WO2017097865A9 - Combination of caloric restriction (cr) or igf1/insulin receptor inhibitor with lsd1 inhibitor - Google Patents

Combination of caloric restriction (cr) or igf1/insulin receptor inhibitor with lsd1 inhibitor Download PDF

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Publication number
WO2017097865A9
WO2017097865A9 PCT/EP2016/080156 EP2016080156W WO2017097865A9 WO 2017097865 A9 WO2017097865 A9 WO 2017097865A9 EP 2016080156 W EP2016080156 W EP 2016080156W WO 2017097865 A9 WO2017097865 A9 WO 2017097865A9
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WIPO (PCT)
Prior art keywords
inhibitor
phenyl
trans
methyl
cancer
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PCT/EP2016/080156
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French (fr)
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WO2017097865A1 (en
Inventor
Luca MAZZARELLA
Saverio Minucci
Pier Giuseppe Pelicci
Rani Pallavi
Tiphanie DURFORT
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Istituto Europeo Di Oncologia
Università Degli Studi Di Milano
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Publication of WO2017097865A1 publication Critical patent/WO2017097865A1/en
Publication of WO2017097865A9 publication Critical patent/WO2017097865A9/en

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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
    • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present application relates to the use of an LSD l inhibitor in combination with a caloric restricted diet, a calorie restriction mimetic and'or an IGF 1 /Insulin receptor inhibitor for the treatment of cancer, e.g., a leukemia, such as acute myeloid leukemia, acute promyelocyte leukemia.
  • a leukemia such as acute myeloid leukemia, acute promyelocyte leukemia.
  • the application is based on the data disclosed herein which show that the combination of LSD l inhibition (also known as KDM 1 ) and insulin/IGF 1 signaling reduction by pharmacological or dietary intervention is a highly effective therapeutic strategy for the treatment of cancer.
  • this application pertains to methods of treating and/or preventing cancer in subject in need thereof.
  • this application pertains to a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of an LSD l inhibitor, wherein the method further comprises: a. administration of at least one calorie restriction mimetic; or
  • the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor and a calorie restriction mimetic, wherein the subject is optionally on a calorie restricted diet.
  • the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor and a calorie restriction mimetic, wherein the subject is on a calorie restricted diet.
  • the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor and a calorie restriction mimetic, wherein the subject is on a standard diet.
  • the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor and an IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
  • the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor and an IGFl/insulin inhibitor, wherein the subject is on a calorie restricted diet.
  • the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor and an IGFl/insulin inhibitor, wherein the subject is on a standard diet.
  • the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
  • the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is on a calorie restricted diet.
  • the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is on a standard diet.
  • this application pertains to a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of an LSDl inhibitor, wherein the method further comprises: a. administration of at least one calorie restriction mimetic; or
  • LSDl inhibitor is selected from any compound of Formula (I), Formula (la), Formula (II), Formula (III), any other compound indicated as an LSDl inhibitor, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • the LSDl inhibitor is selected from the group consisting of:
  • the LSD1 inhibitor is N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin- 1 -yl)benzamide dihydrochloride .
  • the IGFl/insulin inhibitor is selected from the group consisting of: inhibitor of IGFl receptor, inhibitor of insulin receptor, and inhibitor of both IGFl receptor and insulin receptor.
  • the IGFl/insulin inhibitor is 3-[8-Amino-l-(2-phenyl-7- quinolyl)imidazo[l,5-a]pyrazin-3-yl]-l-methyl-cyclobutanol.
  • the calorie restriction mimetic is a sirtuin-activating compound.
  • this application pertains to a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of an N-[4- [iraws-l-aminocyclopropyljphenyl] -4-(4-methylpiperazin- 1 -yl)benzamide dihydrochloride, wherein the method further comprises:
  • the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride and a calorie restriction mimetic, wherein the subject is optionally on a calorie restricted diet.
  • the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride and a calorie restriction mimetic, wherein the subject is on a calorie restricted diet.
  • the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride and a calorie restriction mimetic, wherein the subject is on a standard diet.
  • the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride and an IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
  • the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride and an IGFl/insulin inhibitor, wherein the subject is on a calorie restricted diet.
  • the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride and an IGFl/insulin inhibitor, wherein the subject is on a standard diet.
  • the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
  • the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is on a calorie restricted diet.
  • the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is on a standard diet.
  • the cancer is a tumor of the hematopoietic and lymphoid tissues.
  • the tumor of the hematopoietic and lymphoid tissues is a leukemia.
  • the leukemia is acute myeloid leukemia or acute promyelocytic leukemia.
  • the cancer is characterized in that the cancer cells have features of cancer stem cells
  • the cancer is a drug resistant cancer.
  • the drug resistant cancer is drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia.
  • this application pertains to a method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia in a subject in need thereof, comprising administering to the subject an effective amount of an N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride, wherein the method further comprises:
  • the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride and a calorie restriction mimetic, wherein the subject is optionally on a calorie restricted diet.
  • the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride and a calorie restriction mimetic, wherein the subject is on a calorie restricted diet.
  • the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride and a calorie restriction mimetic, wherein the subject is on a standard diet.
  • the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride and an IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
  • the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride and an IGFl/insulin inhibitor, wherein the subject is on a calorie restricted diet.
  • the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride and an IGFl/insulin inhibitor, wherein the subject is on a standard diet.
  • the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
  • the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is on a calorie restricted diet.
  • the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is on a standard diet.
  • this application pertains to an LSD1 inhibitor, a calorie restricted diet, at least one caloric restriction mimetic, at least one IGFl/insulin inhibit, or any combination thereof for use in the treatment or prevention of cancer
  • the application pertains to an LSD1 inhibitor and
  • the application pertains to an LSD1 inhibitor and
  • the application pertains to a combination of an LSD1 inhibitor and
  • the application also pertains to a combination of an LSD1 inhibitor and at least one IGFl/insulin inhibitor for use in the treatment and/or in the prevention of cancer.
  • the application pertains to a combination of an LSD1 inhibitor and
  • the application pertains to a pharmaceutical composition comprising an LSD1 inhibitor and
  • the application pertains to an LSD1 inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the caloric restriction mimetic is a sirtuin-activating compound.
  • the application pertains to an LSD1 inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the IGFl/insulin inhibitor is selected from the group consisting of: inhibitor of IGF 1 receptor, inhibitor of insulin receptor, and inhibitor of both IGF1 receptor and insulin receptor.
  • the application pertains to an LSD1 inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the IGFl/insulin inhibitor is 3-[8-Amino-l-(2-phenyl-7-quinolyl)imidazo[l,5-a]pyrazin-3-yl]-l-methyl- cyclobutanol.
  • the application pertains to an LSD1 inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the LSDl inhibitor is selected from a compound as described in WO2013057322, WO2011131576, WO2014086790, WO2012135113, or WO 2015/181380.
  • the application pertains to an LSDl inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the LSDl inhibitor is selected from the group consisting of:
  • the application pertains to an LSDl inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the LSDl inhibitor is N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l-yl)benzamide dihydrochloride .
  • the application pertains to an LSDl inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the cancer is a tumor of the hematopoietic and lymphoid tissues.
  • the application pertains to an LSDl inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the cancer is a tumor of the hematopoietic and lymphoid tissues and the tumor of the hematopoietic and lymphoid tissues is a leukemia.
  • the application pertains to an LSDl inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the cancer is a tumor of the hematopoietic and lymphoid tissues, the tumor of the hematopoietic and lymphoid tissues is a leukemia, and the leukemia is acute myeloid leukemia (AML) or acute promyelocytic leukemia (APL).
  • AML acute myeloid leukemia
  • APL acute promyelocytic leukemia
  • the application pertains to an LSDl inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the cancer is characterized in that the cancer cells have features of cancer stem cells.
  • the application pertains to an LSD1 inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the cancer is a drug resistant cancer, for example, drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia.
  • the application also pertains to the use of an LSD1 inhibitor, any of the combinations disclosed herein or any of the pharmaceutical compositions disclosed herein in the manufacture of a medicament for the treatment and/or in the prevention of cancer.
  • the cancer is a tumor of the hematopoietic and lymphoid tissues.
  • the tumor of the hematopoietic and lymphoid tissues is a leukemia.
  • the leukemia is acute myeloid leukemia (AML) or acute promyelocytic leukemia (APL).
  • the cancer is characterized in that the cancer cells have features of cancer stem cells.
  • the LSD1 inhibitor is N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin- 1 -yl)benzamide dihydrochloride.
  • the application also pertains to a method of treatment of cancer comprising administering to a subject in need thereof
  • the application also pertains to a kit comprising an LSD1 inhibitor and
  • the kit comprising an LSD1 inhibitor further comprises a caloric restriction mimetic that is a sirtuin- activating compound.
  • the kit comprising an LSD1 inhibitor further comprises an
  • IGFl/insulin inhibitor that is selected from the group consisting of: inhibitor of IGF1 receptor, inhibitor of insulin receptor, and inhibitor of both IGF1 receptor and insulin receptor.
  • the kit comprising an LSD1 inhibitor further comprises an
  • the kit comprises an LSDl inhibitor that is selected from a compound as described in WO2013057322, WO2011131576, WO2014086790, WO2012135113, or WO2015/181380.
  • the kit comprises an LSDl inhibitor that is selected from the group consisting of:
  • the kit comprises an LSDl inhibitor that is N-[4-[trans-2- aminocyclopropyl]phenyl] -4-(4-methylpiperazin- 1 -yl)benzamide dihydrochloride.
  • the present application also provides a combination of at least one LSDl inhibitor and a calorie restricted diet and/or a caloric restriction mimetic for use in the treatment and/or in the prevention of cancer.
  • the application also pertains to a combination of at least one LSDl inhibitor and at least one IGFl/insulin inhibitor for use in the treatment and/or in the prevention of cancer.
  • the application also pertains to a combination of at least one LSDl inhibitor and a calorie restricted diet and/or a caloric restriction mimetic and at least one IGFl/insulin inhibitor for use in the treatment and/or in the prevention of cancer.
  • the application also pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising an LSDl inhibitor and at least one caloric restriction mimetic and/or at least one IGFl/insulin inhibitor as defined above for use in the treatment and/or in the prevention of cancer.
  • the cancer is a tumor of the hematopoietic and lymphoid tissues.
  • the tumor of the hematopoietic and lymphoid tissues is a leukemia.
  • the leukemia is acute myeloid leukemia (AML) or acute
  • APL promyelocytic leukemia
  • the cancer is characterized in that the cancer cells have features of cancer stem cells.
  • the cancer is a drug resistant cancer, for example, drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia.
  • the application also pertains to a kit comprising an LSDl inhibitor and at least one caloric restriction mimetic and/or at least one IGFl/insulin inhibitor as defined above.
  • the application also pertains to a method of treatment of cancer comprising
  • administering to a subject in need thereof at least one LSDl inhibitor and a calorie restricted diet and/or at least one caloric restriction mimetic and/or at least one IGFl/insulin inhibitor.
  • the application also pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising an LSDl inhibitor of the disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof and a pharmaceutically acceptable carrier and/or diluent.
  • the disease or disorder is cancer.
  • the application also pertains to the use of a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of the disclosure in the manufacture of a medicament for preventing or treating a disease or disorder in a subject in need thereof.
  • Figure 1A-1D Graphs showing the effect of caloric restriction (CR) on leukemic blasts.
  • Figure 2A-2B Graphs showing the effect of CR on survival of mice with APL.
  • Figure 3A-3B Graphs showing the effect of CR on leukemia initiating cells in tertiary recipients.
  • Figure 4A-4F Charts and Graphs Transcriptional analysis, gene set enrichment of leukemia in CR vs SD by RNAseq. Analysis.
  • Figure 5 Graph showing change in transcription of 104 superenhancer-associated genes compared to all genes for CR versus SD.
  • Figure 6A-6C Graphs and charts showing synergy between CR and LSDl inhibition by compound 1.
  • Figure 7 Graph showing synergy between OSI906 and LSDl inhibition by compound 1.
  • Figure 8A-8B Graph and picture describing in vitro system to mimic CR/LSD1 inhibition synergy.
  • Figure 9 Graph summarizing screening for additional leukemia cell lines.
  • Figure 10 Graph displaying cell cycle analysis using propidium iodide and Ki67.
  • Figure 11 Graphs displaying analysis of TCGA data expression.
  • Figure 12 Graphs displaying analysis of tumor growth data in NB4 cells wild-type
  • Figures 13A-C Charts and graphs showing that LSDl inhibitor significantly alters gene expression in APL cells.
  • Figures 14A-D Graphs summarizing experiments with OSI906 and LSDl inhibitor on a mouse model of NPMc/FLT3ITD (AML).
  • the present application is based on the finding disclosed herein that LSDl regulates metabolic adaptability and is a therapeutic target upon metabolic modulation through caloric restriction (CR) in cancer.
  • the cancer is selected from acute myeloid leukemia (AML) or acute pro myelocytic leukemia (APL).
  • the LSDl inhibitor is any known LSDl inhibitor, for instance an LSDl inhibitor as described in WO2013057322, WO2011131576, WO2014086790, WO2012135113, WO 2015/181380 and WO 2016/34946, each of which are incorporated herein by reference in their entireties.
  • the LSDl inhibitor may also be an antisense, an antibody, or a monoclonal antibody.
  • the LSDl inhibitor is selected from a compound of Formula (I)
  • R 1 is heterocyclyl or heterocyclyl substituted by oxo, wherein the heterocyclyl is unsubstituted or substituted by one or more C1-C6 alkyl;
  • R 2 is hydrogen, halogen, C1-G5 alkyl, C1-G5 alkoxy, C1-C6 haloalkyl, C1-G5 haloalkoxy, or benzyloxycarbonylamino.
  • the LSDl inhibitor is selected from a compound of Formula (I) that is: N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l-yl)benzamide; N-[4- [iraw5 , -2-aminocyclopropyl]phenyl]-4-(l-methyl-4-piperidyl)benzamide; N-[4-[trans-2- aminocyclopropyl]phenyl]-3-(2-oxooxazolidin-3-yl)benzamide; N-[4-[trans-2- aminocyclopropyl]phenyl]-4-morpholino-benzamide; N- ⁇ -firara ⁇ -aminocyclopropylJphenyl]- 4-(2-oxooxazolidin-3-yl)benzamide; benzyl N-[5-[[4-[(tran,s-2- aminocyclopropyl]phenyl]-4-(4-methyl
  • the LSDl inhibitor is selected from a compound of Formula (la)
  • X is CH or N
  • R is Ll-R 4 ;
  • R 1 is H, halogen, Ci-Ce-alkyl, Ci-C 6 -alkoxy, -CH 2 -Z-R 5 , or -Z-CH 2 -R 6 ;
  • R 2 and R 3 are Ci-C 4 -alkyl
  • LI is -(CH 2 )j-Y-, -Y-(CH 2 ) k -, -CH 2 -CH 2 - or -CO-NH-;
  • j and k are, independently, each an integer from 1 to 6;
  • Y is oxygen, sulphur, NH or N(Ci-C6-alkyl);
  • Z is a bond, oxygen, sulphur, NH or N(Ci-C6-alkyl);
  • R 4 , R 5 , and R 6 are, independently, Ci-C6-alkyl, aryl, heteroaryl, wherein the aryl or heteroaryl are optionally substituted by halogen, Ci-C6-alkyl, or L2-R 7 ; or heterocyclyl, wherein the heterocyclyl is optionally substituted by Ci-C6-alkyl;
  • L2 is -(CH 2 )m- or -(CH 2 ) n -W-(CH 2 ) 0 -;
  • R 7 is Ci-C6-alkylamino, C3-C7 cycloalkyl or heterocyclyl, wherein the C3-C7 cycloalkyl or heterocyclyl are optionally substituted by Ci-C6-alkyl, or NH 2 ; or guanidine;
  • n, o are, independently, each zero or an integer from 1 to 6;
  • W is oxygen, sulphur, NH, or CH 2 ;
  • aryl is a mono or bicyclic aromatic ring system of 6 or 9 or 10 atoms
  • heteroaryl is a mono or bicyclic heteroaromatic ring system of 5 to 10 members, which contains one, two, three or four heteroatoms selected from nitrogen, oxygen and sulphur, and one to nine carbon atoms
  • heterocyclyl is a mono, bicyclic or a spirocyclic saturated or partially saturated non- aromatic ring system of 4 to 12 members, which contains one, two, or three heteroatoms selected from nitrogen, oxygen, and sulphur, and three to eleven carbon atoms
  • the LSDl inhibitor is selected from a compound of Formula (la) that is: 4-methyl-N-[2-[[4-(4-piperidyloxy)phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5- carboxamide; 4-methyl-N-[2-[[4-(4-piperidylmethoxy)phenoxy]methyl]phenyl]thieno-[3,2- b]pyrrole-5-carboxamide; N-[2-[[4-[(l-ethyl-4-piperidyl)oxy]phenoxy]methyl]phenyl]-4- methyl-thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[2-[[4-[[[(3R)-pyrrolidin-3- yl]methoxy]phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[2-[[4-[[(3R)-pyrrolidin-3-
  • the LSD1 inhibitor is selected from a compound of Formula (II)
  • A is aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, Ci- Ce alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, CN, nitro, NH 2 , azide, OH, C1-C6 alkylamino, and R-L-;
  • R is aryl, wherein the aryl may be optionally substituted by one, two or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, CN, nitro, NH 2 , azide, C1-C6 alkylamino optionally substituted by OH, heterocyclylamino optionally substituted by C1-C6 alkyl, OH, phenyl, heterocyclyl optionally substituted by C1-C6 alkyl, heterocyclyl substituted by oxo, heteroaryl, and benzyloxycarbonylamino; or heteroaryl;
  • L is a single bond; Ci-C 6 alkylene; C 2 -C 6 alkenylene; -(CH 2 ) m X-(CH 2 ) n -; -(CH 2 ) 0 (S0 2 )NH-; -
  • R 1 is C1-C6 alkyl, optionally substituted by aryl or heteroaryl; aryl; heteroaryl; or -(CH 2 ) r -Y-R 5 ; and wherein the aryl or heteroaryl group may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, nitro, acetamido, and phenyl;
  • R 2 is hydrogen; C1-C6 alkyl, optionally substituted by aryl, heteroaryl, or by heterocyclyl and wherein the aryl or heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, Ci-C 6 haloalkoxy, and NH 2 ; or -CH 2 (CO)NR 6 R 7 ;
  • n, o, p, q are, independently, zero or an integer from 1 to 6;
  • r is an integer from 1 to 6;
  • X and Y are, independently, NR 8 ; O; or S;
  • R 3 and R 4 are, independently, hydrogen; or C1-C6 alkyl
  • R 5 is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and phenyl;
  • R 6 and R 7 are, independently, hydrogen; C1-C6 alkyl; or R 6 and R 7 together with the nitrogen to which they are bound form a C4-Cio-heterocyclic ring, optionally containing one or more further heteroatoms in the ring independently selected from NR 9 , O or S and being optionally substituted by NH 2 ;
  • R 8 is hydrogen; C1-C6 alkyl, optionally substituted by aryl or heterocyclyl; or C3-6 cycloalkyl;
  • R 9 is hydrogen or C1-C6 alkyl;
  • the LSD1 inhibitor is selected from a compound of Formula (II) that is: (lS,2R)-l-ethyl-2-phenyl-cyclopropanamine; (lR,2S)-l-ethyl-2-phenyl- cyclopropanamine; trans- l-methyl-2-phenyl-cyclopropanamine; (1R,2S)- l-methyl-2-phenyl- cyclopropanamine; ( 1 S,2R)- 1 -methyl-2-phenyl-cyclopropanamine; trans- 1 -propyl-2-phenyl- cyclopropanamine; trans- l-isopropyl-2-phenyl-cyclopropanamine; trans- l-benzyl-2-phenyl- cyclopropanamine; ( 1 S,2S)- 1 -benzyl-2-phenyl-cyclopropanamine; ( 1R,2R)- 1 -benzyl-2-phenyl-cyclopropanamine
  • the LSDl inhibitor is selected from a compound of Formula (III) R3
  • A is R or CH(Ri)-NH-CO-R 2 ;
  • R and R 2 are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, heterocycloalkylalkylamino;
  • Ri is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl;
  • R 3 is H, Ci-C 6 alkyl.
