
  • the invention provides a method for inhibiting mTOR comprising administering an effective amount of a compound having one of the following structures:
  • the present invention also provides a compound for inhibiting mTOR, wherein the compound has one of the above structures or a prodrug, salt, or solvate thereof.
  • the compounds above or prodrugs, salts, or solvates thereof inhibit the activation of Akt, particularly Aktl in certain cancer cell types, hi an embodiment, the compounds inhibit the binding of Akt's pleckstrin homology (PH) domain to a
  • AMPK AMP-activated protein kinase
  • preferred compounds include NSC
  • NSC 743402 NSC 743403, NSC 743404, NSC 743407, NSC 743408, NSC 743409, NSC 743410, and NSC 743411. More preferred compounds include NSC 743404, NSC 743408, and NSC 743411, whose structures are set forth below, respectively. NSC 743411 is further preferred.
  • the above compounds, or prodrugs, salts, or solvates thereof are targeted for use in the treatment of cancer, prevention of cancer, and in preventing the progress of development of precancerous lesions into cancer, wherein the cancer can be a cancer in any organ, for example, a cancer selected from the group consisting of glioma, thyroid carcinoma, breast carcinoma, small-cell lung carcinoma, non-small-cell carcinoma, gastric carcinoma, colon carcinoma, gastrointestinal stromal tumor, pancreatic carcinoma, bile duct carcinoma, CNS carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, renal carcinoma, anaplastic large-cell lymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, and combinations thereof, particularly a cancer selected from the group consisting of leukemia, non- small-cell carcinoma, breast carcinoma, colon carcinoma, CNS carcinoma, melanoma, ovarian carcinoma, renal carcinoma, and prostate carcinoma, more particularly, the cancer is a non-
  • A is C 6 -C 20 aryl, C 6 -C 20 aryl C 1 -C 6 alkyl C 6 -C 20 aryl, heteroaryl, or
  • heteroaryl C 1 -C 6 alkyl optionally further substituted, at the aryl, alkyl, or at the heteroaryl moiety, with one or more substituents selected from the group consisting of C 2 -C 6 alkenyl, halo, monohalo C 1 -C 6 alkyl, dihalo Ci-C 6 alkyl, trihalo Ci-C 6 alkyl, Cj-C 6 alkoxy, and hydroxy C]-C 6 alkyl;
  • R 1 is selected from the group consisting Of C 1 -C 6 alkyl, monohalo Ci-C 6 alkyl, dihalo Ci-C 6 alkyl, trihalo Ci-C 6 alkyl, Ci-C 6 alkoxy, and nitro;
  • R 2 is selected from the group consisting of hydrogen, C 2 -C 6 alkenyl, halo, monohalo Ci-C 6 alkyl, dihalo Ci-C 6 alkyl, trihalo Ci-C 6 alkyl, Ci-C 6 alkoxy, hydroxy C 1 - C 6 alkyl, and heterocyclyl which may be optionally substituted with a substituent selected from the group consisting of hydroxy, C 2 -C 6 alkenyl, and Ci-C 6 alkoxy carbonyl amino C 1 -C 6 alkyl;
  • R 4 is selected from the group consisting of carboxy Ci-C 6 alkyl, carboxy Cj-C 6 alkoxy, and carboxy Ci-C 6 alkylthio;
  • R 5 is hydrogen, C 6 -C 2O aryl which may be linked at one carbon atom or on two carbon atoms as fused, C 2 -C 6 alkenyl, halo, monohalo Q-C 6 alkyl, dihalo Ci-C 6 alkyl, trihalo Ci-C 6 alkyl, Ci-C 6 alkoxy, hydroxy Cj-C 6 alkyl, and heterocyclyl, which may be optionally substituted with a substituent selected from the group consisting of Ci-C 6 alkyl, halo, nitro, hydroxy, C 2 -C 6 alkenyl, and Ci-C 6 alkoxy carbonyl amino C]-C 6 alkyl; and a, b, c, d, and e are independently 0 to 6;
  • the present invention provides a compound for inhibiting mTOR, wherein the compound is of formula (I), (II), (III), or (IV) above or a prodrug, salt, or solvate thereof.
