WO2023140846A1 - Polythérapie anticancéreuse associant des inhibiteurs de dyrk1 et des inhibiteurs de la voie ras-raf-mek-erk (mapk) - Google Patents

Polythérapie anticancéreuse associant des inhibiteurs de dyrk1 et des inhibiteurs de la voie ras-raf-mek-erk (mapk) Download PDF

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WO2023140846A1
WO2023140846A1 PCT/US2022/013081 US2022013081W WO2023140846A1 WO 2023140846 A1 WO2023140846 A1 WO 2023140846A1 US 2022013081 W US2022013081 W US 2022013081W WO 2023140846 A1 WO2023140846 A1 WO 2023140846A1
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inhibitor
cancer
alkyl
substituted
cells
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PCT/US2022/013081
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Maria Vilenchik
Michael Frid
Alexandra KUZNETSOVA
Karina Barseguian
Marc DUEY
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Felicitex Therapeutics, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1205—Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases

Definitions

  • Cancer cell quiescence effectively a cell in a state of sleep, has been recognized recently as a major mechanism of the resistance of cancer cells to treatments and for providing a pathway for disease recurrence.
  • Quiescence alternatively called cellular dormancy, is due to arrest of a cell in the Go phase of the cell cycle.
  • a cell enters a cell cycle from gap phase 1 (Gi). After a synthesis phase (S) and a short pre-mitotic interval (G2), the cell divides by mitosis (M) followed by a return to Gi. Instead of Gi, however, a cell can enter cellular dormancy, also termed quiescence, designated as the Go phase.
  • Cancer cells can enter this reversible, quiescent Go state from which they could resume cycling (Coller HA, Sang L, and Roberts JM (2006) A new description of cellular quiescence, PLoS Biology 4, e83).
  • a fraction of a population of cells naturally may be in a quiescent state at any given time and remain quiescent for an indeterminate period until receipt of a signal to enter the cell division cycle.
  • the proportion of cancer cells in quiescent state within a cell population may be increased by environmental factors, such as lack of nutrients, hypoxia, high concentration of reactive oxygen species, etc. Cells may also be induced into the quiescent state by the action of a drug substance, as in pharmacological quiescence.
  • a quiescent cancer cell is resistant to treatments that affect one or more cellular proliferation processes by means of damaging exposed DNA, interfering with DNA replication or repair, interfering with mitosis, or other mechanisms.
  • DYRKIB/Mirk is a member of the Minibrain/DYRK family of kinases which mediates survival and differentiation in certain normal tissues.
  • Dyrk a dual specificity protein kinase with unique structural features whose activity is dependent on tyrosine residues between subdomains VII and VIII, Journal of Biological Chemistry 271, 3488-3495; Becker W, Weber Y, Wetzel K, Eirmbter K, Tejedor FJ, and Joost HG (1998) Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases, Journal of Biological Chemistry 273, 25893- 25902).
  • DYRK1B is expressed at detectable levels in skeletal muscle cells and testes. Knockout of DYRK1B caused no evident abnormal phenotype in mice even in developing muscle, suggesting that DYRK1B is not an essential gene for normal development. Supporting this interpretation, normal fibroblasts exhibited no alteration in survival after 20-fold depletion of DYRK1B kinase levels. Thus, DYRK1B does not appear to be an essential gene for survival of normal cells yet there is evidence that it is upregulated in certain malignant cancer cells in which DYRK1B is believed to mediate survival by retaining cancer cells in quiescent state. These unusual characteristics suggest that DYRK1B may be an attractive target for therapeutic intervention and in particular for anti-cancer therapy directly against quiescent cancer cells.
  • the KRAS (Kirsten Rat Sarcoma) protein is one of three human RAS GTPases and acts as a master switch of the MAPK pathway: KRAS - ⁇ RAF ERK.
  • KRAS unlike HRAS and NRAS, has preferential specificity for RAF over another RAS downstream effector protein, PI3K (Stalnecker, C. A., and Der, C. J. (2020) RAS, wanted dead or alive: Advances in targeting RAS mutant cancers, Science Signaling 13, eaay6013).
  • KRAS is a proto-oncogene and its mutations are the most common mutations in pancreatic cancer (found in over 90% of cases), colon (over 40%), and non-small cell lung cancer (NSCLC) with adenocarcinoma histology (over 30%).
  • KRAS mutations result in the activation of the RAS-RAF-MEK-ERK or MAPK pathway.
  • the MAPK pathway is regulated by RAS (KRAS, HRAS, NRAS) binding to B-RAF or RAFI, which are mitogen-activated protein kinases (MAP3Ks).
  • MAP3Ks phosphorylate and activate MAP -ERK kinases 1 and 2 (MEK1/2), both of which phosphorylate and activate extracellular signal-regulated kinases (ERK1 and 2).