  • the LSDl inhibitor is selected from a compound of Formula (III) that is: trans benzyl 4-(2-aminocyclopropyl)phenylcarbamate; trans N-(4-(2- aminocyclopropyl)phenyl)benzamide; trans N-(4-(2-aminocyclopropyl)phenyl)- 1 -naphthamide; trans N-(4-(2-aminocyclopropyl)phenyl)-2-naphthamide; trans N-(4-(2- aminocyclopropyl)phenyl)biphenyl-4-carboxamide; trans N-(4-(2-aminocyclopropyl)phenyl)-2- phenylacetamide; trans N-(4-(2-aminocyclopropyl)phenyl)-2-(naphthalen-l-yl)acetamide; trans N-(4-(2-aminocyclopropyl)phenyl)-2
  • the LSD1 inhibitor is selected from: Nl-((trans)-2- phenylcyclopropyl)cyciohexane-l,4-diamine; (cis)-Nl-((lS,2R)-2- phenylcyclopropyl)cyclohexane-l,4-diamine; (trans)-Nl-((lS,2R)-2- phenylcyclopropyl)cyclohexane-l,4-diamine; (cis)-Nl-((lR,2S)-2- phenylcyclopropyl)cyclohexane-l,4-diamine; (trans)-Nl-((lR,2S)-2- phenylcyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-(thiazol-5- yl)cyclopropyl)cyclohexane;
  • the LSDl inhibitor is selected from: 1,1-Dimethylethyl 4-( ⁇ [trans- 2-phenylcyclopropyl]amino ⁇ methyl)-l-piperidinecarboxylate; 1,1-Dimethylethyl 4-( ⁇ [(1R,2S)- 2-phenylcyclopropyl]amino ⁇ methyl)-l-piperidinecarboxylate; 1,1-Dimethylethyl 4-( ⁇ [(1S,2R)- 2-phenylcyclopropyl] amino ⁇ methyl)- 1 -piperidinecarboxylate; [trans-2-Phenylcyclopropyl] ⁇ [ 1 - (phenylmethyl)-4-piperidinyl]methyl ⁇ amine; N-Phenyl-4-(((trans-2- phenylcyclopropyl)amino)methyl)piperidine-l-carboxamide; Phenyl(4-(((trans-2- phenylcyclopropyl]amin
  • the LSD1 inhibitor which may also be referred to as a KDM1A inhibitor, is selected from the group consisting of:
  • the LSD1 inhibitor is N-[4-[iraw5 , -2-aminocyclopropyl]phenyl]-4- (4-methylpiperazin- 1 -yl)benzamide dihydrochloride.
  • the IGFl/insulin inhibitor is selected from inhibitors of IGF 1 receptor, inhibitors of insulin receptor, and inhibitors of both IGF1 receptor and insulin receptor.
  • an inhibitor of IGF 1 is selected from:
  • Tyrphostins such as AG538 and AG1024. These are in early pre-clinical testing. They are not thought to be ATP-competitive, although they are when used in EGFR as described in QSAR studies;
  • Pyrrolo(2,3-d)-pyrimidine derivatives such as NVP-AEW541;
  • Monoclonal antibodies such as figitumumab.
  • the IGFl/insulin inhibitor is 3-[8-Amino-l-(2-phenyl-7- quinolyl)imidazo[l,5-a]pyrazin-3-yl]-l-methyl-cyclobutanol, which is also known as linsitinib or OSI906.
  • Calorie restriction is a dietary regimen that reduces calorie intake without incurring malnutrition or a reduction in essential nutrients.
  • Standard diet i.e., a normal caloric intake
  • age, gender and lifestyle desentary, moderately active, active
  • mice are allowed to eat without restriction and their caloric intake is monitored for a period of time. The average amount of Calories consumed in this period of time is the basis for determining the number of Calories to be fed to mice under Caloric restriction (CR).
  • CR Caloric restriction
  • a Calorie restricted (CR) diet is a diet with less than 90 % normal intake, less than 80% normal intake, less than 75% normal intake, less than 70%, normal intake, less than 65%, normal intake, less than 60%, normal intake, less than 55%, normal intake, or less than 50%, normal intake.
  • a "caloric restriction mimetic,” as used herein, refers to a class of supplements and drugs that mimic the anti-aging effects of calorie restriction, including, for example, the alteration of key metabolic pathways. Caloric restrictions mimetics are also referred to as energy restriction mimetics.
  • caloric restriction mimetic examples include, without limitation, sirtuin-activating compounds.
  • caloric restriction mimetics include, without limitation, resveratrol, butein, piceatannol, isoliquiritigenin, fisetin, and quercetin.
  • Other examples of caloric restriction mimetics include, without limitation, metformin, oxaloacetate, rimonabant, lipoic acid, 2-deoxy-D-glucose, rapamycin, peroxisome proliferator-activate receptor gamma inhibitors (rosigalitazone, gugulipids), exenatide, adiponectin, acipimox, hydroxycitrate, dipeptidyl peptidase 4 inhibitors, iodoacetate, mannoheptulose, modulators of neuropeptide Y, 4-phenylbutyrate, gymnemoside, and spermidine.
  • the pharmaceutical composition comprising an LSD1 inhibitor of the disclosure as defined above, further comprises at least one other therapeutic agent, selected from the group consisting of: histone deacetylase inhibitors, retinoid receptor modulators, antiproliferative/antineoplastic agents, cytostatic agents, agents which inhibit cancer cell invasion, inhibitors of growth factor function, anti-angiogenic agents, cell cycle inhibitors, proteasome inhibitors, HSP90 inhibitors, selective COX-2 inhibitors or a chemotherapeutic agent.
  • at least one other therapeutic agent selected from the group consisting of: histone deacetylase inhibitors, retinoid receptor modulators, antiproliferative/antineoplastic agents, cytostatic agents, agents which inhibit cancer cell invasion, inhibitors of growth factor function, anti-angiogenic agents, cell cycle inhibitors, proteasome inhibitors, HSP90 inhibitors, selective COX-2 inhibitors or a chemotherapeutic agent.
  • phrases containing the term "and/or” such as "A, B and/or C” refer to any of the following: A only; B only; C only; A and B; A and C; B and C; A, B and C.
  • subject refers to a human or non-human.
  • the subject is a mammal. In one embodiment, the subject is a human.
  • terapéuticaally effective amount indicates an amount necessary to administer to a subject, or to a cell, tissue, or organ of a subject, to achieve a therapeutic effect, such as an ameliorating or alternatively a curative effect.
  • the disclosure relates to a pharmaceutical composition in the form of tablets, capsules, oral preparations, powders, granules, pills, injectable or infusible liquid, solutions, suspensions, emulsions, suppositories, ointments, creams, lotions, gels, pastes, or transdermal delivery devices.
  • a reference for the formulations is the book by Remington ("Remington: The Science and Practice of Pharmacy", Lippincott Williams & Wilkins, 2000).
  • Compounds of the application may be administered to a patient in a total daily dose of, for example, from 0.001 to 1000 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The determination of optimum dosages for a particular patient is well known to one skilled in the art. [00137] Any of the compounds, combinations, pharmaceutical compositions, and/or dosage forms described herein can be administered to the patient via an oral, topical, intravenous, inhalational, otic, intramucosal, intraarterial, intraocular, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and/or subcutaneous route of administration.
  • any of the compounds, combinations, pharmaceutical compositions, and/or dosage forms described herein can be administered to the patient on a daily (e.g., 1 , 2, or 3 times daily), weekly (e.g. , 1, 2, 3, 4, or 5 times weekly), or monthly basis (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times monthly). Determination of the appropriate dosing schedule is within the routine level of skill in the art.
  • any of the compounds, combinations, pharmaceutical compositions, and/or dosage forms described herein may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 21st Edition, 2000, Lippincott Williams & Wilkins, which is incorporated herein in its entirety.
  • compositions are normally accompanied by written or printed instructions for use in the treatment in question.
  • kits comprising an LSDl inhibitor, combination or pharamaceutical composition as defined herein and at least one therapeutic agent selected from the group consisting of: histone deacetylase inhibitors, retinoid receptor modulators, antiproliferative/ antineoplastic agents, cytostatic agents, agents which inhibit cancer cell invasion, inhibitors of growth factor function, antiangiogenic agents, cell cycle inhibitors, proteasome inhibitors, HSP90 inhibitors, Selective COX-2 inhibitors and chemotherapeutic agents.
  • at least one therapeutic agent selected from the group consisting of: histone deacetylase inhibitors, retinoid receptor modulators, antiproliferative/ antineoplastic agents, cytostatic agents, agents which inhibit cancer cell invasion, inhibitors of growth factor function, antiangiogenic agents, cell cycle inhibitors, proteasome inhibitors, HSP90 inhibitors, Selective COX-2 inhibitors and chemotherapeutic agents.
  • the compound of the disclosure and the at least one therapeutic agent are in separated containers.
  • the LSDl inhibitor and the at least one caloric restriction mimetic and/or the at least one IGFl/insulin inhibitor are administered simultaneously or sequentially.
  • the LSDl inhibitor may be administered before or after the at least one caloric restriction mimetic and/or the at least one IGFl/insulin inhibitor.
  • the LSDl inhibitor and at least one caloric restriction mimetic and/or at least one IGFl/insulin inhibitor are in separated containers or in the same container.
  • the CR diet may start before the administration of an LSDl inhibitor, after the administration of an LSDl inhibitor, or concurrently with the administration of an LSDl inhibitor.
  • the CR diet starts before the administration of an LSD 1 inhibitor. For example, 1 day, 2 days, 3 day, 4 days, 5 days, 6 days, 14 days, 21 days, 30 days, 60 days, 90 days or any time period in between.
  • the CR diet starts after the administration of an LSDl inhibitor. For example, 1 day, 2 days, 3 day, 4 days, 5 days, 6 days, 14 days, 21 days, 30 days, 60 days, 90 days or any time period in between.
  • the CR diet starts concurrently with the administration of an LSDl inhibitor.
  • mice used in the examples presented herein were either under Caloric-restriction (CR) or a standard diet (SD). Mice were caged individually. Prior to starting the diet (CR), food consumption was monitored for 1 week. Then food was administered daily in doses equal to 70% of the daily intake (30 % caloric restriction). Other mice were under Standard Diet (SD).
  • CR Caloric-restriction
  • SD Standard Diet
  • APL cells were generated in mice expressing the PML-RARa fusion under the control of the Cathepsin G promoter (Westervelt et al, Blood. 2003 Sep 1;102(5): 1857-65). Primary leukemia cells were transplanted into recipients subjected to 30% CR or Standard Diet (SD). We scored the effect of CR alone or in combination with compound 1 (Varasi et al Eur. J. Cancer Vol 50 suppl. info. 6: 185) on mouse survival, leukemia initiating cell (LIC) frequency and epigenomic, transcriptomic and metabolic parameters.
  • LIC leukemia initiating cell
  • OSI906 was purchased from Selleck Chemicals and dissolved in DMSO at 100 mM and subsequently dissolved in 40% PEG in PBS (v/v) at 2 ⁇ g/ml. It was administered by gavage at 20 mg/kg per dose. Administration schedule was for 3 weeks on days 1, 3 or 5 in the morning (6-8 a.m.).
  • RNAseq analysis showed that CR had induced a dramatic transcriptional reprogramming characterized by: i) upregulation of genes controlling oxidative phosphorylation, TCA cycle and a number of anabolic pathways, including nucleotide and protein biosynthesis; ii) downregulation of inflammation and monocytic differentiation-associated pathways ( Figures 4A-4C).
  • Gene set enrichment analysis of RNAseq data obtained from APL cells sorted after 6 weeks of standard diet or caloric restriction showed transcriptional reprogramming of multiple pathways involved in metabolism and inflammation.
  • APL cells were injected in two cohorts of recipient mice: one that had been subjected to CR for the prior two weeks, some had been fed ad libitum with normal food. Two weeks later, each cohort was further randomized into receiving compound 1 by gavage at 45 mg/kg per dose, on days 1, 2 and 3 of each of the subsequent 3 weeks in the evening (6-8 p.m.). Treatment was then stopped, and mice were kept on their respective diet (CR or SD) and monitored for survival. None of the five mice treated with compound 1 under a CR-diet succumbed to disease, whereas all five mice died under SD. Three out of five mice succumbed to disease when compound 1 was administered without CR.
  • APL cells were injected in two cohorts of recipient mice: one that had been subjected to CR for the prior two weeks, some had been fed ad libitum with normal food. Two weeks later, each cohort was further randomized into receiving compound 1 by gavage at 45 mg/kg per dose, on days 1, 2 and 3 of each of the subsequent 2 weeks in the evening (6-8 p.m.). Mice were then sacrificed and the number of leukemic blasts in the bone marrow scored by flow cytometry as CD45-2+. Treatment with compound 1 in mice under a CR-diet resulted in complete disappearance of blasts in 4 out of 6 mice and a 1,000-10,000 fold decrease compared to all other groups in the remaining 2 mice.
  • CR mimetics rapamycin and the IGFIR/Insulin receptor inhibitor OSI906 were evaluated as a possible replacement for a CR-diet.
  • APL cells were injected in mice all fed SD, and then subjected to treatment with OSI906 and compound 1 starting from week 2 after injection.
  • OSI906 was administered by gavage at 20 mg/kg per dose, on days 1, 3 and 5 of each week, in the morning (6-8 a.m.).
  • Compound 1 was administered by gavage at 45 mg/kg per dose, on days 1, 2 and 3, of each week, in the evening (6-8 p.m.). Treatment was continued for 3 weeks and then mice were monitored for survival.
  • MV4-11 and, to a minor extent, OCI-AML3 fit this paradigm
  • MLL-AF9 MLL translocations are present in 21% of AML patients
  • FLT3-ITD present in 27% of AMLs
  • OCI- AML5 s driven by an NPM mutation 27% of AMLs.
  • CR limits the expansion of leukemic cells but enriches for cells with increased ability to regrow.
  • RNAseq of leukemic cells purified during the terminal phase showed that a dramatic transcriptional reprogramming in CR, characterized by upregulation of genes controlling OXPHOS, Krebs cycle and nucleotide and protein biosynthesis, and downregulation of insulin signaling and glucose transporters.
  • Flow cytometry with Mitotracker Red confirmed increased mitochondrial activity.
  • Example 10 Example 10
  • RNAseq was performed on APL cells collected from SD or CR mice, 18 days after injection and/or 1 day after 3 daily administrations of OSI-906 and/or compound 1.
  • Principal Component Analysis revealed that most variation in transcriptomes (PCI, accounting for -60% total variance) could be attributed to treatment with an LSD1 inhibitor, and the second strongest component (PC2, accounting for -20% variance) correlated with metabolic state, with OSI-906 inducing an intermediate state between SD and CR.
  • PCI Principal Component Analysis
  • PC2 the second strongest component
  • OSI-906 inducing an intermediate state between SD and CR.
  • SD and CR-LSD1 were at the two extremes of the PC space, indicating extreme transcriptional variation.
  • CR-LSD1 altered the transcription of 696 genes by at least 2 fold (adjusted p value ⁇
  • OSI906 and compound 1 were effective in reducing cell growth as measured after 4 days by Cell Titer Glo assay, with IC50 values of 1 ⁇ for OSI906 and 1.8 ⁇ for compound

Abstract

The present application relates to the use of an LSD1 inhibitor in combination with a caloric restricted diet, a calorie restriction mimetic and/or an IGF1/Insulin receptor inhibitor for the treatment of cancer, e.g., a leukemia, such as acute myeloid leukemia, acute promyelocytic leukemia.

Description

Combination of Caloric Restriction (CR) or IGFl/insulin receptor inhibitor with LSDl inhibitor
RELATED APPLICATION
[00 11 This application claims the benefit of and priority to U.S. Provisional Application No. 62/263,849 filed December 7, 2015. This document is incorporated by reference herein in its entirety for all purposes.
TECHNICAL FIELD OF THE APPLICATION
[0002] The present application relates to the use of an LSD l inhibitor in combination with a caloric restricted diet, a calorie restriction mimetic and'or an IGF 1 /Insulin receptor inhibitor for the treatment of cancer, e.g., a leukemia, such as acute myeloid leukemia, acute promyelocyte leukemia.
BACKGROUND
1 0031 There is increasing interest in therapeutic modulation of metabolic pathways in cancer. Tumor cells preferentially use aerobic glycolysis to meet their energetic demands. However, glycolysis inhibition alone is unable to bring durable responses because of limited therapeutic index and because of previously underappreciated metabolic adaptability in tumor cells, which can switch to alternative substrate usage when specific nutrients are limiting. The molecular basis of metabolic adaptation is poorly understood. Caloric restriction (CR) is associated with extensive metabolic changes. The effects of CR on metabolism and the underlying mechanisms are diverse and only partially understood.