  • the compounds above or prodrugs, salts, or solvates thereof inhibit the activation of Akt, particularly Aktl in certain cancer cell types.
  • the compounds inhibit the binding of Akt's pleckstrin homology (PH) domain to a phosphoinositide.
  • the compounds above activate AMP-activated protein kinase (AMPK).
  • AMPK AMP-activated protein kinase
  • the above compounds, or prodrugs, salts, or solvates thereof are targeted for use in the treatment of cancer, prevention of cancer, and in preventing the progress of development of precancerous lesions into cancer, wherein the cancer can be a cancer in any organ, for example, a cancer selected from the group consisting of glioma, thyroid carcinoma, breast carcinoma, small-cell lung carcinoma, non-small-cell carcinoma, gastric carcinoma, colon carcinoma, gastrointestinal stromal tumor, pancreatic carcinoma, bile duct carcinoma, CNS carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, renal carcinoma, anaplastic large-cell lymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, and combinations thereof, particularly a cancer selected from the group consisting of leukemia, non-small-cell carcinoma, breast carcinoma, colon carcinoma, CNS carcinoma, melanoma, ovarian carcinoma, renal carcinoma, and prostate carcinoma, more particularly, the cancer is a non-
  • the present invention also provides a compound of one of formulas (I)-(IV):
  • A is C 6 -C 20 aryl, C 6 -C 20 aryl C 1 -C 6 alkyl C 6 -C 2O aryl, heteroaryl, or heteroaryl Ci-C 6 alkyl, optionally further substituted, at the aryl, alkyl, or at the heteroaryl moiety, with one or more substituents selected from the group consisting of C 2 -C 6 alkenyl, halo, monohalo Cj-C 6 alkyl, dihalo Ci-C 6 alkyl, trihalo Ci-C 6 alkyl, Ci-C 6 alkoxy, and hydroxy C 1 -C 6 alkyl;
  • R 1 is selected from the group consisting of Ci-C 6 alkyl, monohalo Ci-C 6 alkyl, dihalo Ci-C 6 alkyl, trihalo C t -C 6 alkyl, Ci-C 6 alkoxy, and nitro;
  • R 2 is selected from the group consisting of hydrogen, C 2 -C 6 alkenyl, halo, monohalo Cj-C 6 alkyl, dihalo C 1 -C 6 alkyl, trihalo Ci-C 6 alkyl, CrC 6 alkoxy, hydroxy C 1 - C 6 alkyl, and heterocyclyl which may be optionally substituted with a substituent selected from the group consisting of hydroxy, C 2 -C 6 alkenyl, and C 1 -C 6 alkoxy carbonyl amino Ci-C 6 alkyl;
  • R 4 is selected from the group consisting of carboxy C]-C 6 alkyl, carboxy Cj-C 6 alkoxy, and carboxy Cj-C 6 alkylthio;
  • R 5 is hydrogen, C 6 -C 20 aryl which may be linked at one carbon atom or on two carbon atoms as fused, C 2 -C 6 alkenyl, halo, monohalo Cj-C 6 alkyl, dihalo Cj-C 6 alkyl, trihalo Cj-C 6 alkyl, Cj-C 6 alkoxy, hydroxy Cj-C 6 alkyl, and heterocyclyl, which may be optionally substituted with a substituent selected from the group consisting of Cj-C 6 alkyl, halo, nitro, hydroxy, C 2 -C 6 alkenyl, and Cj-C 6 alkoxy carbonyl amino Ci-C 6 alkyl; and a, b, c, d, and e are independently 0 to 6;
  • aryl refers to a mono, bi, or tricyclic carbocyclic ring system having one, two, or three aromatic rings, for example, phenyl, naphthyl, anthracenyl, or biphenyl.
  • heteroaryl refers to a cyclic aromatic radical having from five to ten ring atoms of which at least one atom is O, S, or N, and the remaining atoms are carbon.
  • heteroaryl radicals include indolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, and isoquinolinyl.
  • the alkyl group is preferably a Ci -C 3 alkyl.
  • alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and the like. This definition also applies wherever 'alkyl" occurs such as in hydroxyalkyl, monohalo alkyl, dihalo alkyl, and trihalo alkyl.
  • the alkenyl group is preferably a C 2 -C 4 alkenyl.
  • alkenyl group include ethenyl, allyl, 2-propenyl, 1-butenyl, 2- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, and the like.
  • the alkoxy group is preferably a Ci-C 3 alkoxy.
  • alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, n-hexoxy, and the like.
  • halo refers to a halogen selected from the group consisting of fluorine, chlorine, bromine, and iodine, preferably chlorine or bromine.
  • Heterocyclyl groups include heteroaryl groups described above and further include cyclic groups, saturated or unsaturated, having a hetero atom.
  • heterocyclyl groups include indolyl, pyridyl, piperidinyl, piperazinyl, pyrazinyl, pyrolyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, thiophenyl, tetrahydrothiophenyl, purinyl, pyrimidinyl, thiazolyl, thiazolidinyl, thiazolinyl, oxazolyl, triazolyl, tetrazolyl, tetrazinyl, benzoxazolyl, morpholinyl, thiophorpholinyl, quinolinyl, and isoquinolinyl, each of
  • R 1 is preferably hydrogen, methyl, ethyl, nitro, methoxy, ethoxy, or trifluoromethyl.
  • R 2 is preferably allyl, bromo,
  • R 4 is preferably carboxymethylthio or carboxyethylthio.
  • R 5 is preferably phenyl or benzo.
  • the alkyl, alkoxy, and alkylamino groups can be linear or branched.
  • a substituent e.g., halo, amino, alkyl, hydroxyl, alkoxy, and others
  • the aromatic ring hydrogen is replaced with the substituent and this can take place in any of the available hydrogens, e.g., 2, 3, 4, 5, and/or 6-position wherein the 1 -position is the point of attachment of the aryl group in the compound of the present invention.
  • animal refers to any member of the animal kingdom.
  • animal refers to a human, at any stage of development.
  • animal includes mammals, birds, reptiles, amphibians, fish, and worms.
  • the non-human animal is a mammal, e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig.
  • the animal may also be a transgenic animal, genetically engineered animal, or a clone.
  • the method involves administering a compound of formula (I), or a prodrug, salt, or solvate thereof, wherein a, b, and c are 0.
  • the method involves administering a compound of formula (I), or a prodrug, salt, or solvate thereof, wherein a, b, and c are 1.
  • the method involves administering a compound of formula (I), or a prodrug, salt, or solvate thereof, wherein a is 0 and b and c are 0.
  • the method involves administering a compound of formula (I), or a prodrug, salt, or solvate thereof, wherein a and c are 0 and b is 1.
  • the method involves administering a compound of formula (II), or a prodrug, salt, or solvate thereof, wherein a, b, and c are 0.
  • a specific example of compound of formula II includes:
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, prodrug, salt, or solvate described above and a pharmaceutically acceptable carrier.
  • prodrug denotes a derivative of a compound, which derivative, when administered to warm-blooded animals, e.g. humans, is converted into the compound (drug).
  • the enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug form (parent carboxylic acid drug) is released, and the moiety or moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced.
  • Non-limiting examples include esters, amides, ethers, and carbonates.
  • salts or “pharmaceutically acceptable salt” is intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977).
  • they can be a salt of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium of salt.
  • the compounds of the various embodiments of the invention can be obtained from commercial sources or synthesized following procedures taught in the literature, for example, Zawaba, T. P., et al, J Am. Chem. Soc, 2005, 127, 11250-11251 and supplemental materials S1-S28; Zawaba, T. P., et al., Organic Letters, 2007, 9, 2035-2038 and S1-S28; Sherman, E. S., et al., Organic Letters, 2004, 6, 1573-1575 and Sl-SlO; Sherman, E. S., et al., J. Org. Chem., 2007, 72, 3896-3905 and S1-S36.
  • the cancer is characterized by any suitable cell line, particularly A549 and H 1703 cell lines.