  • ERK1 and 2 extracellular signal-regulated kinases
  • Anticancer agents that target RAS-RAF-MEK-ERK pathways include MEK inhibitors, b-Raf inhibitors, and most recently, inhibitors of both wild-type and mutant KRAS, among others. Multiple clinical trials have been conducted investigating the effects on cancers with different mutation profiles of single inhibitors targeting MEK, b-Raf, KRAS and certain KRAS mutants, or combinations of inhibitors targeting proteins within the same pathway or by inhibiting downstream proteins in the MEK-ERK and the PI3K-AKT-mTOR pathways, in combinations with an EGFR TKI therapy, etc. (Kim, Y. H.
  • the present invention provides compositions and methods for the treatment of neoplasms by the treatment with the combination of the therapeutic agents targeting the MAPK pathway and DYRK1 inhibitors.
  • the invention features a method of treating a neoplasm comprising: administering to a subject in need thereof a therapeutically effective amount of at least two or more agents comprising: (a) a first agent being a DYRK1 inhibitor; and (b) the second agent which is an inhibitor of MAPK pathway, such as a MEK inhibitor, a B-RAF inhibitor including a V600E B-RAF mutant, or a pan-KRAS inhibitor, a KRAS-mutant inhibitor, or other inhibitors of MAPK pathway, including but not limited to inhibitors of the KRAS mutants on codons 12, 13, and 61, such as G12C, G12D, G12S, G12V, G12A, G13D, and Q61H, wherein two or more agents can be administered sequentially or concomitantly.
  • a first agent being a DYRK1 inhibitor
  • the second agent which is an inhibitor of MAPK pathway, such as a MEK inhibitor, a B-RAF inhibitor including a V600E B-
  • the neoplasm is a cancer or a population of cancer cells in vitro or in vivo.
  • the subject e.g., human or a mammal subject
  • receiving the treatment is diagnosed with cancer (e.g., metastatic or pre-metastatic) with deregulated MAPK pathway and/or with a mutated KRAS.
  • cancer e.g., metastatic or pre-metastatic
  • the subject has been previously treated with a first-line therapy against cancers with deregulated MAPK pathways or against KRAS-mutated cancer.
  • the subject is treated, or has been treated, with two or more of MAPK pathway inhibitors sequentially or concomitantly.
  • the combined treatment may result in improved outcomes, such as increased survival, reduction of severity, delay or elimination of recurrence, elimination of resistance, increase in treatment durability, or reduced side effects of the primary treatments (i.e., a MEK, B-RAF or KRAS inhibitor).
  • the second agent is administered at a lower dose for a shorter duration when administered as part of the combination as compared to a treatment with the agent alone.
  • the EC50 value of the MAPK pathway inhibitor is at least 20%, 30%, 40%, 50%, 60%, 70, 75%, 80%, 85%, 90%, 95% or lower in the combination treatment with a DYRK1 inhibitor when compared to the same treatment with a MAPK pathway inhibitor as a single agent, as determined, for example, in cellbased assays.
  • the combination treatment increases fraction of apoptotic cells in a treated population as compared to either agent alone, by at least 2-fold as determined, for example, by fraction of sub-Go phase cells in a FACS assay.
  • the therapeutic agent effective against cancer cells is a DYRK1 inhibitor.
  • the DYRK1 inhibitor is a compound that inhibits activity of a DYRK1 kinase, either DYRK1 A and/or DYRK1B (in vitro or in vivo), for example, with an IC50 of 100 nM or lower in biochemical assays.
  • the DYRK1 inhibitor reduces the fraction of quiescent cancer cells (in vitro or in vivo) that would otherwise be found in the absence of such inhibitor, for example, by at least 20%, 30%, 40%, 50%, 60%, 70, 75%, 80%, 85%, 90%, 95% or higher.
  • the DYRK1 inhibitor inhibits both DYRK1 A and DYRK1B.
  • the DYRK1 inhibitor is selective for DYRK1 A and/or DYRK1B.
  • the DYRK1 inhibitor is a compound of formula I (United States Patent 9,446,044):
  • Ri is a substituted or unsubstituted Ci-s alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted benzyl;
  • R2 is phenyl, optionally substituted with up to four groups independently selected from halo, CN, NO2, NHC(0)CI-4 alkyl, C1-4 alkyl, OH, OC1-4 alkyl, wherein two adjacent groups and their intervening carbon atoms may form a 5- to 6-membered ring containing one or more heteroatoms selected from N, O, or S.
  • the compound of Formulas 1-1 to 1-7 is selected from:
  • the DYRK1 inhibitor is a compound of Formula II (United States
  • Patent 10,577,365 or a salt, stereoisomer, tautomer or A -ox ide thereof, wherein
  • R 1 , R 3 , R 4 are independently selected from the group consisting of
  • R 2 is selected from the group consisting of H, halogen, CN, NO2, Ci-Ce-alkyl, Ci-Ce- haloalkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-alkoxy and Ci-Ce-haloalkoxy;
  • R 5 , R 6 , R 6a , R 6b are independently selected from the group consisting of H, Ci-Ce-alkyl, Ci-Ce-haloalkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-alkylcarbonyl, wherein each substitutable carbon atom in the aforementioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R 9 ; and a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moieties is independently unsubstituted or substituted with one or more, same or different substituents R 10 ;
  • R 11 , R lla , R llb are independently selected from the group consisting of H, Ci-Ce-alkyl, C2-C6- alkenyl and C2-Ce-alkynyl; and wherein n is 0, 1 or 2.