SUMMARY
[0004] In one aspect, the application is based on the data disclosed herein which show that the combination of LSD l inhibition (also known as KDM 1 ) and insulin/IGF 1 signaling reduction by pharmacological or dietary intervention is a highly effective therapeutic strategy for the treatment of cancer.
[0005] In one aspect, this application pertains to methods of treating and/or preventing cancer in subject in need thereof.
[0006| In one aspect, this application pertains to a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of an LSD l inhibitor, wherein the method further comprises: a. administration of at least one calorie restriction mimetic; or
b. administration of at least one IGFl/insulin inhibitor; or
c. administration of at least one calorie restriction mimetic and at least one IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
[0007] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor and a calorie restriction mimetic, wherein the subject is optionally on a calorie restricted diet.
[0008] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor and a calorie restriction mimetic, wherein the subject is on a calorie restricted diet.
[0009] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor and a calorie restriction mimetic, wherein the subject is on a standard diet.
[0010] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor and an IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
[0011] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor and an IGFl/insulin inhibitor, wherein the subject is on a calorie restricted diet.
[0012] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor and an IGFl/insulin inhibitor, wherein the subject is on a standard diet.
[0013] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
[0014] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is on a calorie restricted diet.
[0015] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of an LSDl inhibitor, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is on a standard diet.
[0016] In one aspect, this application pertains to a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of an LSDl inhibitor, wherein the method further comprises: a. administration of at least one calorie restriction mimetic; or
b. administration of at least one IGFl/insulin inhibitor; or
c. administration of at least one calorie restriction mimetic and at least one IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet;
and wherein the LSDl inhibitor is selected from any compound of Formula (I), Formula (la), Formula (II), Formula (III), any other compound indicated as an LSDl inhibitor, or a stereoisomer or pharmaceutically acceptable salt thereof.
[0017] In one embodiment, the LSDl inhibitor is selected from the group consisting of:
tranylcypromine ;
Figure imgf000005_0001
;
(R)-4-[5-(Pyrrolidin-3-ylmethoxy)-2-p-tolyl-pyridin-3-yl]-benzonitrile;
l-(4-methyl- l-piperazinyl)-2-[[(lR*,25*)-2-[4- phenylmethoxy)phenyl]cyclopropyl] amino] ethanone dihydrochloride;
Figure imgf000005_0002
Figure imgf000006_0001
N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin- l-yl)benzamide; and a pharmaceutically acceptable salt thereof.
[0018] In one embodiment, the LSD1 inhibitor is N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin- 1 -yl)benzamide dihydrochloride .
[0019] In one embodiment, the IGFl/insulin inhibitor is selected from the group consisting of: inhibitor of IGFl receptor, inhibitor of insulin receptor, and inhibitor of both IGFl receptor and insulin receptor.
[0020] In one embodiment, the IGFl/insulin inhibitor is 3-[8-Amino-l-(2-phenyl-7- quinolyl)imidazo[l,5-a]pyrazin-3-yl]-l-methyl-cyclobutanol.
[0021] In one embodiment, the calorie restriction mimetic is a sirtuin-activating compound.
[0022] In one aspect, this application pertains to a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of an N-[4- [iraws-l-aminocyclopropyljphenyl] -4-(4-methylpiperazin- 1 -yl)benzamide dihydrochloride, wherein the method further comprises:
a. administration of at least one calorie restriction mimetic; or
b. administration of at least one IGFl/insulin inhibitor; or
c. administration of at least one calorie restriction mimetic and at least one IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
[0023] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride and a calorie restriction mimetic, wherein the subject is optionally on a calorie restricted diet.
[0024] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride and a calorie restriction mimetic, wherein the subject is on a calorie restricted diet.
[0025] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride and a calorie restriction mimetic, wherein the subject is on a standard diet. [0026] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride and an IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
[0027] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride and an IGFl/insulin inhibitor, wherein the subject is on a calorie restricted diet.
[0028] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride and an IGFl/insulin inhibitor, wherein the subject is on a standard diet.
[0029] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
[0030] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is on a calorie restricted diet.
[0031] In one embodiment, the method comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l- yl)benzamide dihydrochloride, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is on a standard diet.
[0032] In one aspect, for any of the methods described herein, the cancer is a tumor of the hematopoietic and lymphoid tissues.
[0033] In one embodiment, the tumor of the hematopoietic and lymphoid tissues is a leukemia.
[0034] In one embodiment, the leukemia is acute myeloid leukemia or acute promyelocytic leukemia.
[0035] In one aspect, for any of the methods described herein, the cancer is characterized in that the cancer cells have features of cancer stem cells
[0036] In one aspect, for any of the methods described herein, the cancer is a drug resistant cancer. [0037] In one embodiment, the drug resistant cancer is drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia.
[0038] In one aspect, for any of the methods described herein, this application pertains to a method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia in a subject in need thereof, comprising administering to the subject an effective amount of an N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride, wherein the method further comprises:
a. administration of at least one calorie restriction mimetic; or
b. administration of at least one IGFl/insulin inhibitor; or
c. administration of at least one calorie restriction mimetic and at least one IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
[0039] In one embodiment, the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride and a calorie restriction mimetic, wherein the subject is optionally on a calorie restricted diet.
[0040] In one embodiment, the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride and a calorie restriction mimetic, wherein the subject is on a calorie restricted diet.
[0041] In one embodiment, the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride and a calorie restriction mimetic, wherein the subject is on a standard diet.
[0042] In one embodiment, the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride and an IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
[0043] In one embodiment, the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride and an IGFl/insulin inhibitor, wherein the subject is on a calorie restricted diet.
[0044] In one embodiment, the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride and an IGFl/insulin inhibitor, wherein the subject is on a standard diet.
[0045] In one embodiment, the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
[0046] In one embodiment, the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is on a calorie restricted diet.
[0047] In one embodiment, the method of treating or preventing drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia comprises administering to the subject in need thereof an effective amount of N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide dihydrochloride, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is on a standard diet.
[0048] In one aspect, this application pertains to an LSD1 inhibitor, a calorie restricted diet, at least one caloric restriction mimetic, at least one IGFl/insulin inhibit, or any combination thereof for use in the treatment or prevention of cancer
[0049] In one embodiment, the application pertains to an LSD1 inhibitor and
(i) a calorie restricted diet and/or
(ii) at least one caloric restriction mimetic and/or
(iii) at least one IGFl/insulin inhibitor
for use in the treatment and/or in the prevention of cancer.
[0050] In one embodiment, the application pertains to an LSD1 inhibitor and
(i) at least one caloric restriction mimetic and/or
(ii) at least one IGFl/insulin inhibitor
for use in the treatment and/or in the prevention of cancer. [0051] In one embodiment, the application pertains to a combination of an LSD1 inhibitor and
(i) a calorie restricted diet and/or
(ii) a caloric restriction mimetic
for use in the treatment and/or in the prevention of cancer.
[0052] The application also pertains to a combination of an LSD1 inhibitor and at least one IGFl/insulin inhibitor for use in the treatment and/or in the prevention of cancer.
[0053] In one embodiment, the application pertains to a combination of an LSD1 inhibitor and
(i) a calorie restricted diet and/or
(ii) a caloric restriction mimetic and at least one IGFl/insulin inhibitor
for use in the treatment and/or in the prevention of cancer.
[0054] In one embodiment, the application pertains to a pharmaceutical composition comprising an LSD1 inhibitor and
(i) at least one caloric restriction mimetic, and/or
(ii) at least one IGFl/insulin inhibitor
for use in the treatment and/or in the prevention of cancer.
[0055] In one embodiment, the application pertains to an LSD1 inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the caloric restriction mimetic is a sirtuin-activating compound.
[0056] In one embodiment, the application pertains to an LSD1 inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the IGFl/insulin inhibitor is selected from the group consisting of: inhibitor of IGF 1 receptor, inhibitor of insulin receptor, and inhibitor of both IGF1 receptor and insulin receptor.
[0057] In one embodiment, the application pertains to an LSD1 inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the IGFl/insulin inhibitor is 3-[8-Amino-l-(2-phenyl-7-quinolyl)imidazo[l,5-a]pyrazin-3-yl]-l-methyl- cyclobutanol.
[0058] In one embodiment, the application pertains to an LSD1 inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the LSDl inhibitor is selected from a compound as described in WO2013057322, WO2011131576, WO2014086790, WO2012135113, or WO 2015/181380.
[0059] In one embodiment, the application pertains to an LSDl inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the LSDl inhibitor is selected from the group consisting of:
tranylcypromine ;
Figure imgf000011_0001
(R)-4-[5-(Pyrrolidin-3-ylmethoxy)-2-p-tolyl-pyridin-3-yl]-benzonitrile;
l-(4-methyl- l-piperazinyl)-2-[[(lR*,25*)-2-[4- ylmethoxy)phenyl]cyclopropyl] amino] ethanone dihydrochloride;
Figure imgf000011_0002
Figure imgf000012_0001
N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin- l-yl)benzamide; and a pharmaceutically acceptable salt thereof.
[0060] In one embodiment, the application pertains to an LSDl inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the LSDl inhibitor is N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l-yl)benzamide dihydrochloride .
[0061] In one embodiment, the application pertains to an LSDl inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the cancer is a tumor of the hematopoietic and lymphoid tissues.
[0062] In one embodiment, the application pertains to an LSDl inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the cancer is a tumor of the hematopoietic and lymphoid tissues and the tumor of the hematopoietic and lymphoid tissues is a leukemia.
[0063] In one embodiment, the application pertains to an LSDl inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the cancer is a tumor of the hematopoietic and lymphoid tissues, the tumor of the hematopoietic and lymphoid tissues is a leukemia, and the leukemia is acute myeloid leukemia (AML) or acute promyelocytic leukemia (APL).
[0064] In one embodiment, the application pertains to an LSDl inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the cancer is characterized in that the cancer cells have features of cancer stem cells. [0065] In one embodiment, the application pertains to an LSD1 inhibitor for use in the treatment and/or in the prevention of cancer, or any of the combinations for use disclosed herein in the treatment and/or in the prevention of cancer, or any of the pharmaceutical compositions for use disclosed herein in the treatment and/or in the prevention of cancer, wherein the cancer is a drug resistant cancer, for example, drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia.
[0066] The application also pertains to the use of an LSD1 inhibitor, any of the combinations disclosed herein or any of the pharmaceutical compositions disclosed herein in the manufacture of a medicament for the treatment and/or in the prevention of cancer. In one embodiment, the cancer is a tumor of the hematopoietic and lymphoid tissues. In one embodiment, the tumor of the hematopoietic and lymphoid tissues is a leukemia. In one embodiment, the leukemia is acute myeloid leukemia (AML) or acute promyelocytic leukemia (APL). In one embodiment, the cancer is characterized in that the cancer cells have features of cancer stem cells. In one embodiment, the LSD1 inhibitor is N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin- 1 -yl)benzamide dihydrochloride.
[0067] The application also pertains to a method of treatment of cancer comprising administering to a subject in need thereof
(i) an LSD 1 inhibitor, or
(ii) any of the combinations disclosed herein, or
(iii) any of the pharmaceutical compositions disclosed herein.
[0068] The application also pertains to a kit comprising an LSD1 inhibitor and
(i) a caloric restriction mimetic, or
(ii) an IGFl/insulin inhibitor, or
(iii) a caloric restriction mimetic and an IGFl/insulin inhibitor.
[0069] In one embodiment, the kit comprising an LSD1 inhibitor further comprises a caloric restriction mimetic that is a sirtuin- activating compound.
[0070] In one embodiment, the kit comprising an LSD1 inhibitor further comprises an
IGFl/insulin inhibitor that is selected from the group consisting of: inhibitor of IGF1 receptor, inhibitor of insulin receptor, and inhibitor of both IGF1 receptor and insulin receptor.
[0071] In one embodiment, the kit comprising an LSD1 inhibitor further comprises an
IGFl/insulin inhibitor that is 3-[8-Amino-l-(2-phenyl-7-quinolyl)imidazo[l,5-a]pyrazin-3-yl]-l- methyl-cyclobutanol. [0072] In one embodiment, the kit comprises an LSDl inhibitor that is selected from a compound as described in WO2013057322, WO2011131576, WO2014086790, WO2012135113, or WO2015/181380.
[0073] In one embodiment, the kit comprises an LSDl inhibitor that is selected from the group consisting of:
tranylcypromine ;
Figure imgf000014_0001
;
(R)-4-[5-(Pyrrolidin-3-ylmethoxy)-2-p-tolyl-pyridin-3-yl]-benzonitrile;
l-(4-methyl- l-piperazinyl)-2-[[(lR*,25*)-2-[4- phenylmethoxy)phenyl]cyclopropyl] amino] ethanone dihydrochloride;
Figure imgf000014_0002
N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin- l-yl)benzamide; and a pharmaceutically acceptable salt thereof.
[0074] In one embodiment, the kit comprises an LSDl inhibitor that is N-[4-[trans-2- aminocyclopropyl]phenyl] -4-(4-methylpiperazin- 1 -yl)benzamide dihydrochloride.
[0075] The present application also provides a combination of at least one LSDl inhibitor and a calorie restricted diet and/or a caloric restriction mimetic for use in the treatment and/or in the prevention of cancer.
[0076] The application also pertains to a combination of at least one LSDl inhibitor and at least one IGFl/insulin inhibitor for use in the treatment and/or in the prevention of cancer.
[0077] The application also pertains to a combination of at least one LSDl inhibitor and a calorie restricted diet and/or a caloric restriction mimetic and at least one IGFl/insulin inhibitor for use in the treatment and/or in the prevention of cancer.
[0078] The application also pertains to a pharmaceutical composition comprising an LSDl inhibitor and at least one caloric restriction mimetic and/or at least one IGFl/insulin inhibitor as defined above for use in the treatment and/or in the prevention of cancer.
[0079] In one embodiment, the cancer is a tumor of the hematopoietic and lymphoid tissues.
[0080] In one embodiment, the tumor of the hematopoietic and lymphoid tissues is a leukemia.
[0081] In one embodiment, the leukemia is acute myeloid leukemia (AML) or acute
promyelocytic leukemia (APL).
[0082] In one embodiment, the cancer is characterized in that the cancer cells have features of cancer stem cells.
[0083] In one embodiment, the cancer is a drug resistant cancer, for example, drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia.
[0084] The application also pertains to a kit comprising an LSDl inhibitor and at least one caloric restriction mimetic and/or at least one IGFl/insulin inhibitor as defined above.
[0085] The application also pertains to a method of treatment of cancer comprising
administering to a subject in need thereof at least one LSDl inhibitor and a calorie restricted diet and/or at least one caloric restriction mimetic and/or at least one IGFl/insulin inhibitor.
[0086] The application also pertains to a pharmaceutical composition comprising an LSDl inhibitor of the disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof and a pharmaceutically acceptable carrier and/or diluent.
[0087] The application also pertains to the use of a compound of the disclosure, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of the disclosure for preventing or treating a disease or disorder in a subject in need thereof. In one embodiment, the disease or disorder is cancer.
[0088] The application also pertains to the use of a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of the disclosure in the manufacture of a medicament for preventing or treating a disease or disorder in a subject in need thereof.
[0089] Although methods and materials similar to or equivalent to those described herein can be used in the practice and testing of the application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference.
[0090] The references cited herein are not admitted to be prior art to the claimed application. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
[0091] Other features and advantages of the application will become apparent from the following detailed description in conjunction with the examples.
[0092] The application will be illustrated by means of non-limiting examples in reference to the following figures.
BRIEF DESCRIPTION OF THE FIGURES
[0093] Figure 1A-1D: Graphs showing the effect of caloric restriction (CR) on leukemic blasts.
[0094] Figure 2A-2B: Graphs showing the effect of CR on survival of mice with APL.
[0095] Figure 3A-3B: Graphs showing the effect of CR on leukemia initiating cells in tertiary recipients.
[0096] Figure 4A-4F: Charts and Graphs Transcriptional analysis, gene set enrichment of leukemia in CR vs SD by RNAseq. Analysis.
[0097] Figure 5: Graph showing change in transcription of 104 superenhancer-associated genes compared to all genes for CR versus SD.
[0098] Figure 6A-6C: Graphs and charts showing synergy between CR and LSDl inhibition by compound 1.
[0099] Figure 7: Graph showing synergy between OSI906 and LSDl inhibition by compound 1.
[00100] Figure 8A-8B: Graph and picture describing in vitro system to mimic CR/LSD1 inhibition synergy.
[00101] Figure 9: Graph summarizing screening for additional leukemia cell lines.
[00102] Figure 10: Graph displaying cell cycle analysis using propidium iodide and Ki67. [00103] Figure 11: Graphs displaying analysis of TCGA data expression.
[00104] Figure 12: Graphs displaying analysis of tumor growth data in NB4 cells wild-type
(WT) and knockout (KO) for LSDl expression.
[00105] Figures 13A-C: Charts and graphs showing that LSDl inhibitor significantly alters gene expression in APL cells.
[00106] Figures 14A-D: Graphs summarizing experiments with OSI906 and LSDl inhibitor on a mouse model of NPMc/FLT3ITD (AML).
DETAILED DESCRIPTION
[00107] The present application is based on the finding disclosed herein that LSDl regulates metabolic adaptability and is a therapeutic target upon metabolic modulation through caloric restriction (CR) in cancer. In one aspect, the cancer is selected from acute myeloid leukemia (AML) or acute pro myelocytic leukemia (APL).
[00108] In the present application the LSDl inhibitor is any known LSDl inhibitor, for instance an LSDl inhibitor as described in WO2013057322, WO2011131576, WO2014086790, WO2012135113, WO 2015/181380 and WO 2016/34946, each of which are incorporated herein by reference in their entireties.
[00109] In one embodiment, the LSDl inhibitor may also be an antisense, an antibody, or a monoclonal antibody.
110] In one embodiment the LSDl inhibitor is selected from a compound of Formula (I)
Figure imgf000017_0001
harmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
R1 is heterocyclyl or heterocyclyl substituted by oxo, wherein the heterocyclyl is unsubstituted or substituted by one or more C1-C6 alkyl;
R2 is hydrogen, halogen, C1-G5 alkyl, C1-G5 alkoxy, C1-C6 haloalkyl, C1-G5 haloalkoxy, or benzyloxycarbonylamino.