  • the compound of formulas (I)-(IV) arrest the G2/M phase of the cancer cell cycle.
  • the recitation of a range of 1-8 carbon atoms e.g., Ci-C 8
  • 1-6 carbon atoms e.g., Ci-C 6
  • 1-4 carbon atoms e.g., Cj-C 4
  • 1-3 carbon atoms e.g., C 1 -C 3
  • 2-8 carbon atoms e.g., C 2 -C 8
  • any chemical group e.g., alkyl, haloalkyl, alkylamino, alkenyl, etc. referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, as
  • any sub-range thereof e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1- 4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 5-6 carbon atoms, 5-7 carbon atoms, 5-8 carbon atoms, 6-7 carbon atoms, or 6-8 carbon atoms, as appropriate).
  • the compounds, or a prodrugs, salts, or solvates thereof preferably inhibit the binding of Akt's pleckstrin homology (PH) domain to a phosphoinositide.
  • the cancer can be any cancer in any organ, for example, a cancer is selected from the group consisting of glioma, thyroid carcinoma, breast carcinoma, small-cell lung carcinoma, non- small-cell carcinoma, gastric carcinoma, colon carcinoma, gastrointestinal stromal carcinoma, pancreatic carcinoma, bile duct carcinoma, CNS carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, renal carcinoma, anaplastic large-cell lymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, and combinations thereof.
  • a cancer is selected from the group consisting of glioma, thyroid carcinoma, breast carcinoma, small-cell lung carcinoma, non- small-cell carcinoma, gastric carcinoma, colon carcinoma, gastrointestinal stromal carcinoma, pancreatic carcinoma, bile duct carcinoma, CNS carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, renal carcinoma, anaplastic large-cell lymphoma, leukemia, multiple myeloma, mesotheliom
  • the method can be carried out in conjunction with another cancer therapy.
  • the another cancer therapy comprises chemotherapy, radiation therapy, or biological therapy.
  • the biological therapy involves administration of a protein, which may be an antibody or a recombinant protein.
  • the combination therapy can be carried out such that the two therapies can be administered simultaneously or sequentially, and when administered sequentially, in any order, i.e., a radiation therapy, biological therapy, or a conventional chemotherapeutic agent first followed by the administration of the compound of the invention, or a compound of the invention administered first followed by radiation therapy, biological therapy, or administration of the conventional chemotherapeutic agent.
  • the another cancer therapy comprises
  • chemotherapy which could involve the administration of any suitable chemotherapy agent, for example, an agent selected from the group consisting of abarelix, aldesleukin, alemtuzumab, altretamine, amifostine, aminoglutethimide, anastrazole, arsenic trioxide, asparaginase, azacitidine, azathioprine, BCG vaccine, bevacizumab, bexarotene, bicalutamide, bleomycin sulfate, bortezomib, bromocriptine, busulfan, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, chloroquine phosphate, cladribine, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, daunorubicin citrate liposomal, dexrazoxane
  • the present invention further provides a method of treating an animal for a disease or adverse condition that responds to inhibiting the activity of CSFlR receptor comprising administering to the animal an effective amount of the compound of the formula or a prodrug, salt, or solvate thereof,
  • diseases or the adverse condition include chronic myelomonocytic leukemia, Alzheimer's disease, and brain injury.
  • the compounds, or prodrugs, salts, or solvates thereof can be administered as such or in the form of a pharmaceutical composition.
  • the pharmaceutical composition comprises at least one compound, or a prodrug, salt, or solvate thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may include two, three or more agents, at least one of which is a compound of the invention as described above, in combination with one or more conventional chemotherapeutic agents.
  • the pharmaceutically acceptable carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration. It will be appreciated by one of skill in the art that, in addition to the following described pharmaceutical compositions; the compounds, salts, or conjugates of the present invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
  • compositions described herein for example, vehicles, adjuvants, excipients, or diluents, are well known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compounds and one which has no detrimental side effects or toxicity under the conditions of use.
  • compositions of the present invention are merely exemplary and are in no way limiting.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound, salt, or conjugate dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • the compounds, or prodrugs, salts, or solvates thereof, of the present invention can be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound, or a prodrug, salt, or solvate thereof can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfo succinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl- imidazoline quaternary ammonium salts, and (3) mixtures thereof.