  • R 1 is selected from the group consisting of (i) H, halogen, CN, NO2, Ci-Ce-alkyl, Ci-Ce-haloalkyl, C2-Ce-alkenyl, C2-C6- haloalkenyl, C2-Ce-alkynyl, C2-Ce-haloalkynyl; wherein each substitutable carbon atom in the aforementioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R 7 ;
  • R 1 is selected from the group consisting of H, halogen, CN, NO2, Ci-C 3 -alkyl,
  • R 2 is selected from the group consisting of H, halogen, CN, NO2, Ci-C2-alkyl, vinyl, Ci-C2-alkoxy and Ci-C2-haloalkoxy; and wherein all other substituents have the meaning as defined above.
  • R 3 is selected from the group consisting of:
  • R 3 is selected from the group consisting of H, halogen, CN, NO2, N(R 6a )(R 6
  • R 4 is selected from the group consisting of H, halogen, N(R 6a )(R 6b ), Ci-Ce-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, wherein each substitutable carbon atom in the aforementioned moieties is independently unsubstituted or substituted with one or more, same or different R 7 ; and a 5- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic or bicyclic moieties is independently unsubstituted or substituted with one or more, same or different substituents R 8 ; and wherein all other substituents have the meaning as defined above.
  • R 5 , R 6 , R 6a and R 6b are independently from each other selected from the group consisting of H, Ci-Cs-alkyl, C2-Cs-alkenyl, C2-Cs-alkynyl, wherein each substitutable carbon atom in the aforementioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R 9 ; and a 5- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moieties is independently unsubstituted or substituted with one or more, same or different substituents R 10 .
  • R 7 is selected from the group consisting of halogen, CN, NO2, Ci-Cs-alkyl, Ci-Cs-haloalkyl, C2-Cs-alkenyl, C2-Cs-haloalkenyl, C2-Cs-alkynyl, C2-C5- haloalkynyl, OR 6 , N(R 6a )(R 6b ); and a 5- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 8- to 9-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic or bicyclic moieties is independently
  • R 8 is selected from the group consisting of Ci-Cs-alkyl, C2-C3- alkenyl, Ci-Cs-alkylcarbonyl, C2-C3-alkynyl and N(R 6a )(R 6b ).
  • R 9 is selected from the group consisting of halogen, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, N(R lla )(R llb ) and a 5- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moiety is independently unsubstituted or substituted with one or more, same or different substituents R 10 .
  • R 10 is selected from the group consisting of halogen, C1-C3- alkyl, C2-C3-alkenyl, Ci-C3-alkylcarbonyl, C2-C3-alkynyl and N(R lla )(R llb ).
  • R 11 , R lla and R llb are independently selected from the group consisting of H, Ci-C3-alkyl, C2-C3-alkenyl and C2-C3-alkynyl.
  • the DYRK1 inhibitor is a compound of formula II, or a salt, stereoisomer, tautomer or N-oxide thereof, wherein
  • R 2 is selected from the group consisting of H, F, or Cl;
  • R 3 is H.
  • the compound of formula II is:
  • the methods of the invention further provide (c) administering to the subject another cancer therapy, for example, radiation therapy or other cancer treatment.
  • the methods of the invention comprise: administering to a subject in need thereof a therapeutically effective amount of (a) DYRK1 inhibitor, such as of Formulas 1-1 to 1-7, of Formular II or another DYRK1 -selective inhibitor; (b) a MAPK pathway inhibitor; and (c) radiation therapy; each therapy being administered sequentially or concomitantly.
  • the subject is first treated with radiation therapy, whereupon the subject is administered a DYRK1 inhibitor, alone or in combination with a MEK, a b-Raf, and/or a KRAS inhibitor.
  • the subject is co-administered (a) a DYRK1 inhibitor, (b) a MAPK pathway inhibitor and, optionally (c) radiation therapy.
  • a -MAPK pathway inhibitor is a compound that inhibits activity of a wild-type or a mutant of a truncated MEK kinase (in vitro or in vivo), for example, with the IC50 of 100 nM or lower in biochemical assays.
  • a MAPK pathway inhibitor is a compound that inhibits activity of wild-type or a mutant of a KRAS kinase (in vitro or in vivo). All such compounds that have been or will be approved for the treatment of cancer, or compounds that otherwise demonstrate safety and efficacy in treating cancer in mammalian subject (e.g., mice, rats, dogs, monkeys, humans), or compounds that demonstrate efficacy against neoplastic cells in vitro. Many such compounds are known.
  • the MAPK pathway inhibitor is a MEK inhibitor, either of MEK1 or of MEK2.