[00111] In one embodiment, the LSDl inhibitor is selected from a compound of Formula (I) that is: N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l-yl)benzamide; N-[4- [iraw5,-2-aminocyclopropyl]phenyl]-4-(l-methyl-4-piperidyl)benzamide; N-[4-[trans-2- aminocyclopropyl]phenyl]-3-(2-oxooxazolidin-3-yl)benzamide; N-[4-[trans-2- aminocyclopropyl]phenyl]-4-morpholino-benzamide; N-^-firara^-aminocyclopropylJphenyl]- 4-(2-oxooxazolidin-3-yl)benzamide; benzyl N-[5-[[4-[(tran,s-2- aminocyclopropyl]phenyl]carbamoyl]-2-(4-methylpiperazin- l-yl)phenyl]carbamate; benzyl N- [4-[[4-[iraw5,-2-aminocyclopropyl]phenyl]carbamoyl]-2-(4-methylpiperazin- l- yl)phenyl]carbamate; benzyl N-[5-[[4-[iraw5,-2-aminocyclopropyl]phenyl]carbamoyl]-2-(l- piperidyl)phenyl]carbamate; benzyl N-[5-[[4-[iraw5,-2-aminocyclopropyl]phenyl]carbamoyl]-2- morpholino-phenyl] carbamate ; N- [4- [ ( 1 S ,2R) -2- aminocyclopropyl] phenyl] -4- (4- methylpiperazin-l-yl)benzamide; N-[4-[(lS,2R)-2-aminocyclopropyl]phenyl]-3-(2- oxooxazolidin-3-yl)benzamide; N-[4-[(lR,2S)-2-aminocyclopropyl]phenyl]-4-(4- methylpiperazin-l-yl)benzamide; N-[4-[(lR,2S)-2-aminocyclopropyl]phenyl]-3-(2- oxooxazolidin-3-yl)benzamide; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
[00112 In one embodiment the LSDl inhibitor is selected from a compound of Formula (la)
Figure imgf000018_0001
(la)
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
Figure imgf000018_0002
X is CH or N;
R is Ll-R4;
R1 is H, halogen, Ci-Ce-alkyl, Ci-C6-alkoxy, -CH2-Z-R5, or -Z-CH2-R6;
R2 and R3 are Ci-C4-alkyl;
LI is -(CH2)j-Y-, -Y-(CH2)k-, -CH2-CH2- or -CO-NH-;
j and k are, independently, each an integer from 1 to 6;
Y is oxygen, sulphur, NH or N(Ci-C6-alkyl);
Z is a bond, oxygen, sulphur, NH or N(Ci-C6-alkyl);
R4, R5, and R6 are, independently, Ci-C6-alkyl, aryl, heteroaryl, wherein the aryl or heteroaryl are optionally substituted by halogen, Ci-C6-alkyl, or L2-R7; or heterocyclyl, wherein the heterocyclyl is optionally substituted by Ci-C6-alkyl;
L2 is -(CH2)m- or -(CH2)n-W-(CH2)0-;
R7 is Ci-C6-alkylamino, C3-C7 cycloalkyl or heterocyclyl, wherein the C3-C7 cycloalkyl or heterocyclyl are optionally substituted by Ci-C6-alkyl, or NH2; or guanidine;
m, n, o are, independently, each zero or an integer from 1 to 6;
W is oxygen, sulphur, NH, or CH2;
wherein aryl is a mono or bicyclic aromatic ring system of 6 or 9 or 10 atoms; heteroaryl is a mono or bicyclic heteroaromatic ring system of 5 to 10 members, which contains one, two, three or four heteroatoms selected from nitrogen, oxygen and sulphur, and one to nine carbon atoms; and heterocyclyl is a mono, bicyclic or a spirocyclic saturated or partially saturated non- aromatic ring system of 4 to 12 members, which contains one, two, or three heteroatoms selected from nitrogen, oxygen, and sulphur, and three to eleven carbon atoms;
[00113] In one embodiment, the LSDl inhibitor is selected from a compound of Formula (la) that is: 4-methyl-N-[2-[[4-(4-piperidyloxy)phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5- carboxamide; 4-methyl-N-[2-[[4-(4-piperidylmethoxy)phenoxy]methyl]phenyl]thieno-[3,2- b]pyrrole-5-carboxamide; N-[2-[[4-[(l-ethyl-4-piperidyl)oxy]phenoxy]methyl]phenyl]-4- methyl-thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[2-[[4-[[(3R)-pyrrolidin-3- yl]methoxy]phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[2-[[4- (pyrrolidin-3-ylmethoxy)phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-ethyl- N-[3-[[4-(4-piperidyloxy)phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; N-[2- [[4-(azepan-4-yloxy)phenoxy]methyl]phenyl]-4-methyl-thieno[3,2-b]pyrrole-5-carboxamide; 4- ethyl-N-[2-[[4-(4-piperidyloxy)phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; N-[2-[[4-(cis-4-aminocyclohexoxy)phenoxy]methyl]phenyl]-4-methyl-thieno[3,2-b]pyrrole-5- carboxamide; 4-methyl-N-[3-[[4-(4-piperidyloxy)phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole- 5-carboxamide; 4-methyl-N-[2-[[4-[[(3S)-pyrrolidin-3- yl]methoxy]phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-ethyl-N-[2-[[4-[(l- methyl-4-piperidyl)oxy]phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4- methyl-N-[2-[[4-[(l-methyl-4-piperidyl)oxy]phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5- carboxamide; N-[2-[[4-(trans-4-aminocyclohexoxy)phenoxy]methyl]phenyl]-4-methyl- thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[3-[[4-[(l-methyl-4- piperidyl)oxy]phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[2-[(4- pyrrolidin-3-yloxyphenoxy)methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N- [2-[[3-[(l-methyl-4-piperidyl)oxy]phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5- carboxamide; 4-methyl-N-[2-[[3-(4-piperidyloxy)phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole- 5 -carboxamide; 4-methyl-N-[3-[(l-methyl-3-piperidyl)methoxy]phenyl]thieno[3,2-b]pyrrole-5- carboxamide; 4-methyl-N-[2-[[4-[(4-methylpiperazin-l- yl)methyl]phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[3-(4- pyridylmethoxy)phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[3-(4- pyridyloxymethyl)phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[4-[[4-[(l-methyl- 4-piperidyl)oxy]phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; N-[2-[[4- [[(lS,5R)-8-azabicyclo[3.2.1]octan-3-yl]oxy]phenoxy]methyl]phenyl]-4-methyl-thieno[3,2- b]pyrrole-5-carboxamide; N-[3-[[4-[[(lS,5R)-8-azabicyclo[3.2.1]octan-3- yl]oxy]phenoxy]methyl]phenyl]-4-methyl-thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[3- [[4-(4-piperidylmethoxy)phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4- methyl-N-[2-[[4-(3-piperidyloxy)phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[3-[[4-(3-piperidyloxy)phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5- carboxamide; N-[3-[[4-(trans-4-aminocyclohexoxy)phenoxy]methyl]phenyl]-4-methyl- thieno[3,2-b]pyrrole-5-carboxamide; N-[3-[[4-(azetidin-3-ylmethoxy)phenoxy]methyl]phenyl]-
4- methyl-thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[2-[[4-(3- methylaminopropoxy)phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl- N-[3-[(4-pyrrolidin-3-yloxyphenoxy)methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; N-[3- [[4-(azepan-4-yloxy)phenoxy]methyl]phenyl]-4-methyl-thieno[3,2-b]pyrrole-5-carboxamide; N-[3-[[4-(cis-4-aminocyclohexoxy)phenoxy]methyl]phenyl]-4-methyl-thieno[3,2-b]pyrrole-5- carboxamide; 4-methyl-N-[3-[[4-(pyrrolidin-3-ylmethoxy)phenoxy]methyl]phenyl]thieno[3,2- b]pyrrole-5-carboxamide; 4-methyl-N-[2-[[4-(4- piperidyloxy)phenyl]carbamoyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[2- [(4-piperazin-l-ylphenoxy)methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[2- [[4-[(l-methyl-4-piperidyl)oxy]phenyl]methoxy]phenyl]thieno[3,2-b]pyrrole-5-carboxam 4- methyl-N- [2- [ [4- (4-piperidylamino)phenoxy] methyl] phenyl] thieno [3 ,2-b]pyrrole-5- carboxamide; N-[2-[[4-(azetidin-3-ylmethoxy)phenoxy]methyl]phenyl]-4-methyl-thieno[3,2- b]pyrrole-5-carboxamide; N-[2-[[4-(2,8-diazaspiro[4.5]decan-2- ylmethyl)phenoxy]methyl]phenyl]-4-methyl-thieno[3,2-b]pyrrole-5-carboxamide; N-[3- (methoxymethyl)-2-[[4-[[(3R)-pyrrolidin-3-yl]methoxy]phenoxy]methyl]phenyl]-4-methyl- thieno[3,2-b]pyrrole-5-carboxamide; N-[3-(methoxymethyl)-2-[[4-(4- piperidyloxy)phenoxy]methyl]phenyl]-4-methyl-thieno[3,2-b]pyrrole-5-carboxamide; N-[2-[[4- (azepan-4-yloxy)phenoxy]methyl]-3-(methoxymethyl)phenyl]-4-methyl-thieno[3,2-b]pyrrole-
5- carboxamide; N-[3-(methoxymethyl)-2-[[4-[[(3S)-pyrrolidin-3- yl]methoxy]phenoxy]methyl]phenyl]-4-methyl-thieno[3,2-b]pyrrole-5-carboxamide; N-[3- (ethoxymethyl)-2-[[4-(4-piperidyloxy)phenoxy]methyl]phenyl]-4-methyl-thieno[3,2-b]pyrrole- 5-carboxamide; N-[3-(isopropoxymethyl)-2-[[4-(4-piperidyloxy)phenoxy]methyl]phenyl]-4- methyl-thieno[3,2-b]pyrrole-5-carboxamide; N-[3-(ethoxymethyl)-2-[[4-[[(3R)-pyrrolidin-3- yl]methoxy]phenoxy]methyl]phenyl]-4-methyl-thieno[3,2-b]pyrrole-5-carboxamide; 4-ethyl-N- [3-(methoxymethyl)-2-[[4-[[(3R)-pyrrolidin-3-yl]methoxy]phenoxy]methyl]phenyl]thieno[3,2- b]pyrrole-5-carboxamide; 4-methyl-N-[3-(morpholinomethyl)-2-[[4-(4- piperidyloxy)phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[5- methyl-2-[[4-(pyrrolidin-3-ylmethoxy)phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5- carboxamide; 4-methyl-N-[2-[[5-(4-piperidyloxy)-2-pyridyl]oxymethyl]phenyl]thieno[3,2- b]pyrrole-5-carboxamide; 4-methyl-N-[2-(4-piperidylmethoxy)phenyl]thieno[3,2-b]pyrrole-5- carboxamide; 4-methyl-N-[3-[[3-(4-piperidyloxy)phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole- 5-carboxamide; N-[3-[[4-(guanidinomethyl)phenoxy]methyl]phenyl]-4-methyl-thieno[3,2- b]pyrrole-5-carboxamide; N-[2-[[4-(guanidinomethyl)phenoxy]methyl]phenyl]-4-methyl- thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[2-[2-[4-(4- piperidyloxy)phenyl]ethyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[3-[2-[4- (4-piperidyloxy)phenyl]ethyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 4-methyl-N-[2-[[4- (4-piperidyloxy)anilino]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide; 6-methyl-N-[2- [[3-(4-piperidyloxy)phenoxy]methyl]phenyl]thieno[2,3-b]pyrrole-5-carboxamide; 6-ethyl-N-[2- [[3-(4-piperidyloxy)phenoxy]methyl]phenyl]thieno[2,3-b]pyrrole-5-carboxamide; 6-ethyl-N-[2- [[4-(4-piperidyloxy)phenoxy]methyl]phenyl]thieno[2,3-b]pyrrole-5-carboxamide; 6-methyl-N- [2-[[4-(4-piperidyloxy)phenoxy]methyl]phenyl]thieno[2,3-b]pyrrole-5-carboxamide; 6-methyl- N-[2-[[4-(pyrrolidin-3-ylmethoxy)phenoxy]methyl]phenyl]thieno[2,3-b]pyrrole-5- carboxamide; 4-methyl-N- [4- [[4- (4-piperidyloxy)phenyl] carbamoyl] -2-pyridyl]thieno [3,2- b]pyrrole-5-carboxamide; or a stereoisomer or pharmaceutically acceptable salt thereof.
[00114] In one embodiment, the LSD1 inhibitor is selected from a compound of Formula (II)
H
2
Figure imgf000021_0001
(II), wherein:
A is aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, Ci- Ce alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, CN, nitro, NH2, azide, OH, C1-C6 alkylamino, and R-L-;
R is aryl, wherein the aryl may be optionally substituted by one, two or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, CN, nitro, NH2, azide, C1-C6 alkylamino optionally substituted by OH, heterocyclylamino optionally substituted by C1-C6 alkyl, OH, phenyl, heterocyclyl optionally substituted by C1-C6 alkyl, heterocyclyl substituted by oxo, heteroaryl, and benzyloxycarbonylamino; or heteroaryl;
L is a single bond; Ci-C6 alkylene; C2-C6 alkenylene; -(CH2)mX-(CH2)n-; -(CH2)0(S02)NH-; -
(CH2)p(CO)NR3-; -(CH2)qNR4(CO)-; heterocyclyl substituted by oxo; or heteroaryl;
R1 is C1-C6 alkyl, optionally substituted by aryl or heteroaryl; aryl; heteroaryl; or -(CH2)r-Y-R5; and wherein the aryl or heteroaryl group may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, nitro, acetamido, and phenyl;
R2 is hydrogen; C1-C6 alkyl, optionally substituted by aryl, heteroaryl, or by heterocyclyl and wherein the aryl or heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, Ci-C6 haloalkoxy, and NH2; or -CH2(CO)NR6R7;
m, n, o, p, q are, independently, zero or an integer from 1 to 6;
r is an integer from 1 to 6;
X and Y are, independently, NR8; O; or S;
R3 and R4 are, independently, hydrogen; or C1-C6 alkyl;
R5 is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and phenyl;
R6 and R7 are, independently, hydrogen; C1-C6 alkyl; or R6 and R7 together with the nitrogen to which they are bound form a C4-Cio-heterocyclic ring, optionally containing one or more further heteroatoms in the ring independently selected from NR9, O or S and being optionally substituted by NH2;
R8 is hydrogen; C1-C6 alkyl, optionally substituted by aryl or heterocyclyl; or C3-6 cycloalkyl; R9 is hydrogen or C1-C6 alkyl;
or stereoisomers or pharmaceutically acceptable salts thereof.