  • the parenteral formulations will typically contain from about 0.5 to about 25% by weight of the compound, or a prodrug, salt, or solvate thereof, in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight.
  • HLB hydrophile-lipophile balance
  • Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • the parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the compounds, prodrugs, salts, or solvates thereof, may be made into injectable formulations.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See
  • the compounds, prodrugs, salts, or solvates thereof may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water- soluble bases.
  • bases such as emulsifying bases or water- soluble bases.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • the compounds can be used in any suitable dose. Suitable doses and dosage regimens can be determined by conventional range finding techniques. Generally treatment is initiated with smaller dosages, which are less than the optimum dose.
  • the dosage is increased by small increments until optimum effect under the circumstances is reached.
  • the total daily dosage may be divided and administered in portions during the day if desired, hi proper doses and with suitable administration of certain compounds, the present invention provides for a wide range of responses.
  • the dosages range from about 0.001 to about 1000 mg/kg body weight of the animal being treated/day.
  • the compounds, products, salts, or solvates may be administered from about 100 mg/kg to about 300 mg/kg, from about 120 mg/kg to about 280 mg/kg, from about 140 mg/kg to about 260 mg/kg, from about 150 mg/kg to about 250 mg/kg, from about 160 mg/kg to about 240 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • the compounds, prodrugs, salts, or solvates may be administered at a lower dosage, for example, from about 1 mg/kg to about 80 mg/kg, from about 5 mg/kg to about 70 mg/kg, from about 10 mg/kg to about 70 mg/kg, from about 10 mg/kg to about 60 mg/kg, from about 20 mg/kg to about 70 mg/kg, from about 20 nig/kg to about 60 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired effect.
  • the treatment can be prophylactic or therapeutic.
  • preventing the progression is meant any degree (10, 20, 30, 40, 50, 60, 70, 80, 90% or more) in inhibition of the onset of cancer or progression of precancerous lesions into cancer, including complete inhibition.
  • treatment is meant any degree (10, 20, 30, 40, 50, 60, 70, 80, 90% or more) in inhibition of the growth or metastasis of the cancer in the animal (e.g., human).
  • NSCLC cell lines H157, H1703, H460, PC3 and MDA MB468 were grown and maintained in RPMI 1640 (Life Technologies, Gaithersburg, MD) plus 5 or 10% fetal bovine serum and 50 ug/mL gentamycin. For low serum conditions, the serum
  • Antibodies for western blot analysis were purchased from Cell Signaling Technology (Beverly, MA) except total Akt antibody (BD biosciences, San Jose, CA). Secondary antibodies used for immunofluorescence were anti-mouse Alexa- fluor488 and anti-rabbit Alexa-fluor568 (Molecular Probes). AMPK antibody and secondary antibody were from Cell Signaling. IR dye-linked antibodies were from
  • LY294002 was purchased from Calbiochem EMD
  • PVDF polyvinylidene difluoride
  • Detection of pS473 and total Akt were done simultaneously using two different primary antibody species and secondary antibodies of different wavelengths for simultaneous two- color detection using an Odyssey infrared scanner (Licor, Lincoln, NE). Immunoblot experiments were performed at least three times.
  • NCI 60 Cell Line Screen Upon submission for testing, each compound was given a unique NSC number by the National Cancer Institute, Developmental
  • Xenograft tumors were harvested and frozen in liquid nitrogen. Samples were homogenized, resuspended in RIPA lysis buffer, and western blot analysis performed (15 ⁇ g protein).
  • Akt inhibition was calculated as the relative decrease in the pS473/total Akt ratio compared with the DMSO negative control, and was visibly apparent as a decrease in green signal (pS473). 21 of 105 (20%) compounds inhibited Akt
  • Akt inhibitors 4 Akt activators were identified (data not shown). These 25 Akt inhibitors and activators were tested in another cell line with wild type PTEN (H1703). Surprisingly, two of the compounds that activated Akt in H157 cells inhibited Akt in Hl 703 cells (Table 1).