  • the MEK-RAS-MAPK pathway inhibitor is an inhibitor of b- Raf and an inhibitor of b-Raf with a V600E mutation, such as, for example, vemurafenib, dabrafenib, encorafenib, or sorafenib.
  • MEK-RAS-MAPK pathway inhibitor is an inhibitor of wild type or mutated (mutant) KRAS, including but not limited to KRAS mutants on codons 12, 13, and 61, such as G12C, G12D, G12V, G13D, and Q61H.
  • a MEK inhibitor is, for example, trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CH5126766 (RO5126766), or CI-1040.
  • a KRAS-mutant inhibitor is a pan-RAS inhibitor such as BI 1701963 or BBP-454, affecting this inhibition by means of inhibiting the formation or function of a KRAS-SOS1 complex or by any other means, or an inhibitor of certain mutant KRAS proteins, such as sotorasib (AMG 510), MRTX849, MRTX1257, ARS-853, ARS-3248 (JNJ 74699157).
  • the MEK-RAS-MAPK pathway inhibitor is a combination of two or more inhibitors of MEK, b-Raf, and KRAS.
  • the neoplasm being treated is a cancer, for example, colon, colorectal, breast, brain, prostate, pancreatic or ovarian cancers, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), juvenile myelomonocytic leukemia (JMML), nonsmall cell lung cancer (NSCLC), small cell lung cancer (SCLC), lymphoma, melanoma, or myeloproliferative syndrome (MPS), osteosarcoma, neuroblastoma or glioblastoma.
  • the cancer is primary or metastatic.
  • the cancer is of the type represented by the cell line types shown in the Examples.
  • the subject having cancer possesses a mutation in the KRAS gene having an increased risk of cancer and/or resistance to certain MEK and/or KRAS mutant inhibitors.
  • Figure 1 shows a schematic diagram of a mitotic cycle of a eukaryotic cell.
  • Figure 2 shows a schematic diagram of a mitotic cycle of a eukaryotic cancer cell annotated to indicate the stages of the cell cycle upon which the available anti-cancer therapeutic agents are believed act.
  • Figure 3 shows effect of combination of selumetinib and Compound 1-7 (0, 3, and 6 pM) on the growth of NSCLC A549 cells (KRAS-G12S).
  • Figure 4 shows the effect of combination of selumetinib and Compound 1-7 (0, 2.5, and 5 pM) on the growth of ovarian cancer OVCAR cells (wild KRAS).
  • Figure 5 shows the effect of combination of trametinib and Compound 1-7 (0, 2.2, and 6.7 pM) on the growth of NSCLC A549 cells (KRAS-G12S).
  • Figure 6 shows the effect of combination of trametinib and Compound 1-7 (0, 0.12, and 3.3 pM) on the growth of NSCLC H23 cells (KRAS-G12C).
  • Figure 7 shows the effect of combination of trametinib and Compound 1-7 (0, 5, and 10 pM) on the growth of 3D spheroids of NSCLC H23 cells (KRAS-G12C).
  • Figure 8 shows the effect of combination of MRTX-849 and Compound 1-7 (0, 2.5, and 5 pM) on the growth of NSCLC H2122 cells (KRAS-G12C).
  • Figure 9 shows the effect of combination of AMG-510 and Compound 1-7 (0, 2.5, and 5 pM) on the growth of NSCLC H2122 cells (KRAS-G12C).
  • Figure 10 shows FACS analyses of cell cycle distribution of colon cancer SW620 cells (G12V) incubated for 24 hours in Panel A: FBS+ media; Panel B: FBS- media; Panel C: FBS+ media with 5 pM Compound 1-7; Panel D: FBS+ media with 20 nM trametinib; Panel D: FBS+ media with 5 pM Compound 1-7 and 20 nM trametinib.
  • FIG. 11 FACS analyses of cell cycle distribution of H2122 NSCLC cells (KRAS G12C) incubated for 48 hours in Panel A: FBS+ media; Panel B: FBS+ media with 5 pM Compound 1-7; Panel C: FBS+ media with 100 nM MRTX 849; Panel D: FBS+ media with 5 pM Compound 1-7 and 100 nM MRTX 849.
  • Figure 12 FACS analyses of cell cycle distribution of H2122 NSCLC cells (KRAS G12C) incubated for 48 hours in Panel A: FBS+ media; Panel B: FBS+ media with 5 pM Compound 1-7; Panel C: FBS+ media with 100 nM AMG 510; Panel D: FBS+ media with 5 pM Compound 1-7 and 100 nM AMG-510.
  • Figure 13 shows Western blot analysis showing expression levels of DYRK1B, phosphorylated T10202-MAPK, total MAPK, and P-actin in SW620 cells after 48-hour treatment with 20 nM of trametinib and 5 pM of Compound 1-7 as indicated.
  • Figure 14 shows the effect of combination of AMG-510 and Compound II-l (0, 0.25 pM) on the growth of NSCLC H358 cells (KRAS-G12C).