[00115] In one embodiment, the LSD1 inhibitor is selected from a compound of Formula (II) that is: (lS,2R)-l-ethyl-2-phenyl-cyclopropanamine; (lR,2S)-l-ethyl-2-phenyl- cyclopropanamine; trans- l-methyl-2-phenyl-cyclopropanamine; (1R,2S)- l-methyl-2-phenyl- cyclopropanamine; ( 1 S,2R)- 1 -methyl-2-phenyl-cyclopropanamine; trans- 1 -propyl-2-phenyl- cyclopropanamine; trans- l-isopropyl-2-phenyl-cyclopropanamine; trans- l-benzyl-2-phenyl- cyclopropanamine; ( 1 S,2S)- 1 -benzyl-2-phenyl-cyclopropanamine; ( 1R,2R)- 1 -benzyl-2-phenyl- cyclopropanamine; trans- l-phenethyl-2-phenyl-cyclopropanamine; trans-2-(4-bromophenyl)-l- ethyl-cyclopropanamine; trans- l-benzyl-2-(4-bromophenyl)cyclopropanamine; trans- l-ethyl-2- (6-quinolyl)cyclopropanamine; trans- l-(2-naphthylmethyl)-2-phenyl-cyclopropanamine; trans-
1- ethyl-2-(4-fluorophenyl)cyclopropanamine; trans- l-ethyl-2-(4- chlorophenyl)cyclopropanamine; trans- l-ethyl-2-[3-(trifluoromethyl)phenyl]cyclopropanamine; trans- l-ethyl-2-[4-(trifluoromethyl)phenyl]cyclopropanamine; trans- l-ethyl-2-(3- fluorophenyl)cyclopropanamine; trans- l-ethyl-2-(3-chlorophenyl)-cyclopropanamine; trans- 1- ethyl-2-(3-bromophenyl)-cyclopropanamine; trans- l-ethyl-2-[3- methoxyphenyl]cyclopropanamine; l-ethyl-(trans)-2-[4- (trifluoromethoxy)phenyl]cyclopropanamine; trans- l-ethyl-2-(2- fluorophenyl)cyclopropanamine; trans- 1 -ethyl-2-(2-chlorophenyl)-cyclopropanamine; trans- 1 - ethyl-2-(2-bromophenyl)-cyclopropanamine; trans- l-(l-naphthylmethyl)-2-phenyl- cyclopropanamine; trans-2-(4-bromophenyl)-l-(2-naphthylmethyl)cyclopropanamine; trans-N- [4-[2-amino-2-ethyl-cyclopropyl]phenyl]naphthalene-2-carboxamide; N-[2-[(trans)-2-amino-2- ethyl-cyclopropyl]phenyl]benzamide; benzyl N-[3-[[2-[(trans)-2-amino-2-ethyl- cyclopropyl]phenyl]carbamoyl]phenyl]carba-mate; benzyl N-[3-[[3-[(trans)-2-amino-2-ethyl- cyclopropyl]phenyl]carbamoyl]phenyl]carba-mate; N-[4-[(trans)-2-amino-2-ethyl- cyclopropyl]phenyl]-3-chloro-benzamide N-[4-[(trans)-2-amino-2-ethyl-cyclopropyl]phenyl]-3- phenyl-benzamide; N-[4-[(trans)-2-amino-2-ethyl-cyclopropyl]phenyl]-4-phenyl-benzamide; benzyl N-[3-[[4-[(trans)-2-amino-2-ethyl-cyclopropyl]phenyl]carbamoyl]phenyl]carba-mate; benzyl N-[4-[[4-[(trans)-2-amino-2-ethyl-cyclopropyl]phenyl]carbamoyl]phenyl]carba-mate; N-[4-[(trans)-2-amino-2-ethyl-cyclopropyl]phenyl]-2-phenyl-acetamide; N-[4-[(trans)-2-amino-
2- ethyl-cyclopropyl]phenyl]-3-phenyl-propanamide; 2-(4-benzyloxyphenyl)-trans-l-ethyl- cyclopropanamine; N-[4-[(2-amino-trans-2-ethyl-cyclopropyl]phenyl]benzenesulfonamide; trans- l-benzyl-2-(4-benzyloxyphenyl)cyclopropanamine; N-[4-[trans-2-amino-2-(2- naphthylmethyl)cyclopropyl] phenyl] benzamide; benzyl-N-[3-[[4-[(trans)-2-amino-2-(2- naphthylmethyl)cyclopropyl]phenyl]carbamoyl]phenyl]carbamate; N-[4-[(trans)-2-amino-2-(2- naphthylmethyl)cyclopropyl]phenyl]-2-phenyl-acetamide; N-[4-[trans-2-amino-2-ethyl- cyclopropyl]phenyl]benzamide; trans-4-(2-amino-2-ethyl-cyclopropyl)aniline; trans-2-(3- azidophenyl)- 1-ethyl-cyclopropanamine; l-amino-(trans)-2-phenyl-cyclopropyl]methanol; 1- amino-(cis)-2-phenyl-cyclopropyl]methanol; (lR,2S)-l-ethyl-N-[(2-methoxyphenyl)methyl]-2- phenyl-cyclopropanamine; (1R,2S)- l-ethyl-N-[(2-methoxy- l-naphthyl)methyl]-2-phenyl- cyclopropanamine; 2- [ [( 1 S ,2R)- 1 -methyl-2-phenyl-cyclopropyl] amino] - 1 - (4-methylpiperazin- 1 -yl)ethanone; 2-[[( 1 S,2S)- 1 -methyl-2-phenyl-cyclopropyl] amino] - 1 -(4-methylpiperazin- 1 - yl)ethanone; l-[(3S)-3-aminopyrrolidin-l-yl]-2-[[(lS,2R)-l-methyl-2-phenyl- cyclopropyl] amino] ethanone; trans-2- [ [( 1 -ethyl-2-phenyl-cyclopropyl] amino] - 1 - (4- methylpiperazin- 1 -yl)ethanone; cis-2- [[( 1 -ethyl-2-phenyl-cyclopropyl] amino] - 1 - (4- methylpiperazin- 1 -yl)ethanone; trans- 1 -ethyl-N-methyl-2-phenyl-cyclopropanamine; cis- 1 - ethyl-N-methyl-2-phenyl-cyclopropanamine; trans- l-ethyl-N-ethyl-2-phenyl- cyclopropanamine; cis-l-ethyl-N-ethyl-2-phenyl-cyclopropanamine; trans-2-[[l-ethyl-2- phenyl-cyclopropyl] amino] acetamide; trans-N-benzyl- 1 -ethyl-2-phenyl-cyclopropanamine; trans-N-[(3,4-dimethoxyphenyl)methyl]-l-ethyl-2-phenyl-cyclopropanamine; trans-N-[(4,7- dimethoxy-l-naphthyl)methyl]-l-ethyl-2-phenyl-cyclopropanamine; trans-N-[(2-chloro-3- pyridyl)methyl]-l-ethyl-2-phenyl-cyclopropanamine; trans-N-[(2,2-dimethylchroman-6- yl)methyl] - 1 -ethyl-2-phenyl-cyclopropanamine; cis- 1 ,2-diphenylcyclopropanamine; trans- 1 ,2- diphenylcyclopropanamine; trans- l-ethyl-2-phenyl-cyclopropanamine; trans-2-(4-bromo-3- fhioro-phenyl)- 1-ethyl-cyclopropanamine; trans 2-(3-bromophenyl)- 1-phenethyl- cyclopropanamine; (lR,2S)-l,2-diphenylcyclopropanamine; (1S,2R)-1,2- diphenylcyclopropanamine; trans-2-(4-fluorophenyl)- 1 -(2-naphthylmethyl)cyclopropanamine; trans-2-(4-chlorophenyl)- l-(2-naphthylmethyl)cyclopropanamine; trans-2-(3-chlorophenyl)- 1- (2-naphthylmethyl)cyclopropanamine; trans-2-(3-bromophenyl)-l-(2- naphthylmethyl)cyclopropanamine; trans-2-(4-chlorophenyl)- 1 -phenethyl-cyclopropanamine; trans-2-(4-fluorophenyl)-l-phenethyl-cyclopropanamine; trans-l-benzyl-2-(4- fluorophenyl)cyclopropanamine; trans-l-benzyl-2-(4-chlorophenyl)cyclopropanamine; trans 2- (4-bromophenyl)-l -phenethyl-cyclopropanamine; cis-l-ethyl-2-phenyl-cyclopropanamine; N- [4-(trans-2-amino-2-ethyl-cyclopropyl)phenyl]-3-[(l-methyl-4-piperidyl)amino]-4-phenyl- benzamide; 2-(4-benzyloxyphenyl)- l-(2-naphthylmethyl)cyclopropanamine; N-[4-trans-[2- amino-2-ethyl-cyclopropyl]phenyl]-2-(l-naphthyl)acetamide; N-[4-trans-[2-amino-2-ethyl- cyclopropyl]phenyl]-2-(4-nitrophenyl)acetamide; benzyl N-[4-[[4-[trans-2-amino-2-(2- naphthylmethyl)cyclopropyl]phenyl]carbamoyl] phenyl]carbamate; N-[4-(trans-2-amino-2- ethyl-cyclopropyl)phenyl]naphthalene-l-carboxamide; N-[4-[trans-2-amino-2-(2- naphthylmethyl)cyclopropyl]phenyl]naphthalene-2-carboxamide; N-[4-[trans-2-amino-2-(2- naphthylmethyl)cyclopropyl]phenyl]-4-phenyl-benzamide; N-[4-trans-2-amino-2-ethyl- cyclopropyl]phenyl]-2-(2-naphthyl)acetamide; N-[4-[trans-2-amino-2-phenyl- cyclopropyl]phenyl]benzamide; N-[4-[trans-2-amino-2-(2- naphthylmethyl)cyclopropyl]phenyl]-2-(l-naphthyl)acetamide; N-[3-[trans-2-amino-2-ethyl- cyclopropyl]phenyl]-2-(l-naphthyl)acetamide; N-[4-[trans-2-amino-2-ethyl- cyclopropyl]phenyl]-4-(3-furyl)benzamide; N-[4-[trans-2-amino-2-(2- naphthylmethyl)cyclopropyl]phenyl]-3-chloro-benzamide; N-[3-[trans-2-amino-2-ethyl- cyclopropyl]phenyl]-3-chloro-benzamide; N-[4-[trans-2-amino-2-(2- naphthylmethyl)cyclopropyl]phenyl]-3-phenyl-propanamide; N-[4-[trans-2-amino-2-(2- naphthylmethyl)cyclopropyl] phenyl] - 3 -phenyl -benzamide ; N- [4- [trans-2- amino -2-ethyl- cyclopropyl]phenyl]-4-(2-oxooxazolidin-3-yl)benzamide; benzyl N-[3-[(4-[trans-2-amino-2- phenyl-cyclopropyl]phenyl)carbamoyl]phenyl] carbamate; N-[4-[trans-2-amino-2-phenyl- cyclopropyl]phenyl]naphthalene-2-carboxamide; N-[4-[trans-2-amino-2-ethyl-cyclopropyl]-2- fluoro-phenyl]benzamide; N-[4-[trans-2-amino-2-ethyl-cyclopropyl]-2-fluoro-phenyl]-4- phenyl-benzamide; N-[4-[trans-2-amino-2-ethyl-cyclopropyl]phenyl]-4-morpholino- benzamide; N-[4-[trans-2-amino-2-phenyl-cyclopropyl]phenyl]-4-phenyl-benzamide; N-[4- [trans-2-amino-2-phenyl-cyclopropyl]phenyl]naphthalene-l-carboxamide; N-[3-[trans-2- amino-2-ethyl-cyclopropyl]phenyl]-4-phenyl-benzamide; N-[3-[trans-2-amino-2-ethyl- cyclopropyl]phenyl]naphthalene-2-carboxamide; N-[3-[trans-2-amino-2-ethyl- cyclopropyl]phenyl]benzamide; N-[4-[trans-2-amino-2-ethyl-cyclopropyl]-2-fluoro-phenyl]-2- (l-naphthyl)acetamide; benzyl N-[4-[[4-[trans-2-amino-2-ethyl-cyclopropyl]-2-fluoro- phenyl]carbamoyl]phenyl] carbamate; N-[4-[trans-2-amino-2-ethyl-cyclopropyl]-2-fluoro- phenyl]-4-(4-methylpiperazin-l-yl)benzamide; N-[4-[trans-2-amino-2-ethyl- cyclopropyl]phenyl]-4-(4-methylpiperazin-l-yl)benzamide; N-[4-[trans-2-amino-2-ethyl- cyclopropyl]phenyl]-3-(2-oxooxazolidin-3-yl)benzamide; benzyl N-[5-[[4-[trans-2-amino-2- ethyl-cyclopropyl]phenyl]carbamoyl]-2-morpholino-phenyl]carbamate; N-[4-[trans-2-amino-2- ethyl-cyclopropyl]phenyl]-4-(l-methyl-4-piperidyl)benzamide; N-[4-(trans-2-amino-2-ethyl- cyclopropyl)phenyl]pyridine-4-carboxamide; N-[4-(trans-2-amino-2-ethyl- cyclopropyl]phenyl)-4-(4-pyridyl)benzamide; N-[4-(trans-2-amino-2-phenyl- cyclopropyl]phenyl]-3-chloro-benzamide; N-[4-(trans-2-amino-2-phenyl-cyclopropyl)phenyl]- 2-(l-naphthyl)acetamide; N-[4-(trans-2-amino-2-phenyl-cyclopropyl)phenyl]-2-phenyl- acetamide; N-[4-(trans-2-amino-2-phenyl-cyclopropyl)phenyl]-3-phenyl-benzamide; N-[4- (trans-2-amino-2-phenyl-cyclopropyl)phenyl]-2-(2-naphthyl)acetamide; N-[4-(trans-2-amino-2- phenyl-cyclopropyl)phenyl]pyridine-4-carboxamide; N-[4-(trans-2-amino-2-phenyl- cyclopropyl]phenyl)-4-(l-methyl-4-piperidyl)benzamide; N-[4-(trans-2-amino-2-phenyl- cyclopropyl)phenyl]-4-(4-methylpiperazin-l-yl)benzamide; N-[4-(trans-2-amino-2-phenyl- cyclopropyl)phenyl]-3-(2-oxooxazolidin-3-yl)benzamide; N-[4-(trans-2-amino-2-phenethyl- cyclopropyl)phenyl]pyridine-4-carboxamide; N-[4-(trans-2-amino-2-phenethyl- cyclopropyl)phenyl]-4-phenyl-benzamide; N-[4-trans-2-amino-2-phenethyl- cyclopropyl)phenyl]benzamide; N-[4-(trans-2-amino-2-phenethyl-cyclopropyl)phenyl]-4-(l- methyl-4-piperidyl)benzamide; N-[4-(trans-2-amino-2-phenethyl-cyclopropyl)phenyl]-4-(4- methylpiperazin-l-yl)benzamide; benzyl N-[5-[[4-[trans-2-amino-2-ethyl- cyclopropyl]phenyl]carbamoyl]-2-(4-methylpiperazin-l-yl)phenyl]carbamate; N-[4-(trans-2- amino-2-phenethyl-cyclopropyl)phenyl]-3-(2-oxooxazolidin-3-yl)benzamide; 4-[trans-2-amino- 2- (2-naphthylmethyl)cyclopropyl] aniline; N-[4-(trans-2-amino-2-ethyl-cyclopropyl]phenyl)-4- (2-hydroxyethylamino)benzamide; benzyl N-[3-[l-[4-[2-amino-2-ethyl- cyclopropyl]phenyl]triazol-4-yl]phenyl]carbamate; trans- l-ethyl-2-[3-(4-phenyltriazol- 1- yl)phenyl]cyclopropanamine; benzyl N-[3-[l-[4-[2-amino-2-(2- naphthylmethyl)cyclopropyl]phenyl]triazol-4-yl]phenyl]carbamate; trans- 1-(2- naphthylmethyl)-2-[4-(4-phenyltriazol- l-yl)phenyl]cyclopropanamine; trans l-ethyl-2-[2-(4- phenyltriazol- 1 -yl)phenyl] cyclopropanamine; trans- 1 -benzyl-2- [4- (4-phenyltriazol- 1 - yl)phenyl]cyclopropanamine; N-[4-[(lS,2R)-2-amino-2-ethyl-cyclopropyl]phenyl]-4-phenyl- benzamide; N-[4-[(lR,2S)-2-amino-2-ethyl-cyclopropyl]phenyl]-4-phenyl-benzamide; trans 1- benzyl-2-(3-methoxyphenyl)cyclopropanamine; l-[3-[(trans-2-amino-2-ethyl- cyclopropyl]phenyl]-3-phenyl-imidazolidin-2-one; trans- l-ethyl-2- [4- (4-phenyltriazol- 1- yl)phenyl]cyclopropanamine; trans l-[(benzylamino)methyl]-2-phenyl-cyclopropanamine; trans 1 - [(cyclopropylamino)methyl] -2-phenyl-cyclopropanamine; trans 1 - [(4-methylpiperazin- 1 - yl)methyl]-2-phenyl-cyclopropanamine; 5-[[[trans-l-methyl-2-phenyl- cyclopropyl]amino]methyl]pyrimidin-2-amine; trans-N-[(2-methoxy-3-pyridyl)methyl]-l- methyl-2-phenyl-cyclopropanamine; trans-N-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-l- methyl-2-phenyl-cyclopropanamine; cis-N,l-dimethyl-2-phenyl-cyclopropanamine;2-[[trans- 1 ,2-diphenylcyclopropyl] amino] - 1 -(4-methylpiperazin- 1 -yl)ethanone; 1 -(4-methylpiperazin- 1 - yl)-2-[[trans-l-(2-naphthylmethyl)-2-phenyl-cyclopropyl]amino]ethanone;2-[[(lR,2S)-l- methyl-2-phenyl-cyclopropyl] amino] - 1 -(4-methylpiperazin- 1 -yl)ethanone; 2- [[( 1R,2R)- 1 - methyl-2-phenyl-cyclopropyl] amino] - 1 -(4-methylpiperazin- 1 -yl)ethanone; 2- [[trans- 1 -methyl- 2-phenyl-cyclopropyl] amino] - 1 -(4-methylpiperazin- 1 -yl)ethanone; 2- [[cis- 1 -methyl-2-phenyl- cyclopropyl] amino] - 1 -(4-methylpiperazin- 1 -yl)ethanone; trans-N, 1 -dimethyl-2-phenyl- cyclopropanamine; 2- [[trans- 1 -ethyl-2-phenyl-cyclopropyl] amino] - 1 -( 1 - piperidyl)ethanone;trans-l-ethyl-2-phenyl-N-[2-(l-piperidyl)ethyl]cyclopropanamine; 5- [[[trans-l-methyl-2-phenyl-cyclopropyl]amino]methyl]-l,3,4-oxadiazol-2-amine; trans- 1-(4- nitrophenyl)-2-phenyl-cyclopropanamine; trans-2-(4-chlorophenyl)-l-phenyl- cyclopropanamine; trans-2-(4-bromophenyl)-l-phenyl-cyclopropanamine; N-[4-(trans-l-amino- 2-phenyl-cyclopropyl]phenyl]acetamide; or a stereoisomer or pharmaceutically acceptable salt thereof.
[00116] In one embodiment, the LSDl inhibitor is selected from a compound of Formula (III) R3
Figure imgf000027_0001
or an isomer, tautomer, racemic form, enantiomer, diastereomer, epimer, polymorph, solvate, mixtures thereof, pharmaceutically acceptable salt thereof, wherein:
A is R or CH(Ri)-NH-CO-R2;
R and R2 are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino, heterocycloalkylalkylamino;
Ri is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl;
R3 is H, Ci-C6 alkyl.
[00117] In one embodiment, the LSDl inhibitor is selected from a compound of Formula (III) that is: trans benzyl 4-(2-aminocyclopropyl)phenylcarbamate; trans N-(4-(2- aminocyclopropyl)phenyl)benzamide; trans N-(4-(2-aminocyclopropyl)phenyl)- 1 -naphthamide; trans N-(4-(2-aminocyclopropyl)phenyl)-2-naphthamide; trans N-(4-(2- aminocyclopropyl)phenyl)biphenyl-4-carboxamide; trans N-(4-(2-aminocyclopropyl)phenyl)-2- phenylacetamide; trans N-(4-(2-aminocyclopropyl)phenyl)-2-(naphthalen-l-yl)acetamide; trans N-(4-(2-aminocyclopropyl)phenyl)-2-(naphthalen-2-yl)acetamide; trans benzyl l-(4-(2- aminocyclopropyl)phenylamino)-3-methyl-l-oxobutan-2-ylcarbamate; trans benzyl l-(4-(2- aminocyclopropyl)phenylamino)-4-methyl-l-oxopentan-2- ylcarbamate; trans benzyl l-(4-(2- aminocyclopropyl)phenylamino)-3-cyclohexyl-l-oxopropan-2-ylcarbamate; trans benzyl 2-(4- (2-aminocyclopropyl)phenylamino)-2-oxo-l-phenylethylcarbamate; trans benzyl l-(4-(2- aminocyclopropyl)phenylamino)-l-oxo-3-phenylpropan-2-ylcarbamate; trans benzyl l-(4-(2- aminocyclopropyl)phenylamino)-3-(4-bromophenyl)- l-oxopropan-2-ylcarbamate; trans benzyl l-(4-(2-aminocyclopropyl)phenylamino)-3-(4-methoxyphenyl)-l-oxopropan-2-ylcarbamate; trans benzyl l-(4-(2-aminocyclopropyl)phenylamino)- l-oxo-4-phenylbutan-2-ylcarbamate; trans benzyl l-(4-(2-aminocyclopropyl)phenylamino)- l-oxo-3,3-diphenylpropan-2- ylcarbamate; trans benzyl l-(4-(2-aminocyclopropyl)phenylamino)-3-(naphthalen-l-yl)-l- oxopropan-2-ylcarbamate; trans benzyl l-(4-(2-aminocyclopropyl)phenylamino)-3- (naphthalen-2-yl)-l-oxopropan-2-ylcarbamate; trans benzyl l-(4-(2- aminocyclopropyl)phenylamino)-4-(lH-indol-3-yl)-l-oxobutan-2-ylcarbamate; trans benzyl 1- (4-(2-aminocyclopropyl)phenylamino)-4-(benzo[b]thiophen-3-yl)-l-oxobutan-2-ylcarbamate; trans 4-bromobenzyl l-(4-(2-aminocyclopropyl)phenylamino)-l-oxo-3-phenylpropan-2- ylcarbamate; cis benzyl l-(4-(2-aminocyclopropyl)phenylamino)-l-oxo-3-phenylpropan-2- ylcarbamate; trans Nl-(4-(2-aminocyclopropyl)phenyl)-N8-hydroxyoctanediamide; trans benzyl l-((4-(2-aminocyclopropyl)phenyl)(methyl)amino)-l-oxo-3-phenylpropan-2- ylcarbamate; trans N-(4-(2-aminocyclopropyl)phenyl)-2-(3-benzylureido)-3- phenylpropanamide or a isomer, tautomer, racemic form, enantiomer, diastereomer, epimer, polymorph, solvate, mixtures thereof, pharmaceutically acceptable salt thereof.