  • Table 1 Akt inhibitors identified by in vitro screening on Hl 703, MB468, PC3, H460 and Hl 57 non-small cell lung cancer cell lines.
  • a (-) indicates Akt inhibition and (n) indicates no change, as measured by change in S473 phosphorylation on western blots.
  • GI50 and LC50 the average concentration ( ⁇ M) giving 50% growth inhibition (GI) or death (LC) in the NCI60 cell lines.
  • NSC 743411 activates AMPK.
  • AMPK and Akt are upstream of mTOR.
  • AMPK Activation of AMPK negatively regulates mTOR independently of Akt inhibition, which also negatively regulates mTOR.
  • Activation of AMPK and inhibition of Akt with NSC 743411 occur with similar dose- and time-dependence. Simultaneous inhibition of Akt and activation of AMPK would likely result in profound inhibition of mTOR and enhance the anticancer activity.
  • NSC 743411 was the most potent compound tested in the NCI 60 cell line screen, (Fig. 5), while the composite dose-response curves were similar for NSC 743404 and NSC 743408. For the majority of the cell lines, NSC743411 exhibited little or no inhibition of proliferation at 1 ⁇ M, but had near complete growth inhibition or cytotoxicity at 10 ⁇ M. The average GI50 for NSC 743411 was approximately 4 ⁇ M; the average LC50 was 43.7 ⁇ M. However, more than 30% of the cell lines had total growth inhibition at doses of 10 ⁇ M or less (Fig 5, Table 1). Due to its superior broad-range cytotoxicity, NSC743411 was chosen for further investigation.
  • NSC 743411 induces non-apoptotic cell death.
  • H 1703 cells have high levels of constitutively active Akt and depend upon Akt for survival. Morphological changes consistent with cytotoxicity were apparent in multiple cell lines treated with NSC 743411, but Hl 703 appeared to be among the most sensitive.
  • Hl 703 appeared to be among the most sensitive.
  • NSC 743411 Inhibits At in a Dose- and Time-Dependent Manner. Since Akt inhibition was initially assessed at a single dose and time, additional studies were conducted to determine the dose and time dependence of Akt inhibition by NSC 743411. First, the efficacy of NSC 743411 was assessed in 5% FBS. NSC 743411 inhibited Akt equally well in 0.5% FBS or 5% FBS; thus, all subsequent experiments were performed in 5% FBS. Upon treatment of H1703 cells for 8 h with NSC 743411, Akt phosphorylation was decreased with concentrations as low as 10 ⁇ M.
  • NSC 743411 decreased Akt phosphorylation without affecting total levels of Akt in four NSCLC cell lines (Table 1). Inhibition was observed as early as 6 h with 10 ⁇ M NSC743411, and was sustained for at least 24 hours after treatment, although many cells appeared dead at this time. At 20 uM, Akt inhibition was observed as early as 2h. To verify that loss of Akt phosphorylation on S473 was coupled with loss of Akt kinase activity, imrnunoblots were also probed with antibodies to assess phosphorylation of Akt downstream targets.
  • GSK-3ab (S9/21) is a direct substrate of Akt, whereas pS6 (S235/236) is indirectly phosphorylated following Akt-dependent activation of mTOR and subsequently, S6-kinase.
  • 4EBP-1 is another substrate of mTOR. Phosphorylation of each downstream substrate decreased
  • NSC 743411 suppresses tumor growth in vivo and has limited toxicity in vivo. See Figs. 8 and 9. There is no statistical difference between vehicle and 5 mg/kg but there is between vehicle and 50 mg/kg.
  • NSC 743411 does not inhibit Akt via the kinase domain. Akt inhibition by the lead compounds should not be via the Akt kinase domain since these compounds were specifically screened for binding to the PH domain.
  • NSC 743404, NSC 743408 and NSC743411 were subjected to the Ambit Kineome scan 96, which tests inhibition of ATP binding to active sites of a panel of 96 kinases. This approach has been shown to be an excellent predictor of kinase inhibition by small molecules. None of the 3 lead compounds inhibited binding of ATP to Aktl or Akt2, as expected for a PH-domain selective inhibitor.