  • Figure 15 shows the effect of combination of MRTX-749 and Compound II-l (0, 0.25 pM) on the growth of NSCLC H358 cells (KRAS-G12C).
  • Figure 16 shows the effect of combination of MRTX-749 and Compound II-l (0, 1 pM) on the growth of NSCLC H1975 cells (wild-type KRAS).
  • Figure 17 shows the effect of combination of selumetinib and Compound II-l (0, 1 pM) on the growth of NSCLC H1975 cells (wild-type KRAS).
  • an “alkyl” group is a saturated, straight or branched, hydrocarbon group, comprising from 1 to 8 carbon atoms (Ci-s alkyl group), in particular from 1 to 6, or from 1 to 4 carbons atoms, unless otherwise indicated.
  • alkyl groups having from 1 to 6 carbon atoms inclusive are methyl, ethyl, propyl (e.g., n-propyl, iso-propyl), butyl (e.g., tert-butyl, sec-butyl, n-butyl), pentyl (e.g., neo-pentyl), hexyl (e.g., n-hexyl), 2- methylbutyl, 2-methylpentyl and the other isomeric forms thereof.
  • propyl e.g., n-propyl, iso-propyl
  • butyl e.g., tert-butyl, sec-butyl, n-butyl
  • pentyl e.g., neo-pentyl
  • hexyl e.g., n-hexyl
  • 2- methylbutyl 2-methylpentyl and the other isomeric
  • Alkyl groups may be unsubstituted or substituted by at least one group chosen from halogen atoms, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxyl, alkenyl, alkynyl, CN, nitro, and amino groups.
  • an “alkenyl” group is a straight or branched hydrocarbon group comprising at least one double carbon-carbon bond, comprising from 2 to 8 carbon atoms (unless otherwise indicated).
  • alkenyl containing from 2 to 6 carbon atoms are vinyl, allyl, 1 -propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 -pentenyl, 2-pentenyl, 3 -pentenyl, 4- pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the isomeric forms thereof.
  • Alkenyl groups may be unsubstituted, or substituted by at least one group chosen from halogen atoms, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxyl, alkenyl, alkynyl, CN, nitro, and amino groups.
  • an “alkynyl” group is a straight or branched hydrocarbon group comprising at least one triple carbon-carbon bond, comprising from 2 to 8 carbon atoms.
  • Alkynyl groups may be substituted by at least one group chosen from halogen atoms, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxyl, alkenyl, alkynyl, CN, nitro, and amino groups.
  • an “aryl” group is an aromatic hydrocarbon cycle, comprising from 5 to 14 carbon atoms. Most preferred aryl groups are mono- or bi-cyclic and comprises from 6 to 14 carbon atoms, such as phenyl, alpha-naphtyl, 3-naphtyl, antracenyl, preferably phenyl. “Aryl” groups also include bicycles or tricycles comprising an aryl cycle fused to at least another aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, such as benzodi oxolane, benzodioxane, dihydrob enzofurane or benzimidazole.
  • Aryl groups may be unsubstituted, or substituted by at least one (e.g. 1, 2 or 3) group chosen from halogen atoms, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxyl, alkenyl, alkynyl, CN, nitro and amino groups.
  • aryl groups may be substituted by adjacent substituents which can, taken together with the carbon atom to which they are attached, form a 5- to 6-membered ring which may contain one or more heteroatom(s) selected from N, O, and S.
  • halogen atom or “halo” is a Cl, Br, F, or I atom.
  • an “alkoxyl” group is an alkyl group linked to the rest of the molecule through an oxygen atom, of the formula O-alkyl.
  • an “amino” group is a NH2, NH-alkyl, or N(alkyl)2 group.
  • a “heteroaryl” group is an aryl group whose cycle is interrupted by at least at least one heteroatom, for example a N, O, or S atom, such as thiophene or pyridine.
  • Heteroaryl groups may be unsubstituted, or substituted by at least one (e.g. 1, 2 or 3) group chosen from halogen atoms, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxyl, alkenyl, alkynyl, CN, nitro, and amino groups.
  • heteroaryl groups may be substituted by adjacent substituents which can, taken together with the carbon atom to which they are attached, form a 5- to 6-membered ring which may contain one or more heteroatom(s) selected from N, O, and S.
  • a “cycloalkyl” denotes a saturated alkyl group that forms one cycle having preferably from 3 to 14 carbon atoms, and more preferably 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, cycloalkyl groups may be unsubstituted, or substituted by at least one (e.g.
  • 1, 2 or 3 group chosen from halogen atoms, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxyl, alkenyl, alkynyl, CN, nitro and amino groups.
  • cycloalkyl groups may be substituted by adjacent substituents which can, taken together with the carbon atom to which they are attached, form a 5- to 6-membered ring which may contain one or more heteroatom(s) selected from N, O, and S.
  • a “heterocycloalkyl” group is a cycloalkyl group comprising at least one heteroatom, such as pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, pyran, dioxin, morpholine or piperazine.