[00118] In one embodiment, the LSD1 inhibitor is selected from: Nl-((trans)-2- phenylcyclopropyl)cyciohexane-l,4-diamine; (cis)-Nl-((lS,2R)-2- phenylcyclopropyl)cyclohexane-l,4-diamine; (trans)-Nl-((lS,2R)-2- phenylcyclopropyl)cyclohexane-l,4-diamine; (cis)-Nl-((lR,2S)-2- phenylcyclopropyl)cyclohexane-l,4-diamine; (trans)-Nl-((lR,2S)-2- phenylcyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-(thiazol-5- yl)cyclopropyl)cyclohexane- 1 ,4-diamine; 1 -((trans)-2-(pyridin-3-yl)cyclopropyl)cyclohexane- 1,4-diamine; Nl-((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3- yl)cyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-(3'-(trifluoromethyl)-[l,l'-biphenyl]-4- yl)cyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-(4- (benzyloxy)phenyl)cyclopropyl)cyclohexane-l,4-diamine; 4-(((trans)-2-(6-(3- (trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexanol; 4-(((trans)-2-(6-(3- (trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexanecarboxamide; N-(4- (((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3- yl)cyclopropyl)amino)cyclohexyl)acetamide; (4-(((trans)-2-(6-(3- (trifiuoromethyl)phenyl)pyrldin-3-yl; (R)-l-(4-(((trans)-2- phenylcyclopropyl)amino)cyclohexyl)pyrrolidin-3-amine; Nl-((trans)-2-(4'-chloro-[l,l'- biphenyl] -4-yl)cyclopropyl)cyclohexane- 1 ,4-diamine; N 1 -((trans)-2- (3 '-chloro- [1,1 '-biphenyl] - 4-yl)cyclopropyl)cyclohexane- 1 ,4-diamine; 4'-((trans)-2-((4- aminocyclohexyl)amino)cyclopropyl)- [1,1 '-biphenyl] -3-ol; N-(4'-((trans)-2-((4- aminocyciohexyl)amino)cyclopropyl)-[l,l'-biphenyl]-3-yl)methanesulfonamide; Nl-((trans)-2- (4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-(4-((3- fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-(4-((4- fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-methyl-N4-((trans)-2- phenylcyclopropyl)cyclohexane-l,4-diamine; Nl-methyl-N4-((trans)-2-(3'-(trifluoromethyl)- [1,1 '-biphenyl] -4-yl)cyclopropyl)cyclohexane- 1 ,4-diamine; N 1 - ((trans)-2-(4- (benzyloxy)phenyl)cyciopropyl)-N4-methylcyclohexane-l,4-diamine; Nl-((trans)-2- phenylcyclopropyl)cyclobutane- 1 ,3-diamine; N 1 -((trans)-2-(3'-(trifluoromethyl)- [ 1,1'- biphenyl]-4-yl)cyclopropyl)cyclobutane-l,3-diamine; Nl-((trans)-2-(4- (benzyloxy)phenyl)cyclopropyl)cyclobutane-l,3-diamine; Nl-((trans)-2-phenylcyclopropyl)-
2.3- dihydro- lH-indene- 1 ,3-diamine; Nl -((trans)-2-(3'-(trifluoromethyl)-[ 1 , l'-biphenyl] -4- yl)cyclopropyl)-2,3-dihydro-lH-indene-l,3-diamine; Nl-((trans)-2-(4- (benzyloxy)phenyl)cyclopropyl)-2,3-dihydro-lH-indene-l,3-diamine; Nl-((trans)-2-fluoro-2- phenylcyclopropyl)cyclohexane-l,4-diamine; Nl-((1 S,2S)-2-fluoro-2- phenylcyclopropyl)cyclohexane- 1 ,4-diamine; N 1 -(( 1 R,2R)-2-fluoro-2- phenylcyclopropyl)cyclohexane-l,4-diamine; l-methyl-N4-((trans)-2- phenylcyclopropyl)cyclohexane- 1 ,4-diamine; 4-(aminomethyl)-N-((trans)-2- phenylcyclopropyl)cyclohexanamine; Nl-((trans)-2-phenyicyciopropyl)cyciohexane-l,3- diamine; Nl-((cis)-2-phenylcyclopropyl)cyclohexane-l,4-diamine; tert-butyl (4-(((trans)-2- phenylcyclopropyl)amino)cyclohexyl)carbamate; l-ethyl-3-(4-(((trans)-2- phenylcyclopropyl)amino)cyclohexyl)urea; 4-morpholino-N-((trans)-2- phenylcyclopropyl)cyclohexanamine; Nl-((trans)-2-(4-bromophenyl)cyclopropyl)cyclohexane- 1 ,4-diamine; Nl-{2-(o-tolyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-(2-(4- (trifluoromethyl)phenyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-(2-(4- methoxyphenyl)cyclopropyl)cyclohexane- 1 ,4-diamine; 4-(2-((4- aminocyclohexyl)amino)cyclopropyl)phenol; Nl-(2-(2-fluorophenyl)cyclopropyl)cyclohexane-
1.4- diamine; Nl-(2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-(2- (naphthalen-2-yl)cyclopropyl)cyclohexane-l,4-diamine; Nl-(2-methyl-2- phenylcyclopropyl)cyclohexane-l,4-diamine; (R)- l-(4-(((trans)-2-(3'-(trifluoromethyl)-[l,l'- biphenyl]-4-yl)cyclopropyl)amino)cyclohexyl)pyrrolidin-3-amine; (cis)-Nl-((lS,2R)-2-(3'- (trifluoromethyl)- [ 1 , 1 '-biphenyl] -4-yl)cyclopropyl)cyclohexane- 1 ,4-diamine; (trans)-N 1 - ((lS,2R)-2-(3'-(trifiuoromethyl)-[l, l'-biphenyl] -4-yl)cyclo-propyl)cyclohexane-l,4-diamine; (cis)-N 1 - (( 1 R,2S)-2- (3 '- (trifhioromethyl) -[1,1 '-biphenyl] -4-yl)cyclo-propyl)cyclohexane- 1 ,4- diamine; (Trans)-Nl-({ lR,2S)-2-(3'-(trifluoromethyl)-[l,r-biphenyl]- yl)cyclopropyl)cyclohexane- 1 ,4-diamine ; N 1 - ( (tran s) -2- (4- cyclopropylphenyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-(4-(pyridin-3- yl)phenyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-(4-(lH-indazol-6- yl)phenyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-(4-(lH-pyrazol-5- yl)phenyl)cyclopropyl)cyclohexane-l,4-diamine; 3-(5-((trans)-2-((4- aminocyclohexyl)amino)cyclopropyl)thiophen-2-yl)phenol; 3-(5-((trans)-2-((4- aminocyciohexyl)amino)cyclopropyl)thiazol-2-yl)phenol; 3-(5-((trans)-2-((4- aimnocyclohexyl)amino)cyclopropyl)pyridin-2-yl)-5-methoxybenzonitrile; 5- 5-((trans)-2-((4- aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)-2-methylphenol; N-(4'-((trans)-2-((4- aminocyclohexyl)amino)cyclopropyl)-6-methoxy-[l,l,-biphenyl]-3-yl)methanesulfonamide; N- (3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiazol-2-yl)phenyl)-2- cyanobenzenesulfonamide; N-(4'-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[l,l'- biphenyl]-3-yl)-2-cyanobenzenesulfonamide; 6-amino-N-(4'-((trans)-2-((4- aimnocyclohexyl)amino)cyclopropyl)-[l,l'-biphenyl]-3-yl)pyridine-3-sulfonamide; N-(4'- ((trans)-2-((4-aminocyclohexyl)amino)cyciopropyl)-[l,l'-biphenyi]-3-yl)piperazine-l- sulfonamide; Nl-((cis)-2-fluoro-2-phenylcyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2- (4-((3-(piperazin-l-yl)benzyl)oxy)phenyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2- (4-(pyridin-3-ylmethoxy)phenyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-(6-((3- methylbenzyl)amino)pyridin-3-yl)cyclopropyl)cyclohexane-l,4-diamine; 3-((5-((trans)-2-((4- aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)aminobenzonitrile; Nl-((trans)-2- (naphthalen-2-yl)cyclopropyl)cyclohexane-l ,4-diamine; Nl-((trans)-2-(o- tolyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-(4- (trifluoromethyl)phenyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-(4- methoxyphenyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-(2- fluorophenyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-(3,4- difluorophenyl)cyclopropyl)cyclohexane-l,4-diamine; Nl-((trans)-2-methyl-2- phenylcyclopropyl)cyclohexane-l,4-diamine; (cis)-Nl-((lS,2R)-2-(pyridin-3- yl)cyclopropyl)cyclohexane-l,4-diamine; (trans)-Nl-((lR,2S)-2-(pyridin-3- yl)cyclopropyl)cyclohexane-l,4-diamine; (cis)-Nl-((lR,2S)-2-(pyridin-3- yl)cyclopropyl)cyclohexane-l,4-diamine; (trans)-Nl-((lS,2R)-2-(pyridin-3- yl)cyclopropyl)cyclohexane-l,4-diamine; (cis)-Nl-((lS,2R)-2-phenylcyclopropyl)cyclobutane- 1 ,3-diamine; trans Nl-(lR,2S)-2-phenylcyclopropyl)cyclobutane-1.3-diamine; (cis)-Nl- ((lR,2S)-2-phenylcyclopropyl)cyclobutane-l,3-diamine; (trans)-Nl-((lS,2R)-2- phenylcyclopropyl)cyclobutane-l,3-diamine; (cis)-Nl-((lS,2R)-2-(3,4- difluorophenyl)cyclopropyl)cyclohexane-l,4-diamine; (trans)-Nl-((lR,2S)-2-(3,4- difluorophenyl)cyclopropyl)cyclohexane-l,4-diamine; (cis)-Nl-((lR,2S)-2-(3,4- difluorophenyl)cyclopropyl)cyclohexane-l,4-diamine; (trans)-Nl-(( lS,2R)-2-(3,4- difluorophenyl)cyclopropyl)cyclohexane-l,4-diamine; (cis)-Nl-((lS,2R)-2-(naphthalen-2- yl)cyclopropyl)cyclohexane-l,4-diamine; (trans)-Nl-((lR,2S)-2-(naphthalen-2- yl)cyclopropyl)cyciohexane-l,4-diamine; (cis)- l-((lR,2S)-2-(naphthalen-2- yl)cyclopropyl)cyclohexane-l,4-diamine; (trans)-Nl-((lS,2R)-2-(naphthalen-2- yl)cyclopropyl)cyclohexane-l,4-diamine; (cis)-Nl-((lS,2R)-2-(4-(lH-pyrazol-5- yi)phenyl)cyciopropyl)cyclohexane-l,4-diamine; (trans)-Nl-((lR,2S)-2-(4-(lH-pyrazol-5- yl)phenyl)cyclopropyl)cyclohexane-l,4-diamine; (cis)-Nl-((lR,2S)-2-(4-(lH-pyrazol-5- yl)phenyl)cyclopropyl)cyclohexane-l,4-diamine; (trans)-Nl-((lS,2R)-2-(4-(lH-pyrazol-5- yl)phenyl)cyclopropyl)cyclohexane-l,4-diamine; N-(4'-((lR,2S)-2-(((cis)-4- aminocyclohexyl)amino)cyclopropyl)-[l, -biphenyl]-3-yl)piperazine-l-sulfonamide; N-(4'- ((lS,2R)-2-(((trans)-4-aminocyclohexyl)amino)cyclopropyl)-[l,l'-biphenyl]-3-yl)piperazine-l- sulfonamide; N-(4'-((lS,2R)-2-(((cis)-4-aminocyclohexyl)amino)cyclopropyl)-[l,l'-biphenyl]- 3-yl)piperazine-l-sulfonamide; N-(4'-((lR,2S)-2-(((trans)-4- aminocyciohexyl)amino)cyclopropyl)-[l,l'-biphenyl]-3-yl)piperazin; (cis)-Nl-((lS,2R)-2-(4- ((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-l,4-diamine; (trans)-Nl-((lR,2S)-2-(4- ((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-l,4-diamine; (cis)-Nl-((lR,2S)-2-(4- ((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-l,4-diamine; (trans)-Nl-((lS,2R)-2-(4- ((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-l,4-diamine; or a pharmaceutically acceptable salt or solvate thereof.
[00119] In one embodiment, the LSDl inhibitor is selected from: 1,1-Dimethylethyl 4-({ [trans- 2-phenylcyclopropyl]amino}methyl)-l-piperidinecarboxylate; 1,1-Dimethylethyl 4-({ [(1R,2S)- 2-phenylcyclopropyl]amino}methyl)-l-piperidinecarboxylate; 1,1-Dimethylethyl 4-({ [(1S,2R)- 2-phenylcyclopropyl] amino } methyl)- 1 -piperidinecarboxylate; [trans-2-Phenylcyclopropyl] { [ 1 - (phenylmethyl)-4-piperidinyl]methyl}amine; N-Phenyl-4-(((trans-2- phenylcyclopropyl)amino)methyl)piperidine-l-carboxamide; Phenyl(4-(((trans-2- phenylcyclopropyl)amino)methyl)piperidin-l-yl)methanone; l-(4-(((trans-2- Phenylcyclopropyl)amino)methyl)piperidin- l-yl)ethanone; Benzyl 4-(((trans-2- phenylcyclopropyl)amino)methyl)piperidine-l-carboxylate; 1,1-Dimethylethyl 4-({ [trans-2- phenylcyclopropyl]amino}methyl)hexahydro-lH-azepine-l-carboxylate 2-(4-(((trans-2- phenylcyclopropyl)amino)methyl)piperidin-l-yl)acetic acid; 4-{ [(3R)-3-({ [(lR,2S)-2- Phenylcyclopropyl]amino}methyl)-l-pyrrolidinyl]methyl}benzoic acid; 4-{ [(3S)-3-({ [(1R,2S)- 2-Phenylcyclopropyl]amino}methyl)-l-pyrrolidinyl]methyl}benzoic acid; 4-{3-[4-({ [(1R,2S)- 2-Phenylcyclopropyl] amino } methyl)- 1 -piperidinyl]propyl Jbenzoic acid; trans-2-Phenyl-N-(( 1 - (pyridin-4-ylmethyl)piperidin-4-yl)methyl)cyclopropanamine; trans-N-((l-(2- Fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine; trans-N-((l-(3- Fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine; trans-N-((l-(4- Fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine; trans-N-((l-(2,4- Difluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine; Ethyl 4-((4-(((trans-2- phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)benzoate; trans-N-((l-(4- (Methylsulfonyl)benzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine; 2-((4-(((trans-2- Phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)benzonitrile; trans-2-Phenyl-N-((l-(2- (trifluoromethyl)benzyl)piperidin-4-yl)methyl)cyclopropanamine; trans-N-((l-((5- Methylisoxazol-3-yl)methyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine; trans-N-((l- ((lH-Pyrazol-4-yl)methyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine; N-(4-((4-(((trans- 2-Phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)phenyl)acetamide; 4-((4-(((trans-2- Phenylcyclopropyl)amino)methyl)piperidin- l-yl)methyl)benzo[c] [ 1 ,2]oxaborol- 1 (3H)-ol; 5-((4- (((trans-2-Phenylcyclopropyl)amino)methyl)piperidin- 1 -yl)methyl)benzo[c] [ 1 ,2] oxaborol- l(3H)-ol; (4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-l- yl)methyl)phenyl)boronic acid; 2-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-l- yl)methyl)benzoic acid; 3-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin- 1-yl)- methyl)benzoic acid; 4-((4-(((trans-2-(4-Bromophenyl)cyclopropyl)amino)methyl)piperidin- 1- yl)methyl)benzoic acid; 4-((4-(((trans-2-(4-Chlorophenyl)cyclopropyl)amino)methyl)piperidin-
1- yl)methyl)benzoic acid; 4-((4-(((trans-2-(3,4-
Dichlorophenyl)cyclopropyl)amino)methyl)piperidin-l-yl)methyl)benzoic acid; 4-((4-(((trans-
2- (4-(Trifluoromethyl)phenyl)cyclopropyl)amino)methyl)piperidin- 1 -yl)methyl)benzoic acid; 4-((4-(((trans-2-(3,4-Dimethoxyphenyl)cyclopropyl)amino)methyl)piperidin-l- yl)methyl)benzoic acid; 4-((4-(((trans-2-(4-
Acetamidophenyl)cyclopropyl)amino)methyl)piperidin- l-yl)methyl)benzoic acid; 4-((4- (((trans-2-(4-Benzamidophenyl)cyclopropyl)amino)methyl)piperidin-l-yl)methyl)benzoic acid; trans-2-Phenyl-N-((l-phenylpiperidin-4-yl)methyl)cyclopropanamine; Ethyl 4-(((trans-2- phenylcyclopropyl)amino)methyl)piperidine-l-carboxylate; trans-4-((4-(((trans-2- Phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)cyclohexanecarboxylic acid; (trans)-N- ((l-(Methylsulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine; N-ethyl-4-((((trans)-2- phenylcyclopropyl)amino)methyl)piperidine-l-carboxamide; N-cyclopropyl-4-((((trans)-2- phenylcyclopropyl)amino)methyl)piperidine-l-carboxamide; N,N-dimethyl-4-((((trans)-2- phenylcyclopropyl)amino)methyl)piperidine-l-carboxamide, (4-((((trans)-2- phenylcyclopropyl)amino)methyl)piperidin-l-yl)(pyrrolidin-l-yl)methanone; trans-N-((l- ((cyclopropylsulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine; trans-N-((l- ((isopropylsulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine; trans-N-((l-(3,5- dimethylisoxazol-4-yl)sulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine; trans-N-((l- (( 1 ,2-dimethyl- lH-imidazol-4-yl)sulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine; (trans)-2-Phenyl-N-(2-(l-(pyridin-2-yl)piperidin-4-yl)ethyl)cyclopropanamine; 6-(4-(2- (((trans)-2-Phenylcyclopropyl)amino)ethyl)piperidin-l-yl) nicotinic acid; trans-2-phenyl-N-(2- (l-(pyridin-4-yl)piperidin-4-yl)ethyl)cyclopropanamine; trans-2-phenyl-N-(2-(l-(pyrimidin-4- yl)piperidin-4-yl)ethyl)cyclopropanamine; trans-2-phenyl-N-(2-(l-phenylpiperidin-4- yl)ethyl)cyclopropanamine; trans-2-phenyl-N-(2-(l-(pyridin-3-yl)piperidin-4- yl)ethyl)cyclopropanamine; trans-2-phenyl-N-(2-(l-(pyrimidin-2-yl)piperidin-4- yl)ethyl)cyclopropan- amine; 3-Cyano-4-((4-((((trans)-2- phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)benzoic acid; 2-fhioro-4-((4-((((trans)- 2-phenylcyclopropyl)amino)methyl)piperidin- l-yl)methyl)benzoic acid; 3-fluoro-4-((4- ((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-l-yl- )methyl)benzoic acid; 3-chloro-4- ((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-l-yl- )methyl)benzoic acid; 3- methoxy-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)benzoic acid; 2-chloro-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-l- yl)methyl)benzoic acid; 4-(3-(4-(Cyano(((lR,2S)-2- phenylcyclopropyl)amino)methyl)piperidin-l-yl)propyl)benzoic acid; 4-{3-[4-({ [(trans))-2- phenylcyclopropyl]amino}methyl)-l-piperidinyl]propyl}benzoic acid; 4-(4-(4-((((lR,2S)-2- Phenylcyclopropyl)amino)methyl)piperidin-l-yl)butyl)benzoic acid; 4-(4-(4-(Cyano(((lR,2S)- 2-phenylcyclopropyl)amino)methyl)piperidin- l-yl)butyl)benzoic acid; 4-(2-(4-((((trans)-2- Phenylcyclopropyl)amino)methyl)piperidin-l-yl)ethyl)benzoic acid; 4-(2-(4-((((lR,2S)-2- phenylcyclopropyl)amino)methyl)piperidin-l-yl)ethyl)benzoic acid; 6-((4-((((trans)-2- Phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)-2-naphthoic acid; 6-((4-((((lR,2S)-2- Phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)-2-naphthoic acid; (trans)-N-((l-(4- (lH-Tetrazol-5-yl)benzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine; 2-(4-((4- ((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)benzamido)acetic acid; N- (4-((4-((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-l- yl)methyl)phenyl)methanesulfonamide; (trans)-N-((l-(3-(lH-Tetrazol-5-yl)propyl)piperidin-4- yl)methyl)-2-phenylcyclopropanamine; 4-((4-(2-(((trans)-2-
Phenylcyclopropyl)amino)ethyl)piperidin-l-yl)methyl)- benzoic acid; 6-((4-((((trans)-2- Phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)nicotinic acid; 2-(4-((4-((((trans)-2- Phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)phenyl)acetic acid; 2-((4-((((trans)-2- Phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)o- xazole-4-carboxylic acid; 2-(4-((4- ((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin- l-yl)methyl)phenoxy)acetic acid; N- (Methylsulfonyl)-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-l- yl)methyl)benzamide; 4-((4-((((trans)-2-(4-Iodophenyl)cyclopropyl)amino)methyl)piperidin-l- yl)methyl)benzoic acid; 4-((trans)-2-(((l-Benzylpiperidin-4- yl)methyl)amino)cyclopropyl)benzoic acid; 4-((4-((((trans)-2-(4-(l -Methyl- lH-pyrazol-4- yl)phenyl)cyclopropyl)amino)methyl)piperidin- 1 -yl)methyl)benzoic acid; 4-((4-((((trans)-2-(4- Cyclopropylphenyl)cyclopropyl)amino)methyl)piperidin- l-yl)methyl)benzoic acid; 2-Chloro-4- ((4-((((lR,2S)-2-phenylcyclopropyl)amino)methyl)piperidin- l-yl)methyl)benzoic acid; 3-(3-(4- ((((trans)-2-Phenylcyclopropyl)amino)methyl)piperidin-l-yl)propyl)benzoic acid; or 2-(4-((4- ((((lR,2S)-2-Phenylcyclopropyl)amino)methyl)piperidin- l-yl)methyl)phenyl)acetic acid or a pharmaceutically acceptable salt or solvate thereof.