  • NSC 743408 and NSC743411 had no activity for any of the kinases on the panel, but NSC 743404 inhibited CSFlR binding to ATP by 97% but had no activity for other kinases.
  • NSC743411 in Akt inhibition and cell killing in 10% fetal bovine serum suggests that it has potential for activity under physiological conditions, hi support of this, a small in vivo study showed that 25 mg/kg of NSC743411 can inhibit pS473-Akt in PBMCs 4 h after intraperitoneal injection in mice (Fig. 7) with no obvious adverse health effects.
  • NSC 743411 only targets the PH domain of Aktl, and that active Aktl may be more important for survival of tumor cell lines than the other Akt family members, Akt2 and Akt3.
  • Active Aktl has been shown to be oncogenic, and genetic deletion of Akt can prevent tumorigenesis in mice.
  • a mutation in the PH domain of Aktl was described in breast, colorectal, and ovarian tumors and squamous cell carcinomas of the lung. This mutation causes increased localization of Aktl to the membrane and can transform fibroblasts in culture and cause leukemia in mice.
  • deletion of Aktl alone can prevent tumor formation in mouse models suggesting that inhibition of Aktl may be a potential strategy for tumor prevention and therapy.
  • the lead compound, NSC 743411 inhibited Akt phosphorylation, prevented phosphorylated Akt from localizing to the membrane and led to inhibition of growth and increased cell death in a variety of tumor types at physiologically achievable doses.
  • This example illustrates the activity of a compound in accordance with an embodiment of the invention.
  • Compounds designated as sulfonamide- 1 to sulfonamide- 12, sulfamide-1 to sulfamide-8, and sultam-1 to sultam-3 were tested on Hl 57, A549, and H1703 cell lines.
  • H157 is a lung adenocarcinoma cell line with P-Akt+, p53 codon 285 CAG- AAG;
  • A549 is a lung adenocarcinoma cell line, P-Akt-, p53 wild type;
  • H157 is a lung squamous carcinoma cell line, P-Akt+, p53 nonsense mutation at codon 298.
  • the cells were exposed for 2 hours at 25 ⁇ M of the compounds. Iramunoblotting results are shown in Tables 2-3. The sultam compounds either activated or showed no inhibition of Akt.
  • FIG. 10-16 This example illustrates some other properties of sulfonamide-2 as shown in Figures 10-16.
  • the compound inhibited the growth of A549 cells as shown by the change in cell morphology depicted in Fig. 10.
  • the GI50 values are shown in Fig, 11.
  • the sulfonamide also arrests the G2/M phase of cell growth as shown in Fig. 12.
  • the sulfonamide causes G2/M phase arrest and increases acetylated tubulin expression of A549 cells as shown in Fig. 13.
  • the sulfonamide also caused nonapoptotic cell death on Hl 703 cells (p53-) as shown in Figs. 14-16. It is believed that the cell death results from abnormal mitosis, thus causing mitotic catastrophe.
  • NSC 743404 was put through an Ambit kineome (kinase) screen and it was found that the compound had significant activity against CSFlR, 6.3% of control. The compound was tested at 10 ⁇ M.

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Abstract

La présente invention a pour objet une méthode d’inhibition de Akt, d’activation de AMPK, d’inhibition de mTOR, de traitement ou de prévention du développement du cancer, et/ou de prévention de la progression de lésions prémalignes en cancer chez un animal, comprenant l’administration à l’animal d’une quantité efficace d’un composé tel que décrit ici, par exemple, le NSC 743411, dont la formule est présentée ci-dessous. La méthode implique l’utilisation de ces composés en tant qu’agents uniques ou en combinaison avec une chimiothérapie, une thérapie biologique, ou une radiothérapie classique. L’invention concerne en outre de nouveaux composés et de nouvelles compositions pharmaceutiques destinés à être utilisés dans le traitement ou la prévention du développement du cancer ou la prévention de la progression de lésions prémalignes en cancer. La présente invention concerne également une méthode d’inhibition de CSF1R.
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