  • a heterocycloalkyl group may in particular comprise from four to fourteen carbon atoms, such as morpholinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, dithiolanyl.
  • heterocycloalkyl groups may be unsubstituted or substituted by at least one group chosen from halogen atoms, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxyl, alkenyl, alkynyl, CN, nitro, and amino groups.
  • heterocycloalkyl groups may be substituted by adjacent substituents which can, taken together with the carbon atom to which they are attached, form a 5- to 6-membered ring which may contain one or more heteroatom(s) selected from N, O, and S.
  • a “neoplasm” means an abnormal mass of tissue that results from neoplasia.
  • “Neoplasia” means a process of an abnormal proliferation of cells.
  • a neoplasm is a solid cancer, or alternately a hematopoietic cancer.
  • the neoplasia may be benign, pre-malignant, or malignant.
  • neoplasm encompasses mammalian cancers, in some embodiments, human cancers, and carcinomas, sarcomas, blastomas of any tissue (for example adenocarcinomas, squamous cell carcinomas, osteosarcomas, etc.), germ cell tumors, glial cell tumors, lymphomas, leukemias, including solid and lymphoid cancers, kidney, breast, lung, head and neck, bladder, colon, ovarian, prostate, rectal, pancreatic, stomach, brain, head and neck, skin, uterine, cervical, testicular, esophagus, thyroid, liver cancers, biliary cancer, and cancer of the bone and cartilaginous tissue, including non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas) and Hodgkin's lymphoma, leukemia, multiple myeloma, and myelodysplastic syndrome.
  • the terms “treat,” “treating,” or “treatment,” mean to counteract a medical condition (e.g., cancer) to the extent that the medical condition is improved according to a clinically acceptable standard. Improvement in cancer can include: 1) reduced rate of tumor growth (tumor growth inhibition), 2) tumor shrinkage (regression), 3) decreased amount of the therapeutics required to achieve the tumor shrinkage, 4) remission, whether partial or total, 5) reduction in metastases, 6) prolonging progression free survival, and 7) delay or elimination of recurrence.
  • a medical condition e.g., cancer
  • Improvement in cancer can include: 1) reduced rate of tumor growth (tumor growth inhibition), 2) tumor shrinkage (regression), 3) decreased amount of the therapeutics required to achieve the tumor shrinkage, 4) remission, whether partial or total, 5) reduction in metastases, 6) prolonging progression free survival, and 7) delay or elimination of recurrence.
  • treating includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the cancer mass, or volume, or the malignant cell count; ameliorating or improving a clinical symptom or indicator associated with solid cancers or hematopoietic cancers; delaying, inhibiting, or preventing the progression of solid cancers or hematopoietic cancers; or partially or totally delaying, inhibiting or preventing the onset or development of solid cancers or hematopoietic cancers.
  • “Treatment” also can mean prolonging progression free survival (PFS) or prolonging survival in general as compared to expected PFS or survival without treatment or compared to standard-of-care treatment. Treating includes prophylactic or preventative treatment.
  • “Prophylactic treatment” refers to treatment before appearance or re-appearance of clinical symptoms of a target disorder to prevent, inhibit, or reduce its occurrence, severity, or progression.
  • an “effective amount” refers to an amount of a therapeutic agent or a combination of therapeutic agents that is therapeutically or prophylactically sufficient to effectuate the desired improvement in the targeted disorder.
  • Examples of effective amounts typically range from about 0.0001 mg/ kg of body weight to about 500 mg/kg of body weight per single administered dose, such doses being administered once or over a period of time.
  • An exemplary range is from about 0.0001 mg/kg of body weight to about 5 mg/kg per dose. In other examples, the range can be from about 0.0001 mg/kg to about 5 mg/kg per single administered dose.
  • effective amounts range from about 0.01 mg/ kg of body weight to 50 mg/kg of body weight per single administered dose, or from 0.01 mg/kg of body weight to 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, or 40 mg/kg of body weight per single administered dose.
  • an example of an effective dose is that amount approved of by a regulatory agency for treatment of an indication.
  • the term “subject” refers to a mammal, for example a human, but can also mean an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like), and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • companion animals e.g., dogs, cats, and the like
  • farm animals e.g., cows, sheep, pigs, horses, and the like
  • laboratory animals e.g., rats, mice, guinea pigs, and the like.
  • the term “therapeutic agent” means any chemical molecule used or contemplated for use or investigated for use in cancer treatment, including cytotoxic, cytostatic, or targeted agents, whether small molecules, or peptides, or antibodies, or oligonucleotides, irrespective of mechanism of action.
  • the terms “therapeutic” or “therapeutic agent” refer to either the active pharmaceutical ingredient (API) or its pharmaceutically acceptable salt or hydrate (solvate), or a drug product containing the therapeutic agent, however formulated, and whether API is amorphous or crystalline and of whatever polymorphic form.
  • Formulation means a combination of an active pharmaceutical ingredient (API, drug substance) or ingredients (APIs) combined with excipients and/or delivery vehicle to make an administrable dosage form (drug product).