[00120] In one embodiment, the LSD1 inhibitor, which may also be referred to as a KDM1A inhibitor, is selected from the group consisting of:
tranylcypromine ;
Figure imgf000034_0001
(R)-4-[5-(Pyrrolidin-3-ylmethoxy)-2-p-tolyl-pyridin-3-yl]-benzonitrile;
1 -(4-methyl- 1 -piperazinyl )-2-[[( 1 A'*,2.V* )-2-[4- phenylmethoxy)phenyl]cyclopropyl] amino] ethanone dihydrochloride;
Figure imgf000034_0002
Figure imgf000035_0001
N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin- l-yl)benzamide; and a pharmaceutically acceptable salt thereof. (Maes, T. et al. Current Opinion in Phamacol. 2015, 23:52-60).
[00121] In one embodiment, the LSD1 inhibitor is N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4- (4-methylpiperazin- 1 -yl)benzamide dihydrochloride.
[00122] In one embodiment, the IGFl/insulin inhibitor is selected from inhibitors of IGF 1 receptor, inhibitors of insulin receptor, and inhibitors of both IGF1 receptor and insulin receptor.
[00123] In one embodiment, an inhibitor of IGF 1 is selected from:
1. Tyrphostins such as AG538 and AG1024. These are in early pre-clinical testing. They are not thought to be ATP-competitive, although they are when used in EGFR as described in QSAR studies;
2. Pyrrolo(2,3-d)-pyrimidine derivatives such as NVP-AEW541;
3. Monoclonal antibodies such as figitumumab.
[00124] In one embodiment, the IGFl/insulin inhibitor is 3-[8-Amino-l-(2-phenyl-7- quinolyl)imidazo[l,5-a]pyrazin-3-yl]-l-methyl-cyclobutanol, which is also known as linsitinib or OSI906.
[00125] Calorie restriction (CR), or caloric restriction, or energy restriction, is a dietary regimen that reduces calorie intake without incurring malnutrition or a reduction in essential nutrients.
[00126] Standard diet (SD), i.e., a normal caloric intake, is dependent upon age, gender and lifestyle (sedentary, moderately active, active), but generally ranges from 1,000 to 2,400 Calories for females and 1,000 to 3,200 Calories for males. In the examples disclosed herein, mice are allowed to eat without restriction and their caloric intake is monitored for a period of time. The average amount of Calories consumed in this period of time is the basis for determining the number of Calories to be fed to mice under Caloric restriction (CR).
[00127] A Calorie restricted (CR) diet is a diet with less than 90 % normal intake, less than 80% normal intake, less than 75% normal intake, less than 70%, normal intake, less than 65%, normal intake, less than 60%, normal intake, less than 55%, normal intake, or less than 50%, normal intake.
[00128] A "caloric restriction mimetic," as used herein, refers to a class of supplements and drugs that mimic the anti-aging effects of calorie restriction, including, for example, the alteration of key metabolic pathways. Caloric restrictions mimetics are also referred to as energy restriction mimetics.
[00129] Examples of caloric restriction mimetic include, without limitation, sirtuin-activating compounds.
[00130] Specific examples of caloric restriction mimetics include, without limitation, resveratrol, butein, piceatannol, isoliquiritigenin, fisetin, and quercetin. Other examples of caloric restriction mimetics include, without limitation, metformin, oxaloacetate, rimonabant, lipoic acid, 2-deoxy-D-glucose, rapamycin, peroxisome proliferator-activate receptor gamma inhibitors (rosigalitazone, gugulipids), exenatide, adiponectin, acipimox, hydroxycitrate, dipeptidyl peptidase 4 inhibitors, iodoacetate, mannoheptulose, modulators of neuropeptide Y, 4-phenylbutyrate, gymnemoside, and spermidine.
[00131] In one aspect, the pharmaceutical composition comprising an LSD1 inhibitor of the disclosure as defined above, further comprises at least one other therapeutic agent, selected from the group consisting of: histone deacetylase inhibitors, retinoid receptor modulators, antiproliferative/antineoplastic agents, cytostatic agents, agents which inhibit cancer cell invasion, inhibitors of growth factor function, anti-angiogenic agents, cell cycle inhibitors, proteasome inhibitors, HSP90 inhibitors, selective COX-2 inhibitors or a chemotherapeutic agent.
[00132] As used herein, phrases containing the term "and/or" such as "A, B and/or C" refer to any of the following: A only; B only; C only; A and B; A and C; B and C; A, B and C.
[00133] The term, "subject" as used herein refers to a human or non-human. In one
embodiment, the subject is a mammal. In one embodiment, the subject is a human.
[00134] The phrase, "therapeutically effective amount" as used herein indicates an amount necessary to administer to a subject, or to a cell, tissue, or organ of a subject, to achieve a therapeutic effect, such as an ameliorating or alternatively a curative effect.
[00135] In one aspect, the disclosure relates to a pharmaceutical composition in the form of tablets, capsules, oral preparations, powders, granules, pills, injectable or infusible liquid, solutions, suspensions, emulsions, suppositories, ointments, creams, lotions, gels, pastes, or transdermal delivery devices. A reference for the formulations is the book by Remington ("Remington: The Science and Practice of Pharmacy", Lippincott Williams & Wilkins, 2000).
[00136] Compounds of the application may be administered to a patient in a total daily dose of, for example, from 0.001 to 1000 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The determination of optimum dosages for a particular patient is well known to one skilled in the art. [00137] Any of the compounds, combinations, pharmaceutical compositions, and/or dosage forms described herein can be administered to the patient via an oral, topical, intravenous, inhalational, otic, intramucosal, intraarterial, intraocular, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and/or subcutaneous route of administration.
[00138] Any of the compounds, combinations, pharmaceutical compositions, and/or dosage forms described herein can be administered to the patient on a daily (e.g., 1 , 2, or 3 times daily), weekly (e.g. , 1, 2, 3, 4, or 5 times weekly), or monthly basis (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times monthly). Determination of the appropriate dosing schedule is within the routine level of skill in the art.
[00139] Any of the compounds, combinations, pharmaceutical compositions, and/or dosage forms described herein may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 21st Edition, 2000, Lippincott Williams & Wilkins, which is incorporated herein in its entirety.
[00140] As is common practice, the compositions are normally accompanied by written or printed instructions for use in the treatment in question.
[00141] Another aspect of the disclosure is a kit comprising an LSDl inhibitor, combination or pharamaceutical composition as defined herein and at least one therapeutic agent selected from the group consisting of: histone deacetylase inhibitors, retinoid receptor modulators, antiproliferative/ antineoplastic agents, cytostatic agents, agents which inhibit cancer cell invasion, inhibitors of growth factor function, antiangiogenic agents, cell cycle inhibitors, proteasome inhibitors, HSP90 inhibitors, Selective COX-2 inhibitors and chemotherapeutic agents.
[00142] Optionally, the compound of the disclosure and the at least one therapeutic agent are in separated containers.
[00143] In one embodiment, the LSDl inhibitor and the at least one caloric restriction mimetic and/or the at least one IGFl/insulin inhibitor are administered simultaneously or sequentially. The LSDl inhibitor may be administered before or after the at least one caloric restriction mimetic and/or the at least one IGFl/insulin inhibitor.
[00144] In the kit, the LSDl inhibitor and at least one caloric restriction mimetic and/or at least one IGFl/insulin inhibitor are in separated containers or in the same container.
[00145] In any of the methods described herein, if the subject is under a CR diet, then the CR diet may start before the administration of an LSDl inhibitor, after the administration of an LSDl inhibitor, or concurrently with the administration of an LSDl inhibitor.
[00146] In one embodiment, the CR diet starts before the administration of an LSD 1 inhibitor. For example, 1 day, 2 days, 3 day, 4 days, 5 days, 6 days, 14 days, 21 days, 30 days, 60 days, 90 days or any time period in between.
[00147] In one embodiment, the CR diet starts after the administration of an LSDl inhibitor. For example, 1 day, 2 days, 3 day, 4 days, 5 days, 6 days, 14 days, 21 days, 30 days, 60 days, 90 days or any time period in between.
[00148] In one embodiment, the CR diet starts concurrently with the administration of an LSDl inhibitor.
Materials and methods
[00149] Mice used in the examples presented herein were either under Caloric-restriction (CR) or a standard diet (SD). Mice were caged individually. Prior to starting the diet (CR), food consumption was monitored for 1 week. Then food was administered daily in doses equal to 70% of the daily intake (30 % caloric restriction). Other mice were under Standard Diet (SD).
[00150] APL cells were generated in mice expressing the PML-RARa fusion under the control of the Cathepsin G promoter (Westervelt et al, Blood. 2003 Sep 1;102(5): 1857-65). Primary leukemia cells were transplanted into recipients subjected to 30% CR or Standard Diet (SD). We scored the effect of CR alone or in combination with compound 1 (Varasi et al Eur. J. Cancer Vol 50 suppl. info. 6: 185) on mouse survival, leukemia initiating cell (LIC) frequency and epigenomic, transcriptomic and metabolic parameters.
[00151] Primary leukemia cells isolated from cathepsin G-PML/RARa knockin mice (total spleen cells from moribund mice, >90% infiltrated) were frozen in DMSO, aliquoted and stored in liquid nitrogen. For each experiment, aliquots were thawed and 100,000 live cells (as ascertained by Trypan Blue exclusion) were resuspended in PBS and injected intravenously in the tail vein. Recipient animals were congenic CD45-2 C57B1/6 male mice aged 8-10 weeks.
Drug preparation and administration
[00152] N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l-yl)benzamide:
Figure imgf000038_0001
was prepared as described in WO 2015/181380 and dissolved in 40% poly-ethylene glycol (PEG) in PBS (v/v) at 4.5 μg/ml and administered by gavage at 45 mg/kg per dose. Administration schedule was for 2 or 3 weeks on days 1, 2 or 3, in the evening (6-8 p.m.).
[00153] OSI906 was purchased from Selleck Chemicals and dissolved in DMSO at 100 mM and subsequently dissolved in 40% PEG in PBS (v/v) at 2 μg/ml. It was administered by gavage at 20 mg/kg per dose. Administration schedule was for 3 weeks on days 1, 3 or 5 in the morning (6-8 a.m.).
In vitro conditions for cell line screening
[00154] Growing cell lines were resuspended in their medium at 200,000 cells/mL and OSI906 was added at 1 or 5 μΜ. Cells were grown for 3 days, harvested and replated in fresh medium containing vehicle or OSI/906 at their prior concentration, plus or minus compound 1 at 500 nM. Cells were grown for 2 additional days, harvested and then plated at 2000 cells/mL in methylcellulose/IMDM. Colonies were scored after 8 days by microscopy.
EXAMPLES
Example 1.
[00155] The effect of CR on an established model of cancer, the murine APL (Westervelt et al Blood 2002), was assessed by transplanting primary leukemia cells into recipient mice subjected to CR or standard diet (SD). We observed initially (3-4 weeks) a dramatic decrease in the total leukemic burden, this was followed by a rapid rise in blast numbers (Figure 1A).
Further evidence of the decrease in leukemic burden was found in the bone marrow (Figure IB - 4 weeks, Figure 1C - 6 weeks) and spleen (Figure ID of the mice).
[00156] Survival of mice was significantly prolonged by CR, with a median survival of 91 vs 51 days for SD, p=0.038 (Figure 2A). Initiation of CR after leukemia cell injection is equally effective at extending the lifespan of mice injected with APL cells (Figure 2B).
Example 2.
[00157] To evaluate the effect of CR on leukemia initiating, transplanted leukemic cells were isolated after 6 weeks of SD or CR in limiting dilutions into tertiary recipients. This revealed a ~4-fold increase in leukemia initiating cells (LICs) and a more aggressive phenotype of CR- conditioned leukemia. (Figure 3A - limiting dilution analysis, Figure 3B - survival after injection of 50,000 cells from SD or CR secondary recipient). RNAseq analysis showed that CR had induced a dramatic transcriptional reprogramming characterized by: i) upregulation of genes controlling oxidative phosphorylation, TCA cycle and a number of anabolic pathways, including nucleotide and protein biosynthesis; ii) downregulation of inflammation and monocytic differentiation-associated pathways (Figures 4A-4C). Gene set enrichment analysis of RNAseq data obtained from APL cells sorted after 6 weeks of standard diet or caloric restriction showed transcriptional reprogramming of multiple pathways involved in metabolism and inflammation. (Figure 4D) Caloric restriction leads to increased mitochondrial activity, as shown by upregulation of mitochondrially-transcribed genes coding for respiratory complex subunits (but not mitochondrially encoded tRNAs, Figure 4E) and by increased signal with the vital dye Mitotracker Red (Figure 4F), whose fluorescence intensity is proportional to mitochondrial redox potential.
[00158] Chromatin Immunoprecipitation followed by sequencing (ChlPseq) with antibodies against several histone modifications was performed and, using H3K27ac signal, a group of so- called "super-enhancers" in leukemic cells in SD, characterized by disproportionately high signal and genomic vicinity. Transcription of genes proximal to these super-enhancers was characterized by uniform downregulation upon CR (Figure 5).
[00159] Collectively, these data show that upon CR, leukemic cells undergo an initial phase of adaptation to the new metabolic environment and increased LIC activity, characterized by global transcriptional changes where superenhancer-associated genes play a crucial role.
Example 3.
[00160] Subject mice with leukemia were subjected to CR and then treated with compound 1. Strikingly, the combination of CR and compound 1 resulted in apparent eradication of disease in the majority of tested mice (n=5), as shown by their prolonged survival (all 5 mice were sacrificed in the absence of pathological signs after more than 5 months, Figure 6A). A lack of tertiary leukemia development upon transplantation of whole bone marrow into RAG-/- mice for 4 out of 5 donors was also observed (Figure 6B). Administration of compound 1 on SD-fed mice resulted in 3 out of 5 mice succumbing to disease and subsequent transplantation into RAG-/- mice of the 2 survivors led to leukemia development in 1 case. In an independent experiment, analysis of bone marrow after 2 weeks of treatment with compound 1 revealed complete disappearance of blasts in 4 out of 6 mice and a 1,000-10,000-fold decrease compared to all other groups in the remaining 2 mice (Figure 6C).
[00161] In another series of experiments, APL cells were injected in two cohorts of recipient mice: one that had been subjected to CR for the prior two weeks, some had been fed ad libitum with normal food. Two weeks later, each cohort was further randomized into receiving compound 1 by gavage at 45 mg/kg per dose, on days 1, 2 and 3 of each of the subsequent 3 weeks in the evening (6-8 p.m.). Treatment was then stopped, and mice were kept on their respective diet (CR or SD) and monitored for survival. None of the five mice treated with compound 1 under a CR-diet succumbed to disease, whereas all five mice died under SD. Three out of five mice succumbed to disease when compound 1 was administered without CR.