  • the therapeutic agents of the invention are generally administered with a pharmaceutically acceptable carrier, with respect to standard pharmaceutical practice (such as described in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins). Accordingly, a further object of this invention relates to a pharmaceutical compositions defined herein and pharmaceutically acceptable carriers.
  • inhibitor means any composition that reduces the activity of an enzyme.
  • An example of an inhibitor is a chemical molecule.
  • a measure of the potency of an inhibitor is its “50% inhibitory concentration” (IC50).
  • IC50 concentration or IC50 value is the concentration of an inhibitor at which 50% of the enzymatic activity is inhibited by the inhibitor.
  • IC50 values for example, of kinase inhibitors are known to persons of ordinary skill in the art and include direct and indirect functional assays, such as the HotSpotTM kinase assay technology (Reaction Biology Corporation, Malvern, PA, www.reactionbiology.com) or competition binding assays, such as KINOMEscan® (Eurofins DiscoverX Corporation, Freemont, CA, www.discoverx.com).
  • the IC50 of a DYRK1 inhibitor or a MAPK pathway inhibitor is 100 mM or less, 75 mM or less, 50 mM or less, 25 mM or less, or 10 mM or less.
  • EC50 value is the concentration of a drug that produces half-maximal response, such as, for example, 50% cell growth inhibition or 50% reduction in cell viability.
  • Methods for the determination of EC50 values, for example, of kinase inhibitors are known to persons of ordinary skill in the art.
  • the combination of a DYRK1 and a MAPK pathway inhibitor, EC50 value of the MAPK pathway inhibitor is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more.
  • the term “quiescence” or “quiescent state” refers to the Go state of the cell cycle, as understood by the practitioners of the art.
  • a “quiescent neoplastic cell,” alternately referred to as a “quiescent cancer cell” means a cancer cell that exists in the quiescent, or Go, state of the cell cycle.
  • a “fraction of quiescent neoplastic cells” or “fraction of quiescent cancer cells”, as used herein, means the portion of a cancer cell population that exists in the Go state of the cell cycle. Determining the fraction of quiescent neoplastic cells includes characterizing a cell population by distribution of its constituent cells within the stages of the cell cycle. The fraction of cells in the Go state (i.e., quiescent neoplastic cells) is quantified relative to the total cell population. The fraction may be expressed as a percentage of the total cell population (i.e.
  • Characterization of the cell population by distribution of its constituent cells within the stages of the cell cycle may be achieved by techniques known to persons of ordinary skill in the art, and may include analysis by DNA and/or RNA content distribution within the cell cycle using flow cytometry methods, for example, fluorescence-activated cell sorting (FACS).
  • FACS fluorescence-activated cell sorting
  • DYRK1 inhibitor refers to the inhibitor of either DYRK1B or DYRK1 A, or a dual inhibitor of DYRK1 A and DYRK1B.
  • DYRK1 inhibitors both DYRK1 A and DYRK1B, include both reversible and irreversible small molecule inhibitors including inhibitors of Formulas I-1-I-7 and II-l.
  • MAPK pathway inhibitors including MEK inhibitors, b-RAF inhibitors, and mutant KRAS inhibitors and wild-type KRAS inhibitors, include both reversible and irreversible small molecule inhibitors specified throughout this specification.
  • the present invention provides compositions and methods for the treatment of neoplasms, in particular, by targeting cancers cells with DYRK1 inhibitors in combination with MAPK pathway inhibitors, (e.g., a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor therapeutic agents) that is particularly advantageous for certain neoplastic conditions, specifically, as an anti-cancer treatment with.
  • MAPK pathway inhibitors e.g., a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor therapeutic agents
  • the invention features a method of treating a neoplasm comprising: administering to a subject in need thereof a therapeutically effective amount of (a) a first agent being a DYRK1 inhibitor; and (b) second agent which is a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor, wherein the two agents can be administered sequentially or concomitantly.
  • the neoplasm is a cancer or a population of cancer cells in vitro or in vivo.
  • the subject receiving the treatment is diagnosed with cancer (e.g., metastatic or pre-metastatic).
  • the subject has been treated previously with a first-line therapy against cancer.
  • the subject has been treated previously with second-line and/or other therapies.
  • the subject is treated, or has been treated, with radiation therapy.
  • the subject was treated with surgery, for example, to resect or debulk a tumor.
  • the subject’s neoplasm has recurred.
  • the subject is treated, or has been treated, with two or more of: a MEK inhibitor, a b-RAF inhibitor, and a KRAS inhibitors, sequentially or concomitantly.
  • the combined treatment may result in improved outcomes, such as increased survival, reduction of severity, delay or elimination of recurrence, reduced required dose of the primary treatments, or reduced side effects of the primary treatments (i.e., a MEK inhibitor, a b-RAF inhibitor, or a KRAS inhibitor).
  • the second agent is administered at lower dose and/or for a shorter duration when administered as part of the combination as compared to a treatment with the agent alone.