[00162] In another series of experiments, APL cells were injected in two cohorts of recipient mice: one that had been subjected to CR for the prior two weeks, some had been fed ad libitum with normal food. Two weeks later, each cohort was further randomized into receiving compound 1 by gavage at 45 mg/kg per dose, on days 1, 2 and 3 of each of the subsequent 2 weeks in the evening (6-8 p.m.). Mice were then sacrificed and the number of leukemic blasts in the bone marrow scored by flow cytometry as CD45-2+. Treatment with compound 1 in mice under a CR-diet resulted in complete disappearance of blasts in 4 out of 6 mice and a 1,000-10,000 fold decrease compared to all other groups in the remaining 2 mice.
Example 4
[00163] CR mimetics rapamycin and the IGFIR/Insulin receptor inhibitor OSI906 were evaluated as a possible replacement for a CR-diet. APL cells were injected in mice all fed SD, and then subjected to treatment with OSI906 and compound 1 starting from week 2 after injection. OSI906 was administered by gavage at 20 mg/kg per dose, on days 1, 3 and 5 of each week, in the morning (6-8 a.m.). Compound 1 was administered by gavage at 45 mg/kg per dose, on days 1, 2 and 3, of each week, in the evening (6-8 p.m.). Treatment was continued for 3 weeks and then mice were monitored for survival. The combination with OSI906 was synergistic, significantly prolonging survival (median 121 vs 50 days, p=0.0143). (Figure 7). Rapamycin had no effect, neither alone nor in combination (not shown).
Example 5
[00164] In order to identify other types of leukemia where IGFIR/Insulin receptor inhibition could synergize with LSDl inhibition, we developed an in vitro screening system using the established APL cell line NB4. Cells were treated with OSI906 or vehicle for 3 days (to mimic CR conditioning), and then with or without an LSDl inhibitor (compound 1) for two additional days. After scoring cell viability (reduced by half by OSI906, not shown), cells were plated in a semi-solid medium to score colony-forming ability (Figure 8A, upper panel). Treatment with OSI906 induced a dose-dependent increase in colony formation, but this was entirely abrogated by treatment with the LSDl inhibitor (compound 1) (Figure 8 A, bottom panel). Interestingly, treatment with OSI906 led to increased LSD1 protein and decreased H3K4me2 levels, suggestive of higher enzymatic activity; this again was abrogated by the LSD1 inhibitor (compound 1) (Figure 8B). Thus, this in vitro system reproduces essential features of CR (e.g., increased self-renewal and the mechanistic involvement of LSD1) and can be used to rapidly identify cancer cell lines sensitive to CR plus LSD1 inhibition. Thus, we screened for leukemia cell lines in which: i) IGF1R inhibitor is able to increase colony formation and ii) LSD1 inhibitor (compound 1) abrogates this increase. As can be seen in Figure 9, MV4-11 and, to a minor extent, OCI-AML3 fit this paradigm These cell lines are widely used model for the investigation of common leukemic mutations: MV4-11 bears MLL-AF9 (MLL translocations are present in 21% of AML patients) and FLT3-ITD (present in 27% of AMLs), whereas OCI- AML5 s driven by an NPM mutation (27% of AMLs). These findings indicate that the synergy between CR or IGF1R inhibitor is not limited to the PML/RARa-bearing acute promyelocytic leukemia but occurs also in other leukemias.
[00165] Compared to SD controls, CR-fed mice experienced an initial dramatic decrease in the total leukemic burden accompanied by cell cycle slowdown ("adaptation phase"); this was followed by a delayed disease progression that brought animals to death ("terminal phase") (median survival 91 vs 51 days, p=0.038). Limiting-dilution transplantation of CR-conditioned leukemias revealed increased frequency of LICs (estimated frequency 1/3064 cells in SD vs 1/947 in CR, p=0.003) and increased aggressiveness (median survival reduced to 49 vs 70.5 days with 5000 cells injected, p<0.0001). Thus, CR limits the expansion of leukemic cells but enriches for cells with increased ability to regrow.
Example 6
[00166] Cell cycle analysis using propidium iodide and Ki67 to discriminate cells in GO (PI-low, Ki67-low), Gl (PI-low, Ki67-high), and S-G2-M (Pi-high, Ki67-high or low) shows that caloric restriction induces cell cycle slowdown (increase in the percentage of GO cells), which is reversed by the use of LSD1 inhibitor (compound 1) (Figure 10).
Example 7
[00167] Analysis of the Cancer Genome Atlas (TCGA) data expression suggests that a subset of AMLs express elevated levels of IGFl receptor and is a likely candidate for response to the combination of caloric restriction or OSI-906 and LSD1 inhibitor(compound 1) (Figure 11). Example 8
[00168] RNAseq of leukemic cells purified during the terminal phase (but not earlier) showed that a dramatic transcriptional reprogramming in CR, characterized by upregulation of genes controlling OXPHOS, Krebs cycle and nucleotide and protein biosynthesis, and downregulation of insulin signaling and glucose transporters. Flow cytometry with Mitotracker Red confirmed increased mitochondrial activity. Thus, leukemic cells exposed to CR put in place adaptive transcriptional changes to allow survival in a nutrient/growth factor deprived environment.
[00169] To investigate the basis of these transcriptional changes, we revised ChlPseq analysis of LSD1 binding in human APL cell lines and found a significant enrichment for i) NRF1 consensus binding motif and ii) promoters of genes encoding for OXPHOS and Krebs cycle enzymes. NRF1 binding to OXPHOS/Krebs enzymes was confirmed on mouse leukemias by ChlPseq. These data suggested that the CR-induced adaptive changes could be mediated by LSD1/NRF1.
[00170] Strikingly, co-treatment of leukemic mice with CR and compound 1 resulted in macroscopic and microscopic eradication of disease (p=0.0018 compared to SD). In these conditions, leukemic cells completely disappeared in 4/6 mice after 4 weeks. LSD1 inhibition alone was also effective but did not produce bona fide disease eradication. Importantly, some of the features of the CR-LSD1 interaction could be modeled by combining LSD1 and an
IGFl/Insulin inhibitor. In vivo, this combination was synergistic and led to durable responses (median survival 121 vs 50 days in untreated controls, p=0.0143, vs 65.5 and 78.5 days with Insulin/IGF 1 Inhibitor and compound 1 respectively).
Example 9
[00171] Experiments involving NB4 cells (an established model for human APL) in which the LSD1 locus was stably knocked out using CRISPR-CAS9 technology were conducted. Equal numbers of NB4 cells wild- type (WT) and knockout (KO) for LSD1 were implanted subcutaneously in the two flanks of immunodeficient NOD-SCID-IL2Rg KO (NSG) mice, and recipient mice were randomized to either standard diet (SD) or caloric restriction (CR). This design allowed to perfectly control the experiment, since both WT and KO cells are exposed to the same metabolic environment. As shown in Figure 12, LSD1 very significantly decreased tumor growth in CR mice, but not in SD mice. (Left panel = tumor volume; right panel = tumor weight). Genetic loss of LSD1 function synergizes with CR, thus the observed effect of the LSD1 inhibitor is in fact due to specific inhibition of LSD1, and not off-target effects. Example 10
[00172] RNAseq was performed on APL cells collected from SD or CR mice, 18 days after injection and/or 1 day after 3 daily administrations of OSI-906 and/or compound 1. Principal Component Analysis (PCA, Figure 13 A) revealed that most variation in transcriptomes (PCI, accounting for -60% total variance) could be attributed to treatment with an LSD1 inhibitor, and the second strongest component (PC2, accounting for -20% variance) correlated with metabolic state, with OSI-906 inducing an intermediate state between SD and CR. Importantly, SD and CR-LSD1 were at the two extremes of the PC space, indicating extreme transcriptional variation. CR-LSD1 altered the transcription of 696 genes by at least 2 fold (adjusted p value <
0.01) compared to CR (Figure 13B), and the top differentially expressed gene sets were related to interferon and apoptosis signaling, according to Gene Set Enrichment Analysis (Figure 13C). The same pathways are not activated by CR alone. Thus, the mechanism of CR+LSD1 inhibition-induced death of APL cells is likely to involve interferon signaling and activation of apoptosis, which are both well known to be involved in the eradication of leukemia stem cells. Compound 1 significantly alters gene expression in APL cells, suggesting that lethality is due to specific transcriptional changes involving the interferon and apoptotic pathways.
Example 11
[00173] The efficacy of OSI906 and compound 1 was assessed alone and in combination on a mouse AML cell line derived from an in vivo AML mouse model based on the combination of NPM1 and FLT3 mutations (Mallardo M et al, Leukemia. 2013 Nov;27(l l):2248-51). NPM1 and FLT3 are the most frequently mutated genes in AML, each occurring in 30-40% of the cases and in combination in 10%. Double mutant AMLs are characterized by a poor prognosis, with approximately 50% survival after 5 years (Papaemmanuil et al, N. Engl. J. Med. 2016 Jun 9;374(23):2209-21).
[00174] Both OSI906 and compound 1 were effective in reducing cell growth as measured after 4 days by Cell Titer Glo assay, with IC50 values of 1 μΜ for OSI906 and 1.8 μΜ for compound
1. (Figures 14A and 14B) Combining the two had a synergistic effect, as demonstrated by combination analysis using the median-effect method of Chou and Talalay (Chou T, Cancer Res. 2010 Jan 15;70(2):440-6). Combination index was consistently below 1 for a wide range of drug combinations, indicating bona fide synergy between the two drugs (Figures 14C and 14D). Thus, OSI-906 and LSD1 inhibitors, e.g., compound 1, have synergistic activity on a mouse model of NPMc/FLT3ITD (AML). EQUIVALENTS
[00175] The application can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the application described herein. Scope of the application is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. A method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of an LSDl inhibitor, wherein the method further comprises:
a. administration of at least one calorie restriction mimetic; or
b. administration of at least one IGFl/insulin inhibitor; or
c. administration of at least one calorie restriction mimetic and at least one IGFl/insulin inhibitor,
wherein the subject is optionally on a calorie restricted diet.
2. The method of claim 1, comprising administering to the subject in need thereof an effective amount of an LSDl inhibitor and a calorie restriction mimetic, wherein the subject is optionally on a calorie restricted diet.
3. The method of claim 1, comprising administering to the subject in need thereof an effective amount of an LSDl inhibitor and an IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
4. The method of claim 1, comprising administering to the subject in need thereof an effective amount of an LSDl inhibitor, a calorie restriction mimetic, and an IGFl/insulin inhibitor, wherein the subject is optionally on a calorie restricted diet.
5. The method of any one of claim 1-4, wherein the LSDl inhibitor is selected from any compound of Formula (I), Formula (la), Formula (II), Formula (II), any other compound indicated as an LSDl inhibitor, or a stereoisomer or pharmaceutically acceptable salt thereof.
6. The method of any one of claim 1-4, wherein the LSDl inhibitor is selected from the group consisting of:
tranylcypromine ;
Figure imgf000046_0001
(R)-4-[5-(Pyrrolidin-3-ylmethoxy)-2-p-tolyl-pyridin-3-yl]-benzonitrile; l-(4-methyl-l-piperazinyl)-2-[[(lR*,25*)-2-[4- phenylmethoxy)phenyl]cyclopropyl] amino] ethanone dihydrochloride;
Figure imgf000047_0001
N-[4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin- l-yl)benzamide; and a pharmaceutically acceptable salt thereof.
7. The method of claim 5, wherein the LSD1 inhibitor is N-[4-[trans-2- aminocyclopropyl]phenyl] -4-(4-methylpiperazin- 1 -yl)benzamide dihydrochloride.
8. The method of any one of claims 1, 3 or 4, wherein the IGFl/insulin inhibitor is selected from the group consisting of: inhibitor of IGF 1 receptor, inhibitor of insulin receptor, and inhibitor of both IGF1 receptor and insulin receptor.
9. The method of any one of claims 1, 3, 4 or 8, wherein the IGFl/insulin inhibitor is 3-[8-Amino-l-(2-phenyl-7-quinolyl)imidazo[l,5-a]pyrazin-3-yl]-l-methyl-cyclobutanol.
10. The method of any one of claims 1, 2 or 4, wherein the calorie restriction mimetic is a sirtuin-activating compound.
11. The method of any one of claims 1-10, wherein the cancer is a tumor of the hematopoietic and lymphoid tissues.
12. The method of claim 11, wherein the tumor of the hematopoietic and lymphoid tissues is a leukemia.
13. The method of claim 12, wherein the leukemia is acute myeloid leukemia or acute promyelocytic leukemia.
14. The method of any one of claims 1-10, wherein the cancer is characterized in that the cancer cells have features of cancer stem cells.
15. The method of any one of claims 1-10, wherein the cancer is a drug resistant cancer.
16. The method of claim 15, where in the drug resistant cancer is drug resistant relapsed acute promyelocytic leukemia or drug resistant acute myeloid leukemia.
17. An LSD 1 inhibitor and
(i) a calorie restricted diet and/or
(ii) at least one caloric restriction mimetic and/or
(iii) at least one IGFl/insulin inhibitor
for use in the treatment and/or in the prevention of cancer.
18. An LSD 1 inhibitor and
(i) at least one caloric restriction mimetic and/or
(ii) at least one IGFl/insulin inhibitor
for use in the treatment and/or in the prevention of cancer.
19. A combination of an LSD 1 inhibitor and
(i) a calorie restricted diet and/or
(ii) a caloric restriction mimetic
for use in the treatment and/or in the prevention of cancer.
20. A combination of an LSD1 inhibitor and at least one IGFl/insulin inhibitor for use in the treatment and/or in the prevention of cancer.
21. A combination of an LSD 1 inhibitor and
(i) a calorie restricted diet and/or
(ii) a caloric restriction mimetic and at least one IGFl/insulin inhibitor for use in the treatment and/or in the prevention of cancer.
22. A pharmaceutical composition comprising an LSD1 inhibitor and
(i) at least one caloric restriction mimetic, and/or
(ii) at least one IGFl/insulin inhibitor
for use in the treatment and/or in the prevention of cancer.
23. The LSD1 inhibitor for use according to any one of claims 17 or 18, or the combination for use according to any one of claims 19 to 21, or the pharmaceutical composition for use according to claim 22, wherein the caloric restriction mimetic is a sirtuin- activating compound.
24. The LSD1 inhibitor, the combination, or the pharmaceutical composition for use according to any one of claims 16 to 23 wherein the IGFl/insulin inhibitor is selected from the group consisting of: inhibitor of IGFl receptor, inhibitor of insulin receptor, and inhibitor of both IGFl receptor and insulin receptor.
25. The LSD1 inhibitor, the combination, or the pharmaceutical composition for use according to any one of claims 16 to 24 wherein the IGFl/insulin inhibitor is 3-[8-Amino-l- (2-phenyl-7 -quinolyl)imidazo [ 1 , 5 - a] pyrazin- 3 -yl] - 1 -methyl- cyclobutanol .
26. The LSD1 inhibitor, the combination, or the pharmaceutical composition for use according to any one of claims 16 to 25 wherein the LSD1 inhibitor is selected from a compound as described in WO2013057322, WO2011131576, WO2014086790, WO2012135113, or WO2015/181380.
27. The LSD1 inhibitor, the combination, or the pharmaceutical composition for use according to any one of claims 16 to 26 wherein the LSD1 inhibitor is N-[4-[trans-2- aminocyclopropyl]phenyl] -4-(4-methylpiperazin- 1 -yl)benzamide dihydrochloride.
28. The LSD1 inhibitor, the combination, or the pharmaceutical composition for use according to any one of claims 16 to 27 wherein the cancer is a tumor of the hematopoietic and lymphoid tissues.
29. The LSD1 inhibitor, the combination, or the pharmaceutical composition for use according to claim 28 wherein the tumor of the hematopoietic and lymphoid tissues is a leukemia.
30. The LSD1 inhibitor, the combination, or the pharmaceutical composition for use according to claim 29 wherein the leukemia is acute myeloid leukemia (AML), preferably APL (acute promyelocytic leukemia).
31. The LSD1 inhibitor, the combination, or the pharmaceutical composition for use according to any one of claims 17-30 wherein the cancer is characterized in that the cancer cells have features of cancer stem cells.
32. The LSD1 inhibitor, the combination, or the pharmaceutical composition for use according to any one of claims 17-31 wherein the cancer is a drug resistant cancer, preferably drug resistant relapsed acute promyelocytic leukemia and drug resistant acute myeloid leukemia.
33. Use of the LSD1 inhibitor according to any one of claims 17-18 or 23-32, or the combination according to any one of claims 18-20 or 23-32, or the pharmaceutical composition according to any one of claims 22-32 in the manufacture of a medicament for the treatment and/or in the prevention of cancer.
34. A method of treatment of cancer comprising administering to a subject in need thereof
(i) the LSD1 inhibitor according to any one of claims 17-18 or 23-32, or
(ii) the combination according to any one of claims 18-20 or 23-32, or (iii) the pharmaceutical composition according to any one of claims 22-32.
35. A kit comprising an LSD1 inhibitor and
(i) a caloric restriction mimetic, or
(ii) an IGFl/insulin inhibitor, or
(iii) a caloric restriction mimetic and an IGFl/insulin inhibitor.
36. The kit according to claim 35, wherein the caloric restriction mimetic is a sirtuin- activating compound.
37. The kit according to any one of claims 35 or 36, wherein the IGFl/insulin inhibitor is selected from the group consisting of: inhibitor of IGFl receptor, inhibitor of insulin receptor, and inhibitor of both IGFl receptor and insulin receptor.
38. The kit according to any one of claims 35 to 37, wherein the IGFl/insulin inhibitor is 3-[8-Amino-l-(2-phenyl-7-quinolyl)imidazo[l,5-a]pyrazin-3-yl]-l-methyl-cyclobutanol.
39. The kit according to any one of claims 35 to 38, wherein the LSD1 inhibitor is selected from a compound as described in WO2013057322, WO2011131576, WO2014086790, WO2012135113, or WO2015/181380.
40. The kit according to any one of claims 35 to 39, wherein the LSD1 inhibitor is N- [4-[iraw5,-2-aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l-yl)benzamide
dihydrochloride .
PCT/EP2016/080156 2015-12-07 2016-12-07 Combination of caloric restriction (cr) or igf1/insulin receptor inhibitor with lsd1 inhibitor WO2017097865A1 (en)

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