  • the EC50 value of a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor is at least 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90% lower in the combination treatment with DYRK1 inhibitor when compared to the same treatment with a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor as a single agent, as determined, for example, in cell-based assays.
  • the combination treatment increases fraction of apoptotic cells in a treated cancer cell population as compared to either agent alone, by at least by 2-fold, 3-fold, 4-fold, 5- fold, or 10-fold as determined, for example, by fraction of sub-Go phase cells as determined by a FACS assay.
  • the fraction of quiescent cancer Go cells is decreased by at least 20%, 25%, 30%, 40%, 50% or more in the combination treatment with a DYRK1 inhibitor when compared to the same treatment with a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor as a single agent, as determined, for example, in cell-based assays.
  • the combination of a DYRK1 inhibitor and a second agents are additive.
  • the combination of a DYRK1 inhibitor and a second agents are synergetic, as determined, for example, in cell-based assays via Chou-Talalay method or other methods known those skilled in the art.
  • the therapeutic agent is a DYRK1 inhibitor.
  • the DYRK1 inhibitor is a compound that inhibits activity of a DYRK1 kinase, either DYRK1 A or DYRK1B (in vitro or in vivo), for example, with an IC50 value of ⁇ 100 nM, ⁇ 90 nM, ⁇ 80 nM, ⁇ 70 nM, ⁇ 60 nM, ⁇ 50 nM, ⁇ 40 nM, ⁇ 30 nM, ⁇ 20 nM, ⁇ 10 nM, ⁇ 5 nM or lower in biochemical assays.
  • the DYRK1 inhibitor reduces the fraction of quiescent cancer cells in vitro or in vivo) in a population or a tumor that would otherwise be found in the absence of such inhibitor, for example, by at least 5%, 10%, 15%, 20%, 25%, 30%. 40%. 50%, or more.
  • the DYRKI inhibitor inhibits both DYRKI A and DYRK1B.
  • the DYRKI inhibitor is selective for DYRKI A, with ratio of DYRK1B IC50 to DYRKI A IC50 of 1000, 100, 50, 25, 10 to 1.
  • the DYRKI inhibitor is selective for DYRK1B, with ratio of DYRKI A IC50 to DYRK1B IC50 of 1000, 100, 50, 25, 10 to 1. In some embodiments, the DYRKI inhibitor is selective for DYRKI by at least 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold as compared to DYRK2 and/or DYRK3 and/or DYRK4, as determined by ratios of IC50 values.
  • the DYRKI inhibitor is selective for DYRKI by at least 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 500-fold, 1000-fold as compared to cyclin dependent kinases (CDKs) such as, for example, CDK2, CDK4, or CDK6, as determined by ratios of IC50 values.
  • CDKs cyclin dependent kinases
  • the DYRKI inhibitor is selective for DYRKI by at least 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 500-fold, 1000-fold as compared to GSK3P, as determined by ratios of IC50 values.
  • DYRK1 inhibitors examples include: AZ191, DYRKi, harmine, ID-8, leucettine L41, NCGCOO 185981, INDY, ProINDY, TC-S 7004, and TG003.
  • At least one known DYRKI inhibitor, TC-S 7004, (US20120184562) is reported to be effective against both quiescent and proliferating cancer cells in vitro (Ewton DZ, Hu J, Vilenchik M, Deng X, Luk KC, Polonskaia A, Hoffman AF, Zipf K, Boylan JF, and Friedman EA. (2011) Inactivation of MIRK/DYRK1B kinase targets both quiescent and proliferating pancreatic cancer cells. Molecular Cancer Therapeutics 10: 2104-2114).
  • the DYRKI inhibitor is a compound of formula I (United States Patent 9,446,044): NH or a pharmaceutically acceptable salt or solvate thereof, wherein,
  • Ri is a substituted or unsubstituted Ci-s alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted benzyl;
  • R2 is phenyl, optionally substituted with up to four groups independently selected from halo, CN, NO2, NHC(0)CI-4 alkyl, C1-4 alkyl, OH, OC1-4 alkyl, wherein two adjacent groups and their intervening carbon atoms may form a 5- to 6-membered ring containing one or more heteroatoms selected from N, O, or S.
  • the compound of formula I is selected from:
  • the DYRK1 inhibitor is a compound of Formula II (United States
  • Patent 10,577,365 or a salt, stereoisomer, tautomer or A -ox ide thereof, wherein
  • R 1 , R 3 , R 4 are independently selected from the group consisting of
  • R 2 is selected from the group consisting of H, halogen, CN, NO2, Ci-Ce-alkyl, Ci-Ce- haloalkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-alkoxy and Ci-Ce-haloalkoxy;
  • R 5 , R 6 , R 6a , R 6b are independently selected from the group consisting of H, Ci-Ce-alkyl, Ci-Ce-haloalkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-alkylcarbonyl, wherein each substitutable carbon atom in the aforementioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R 9 ; and a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moieties is independently unsubstituted or substituted with one or more, same or different substituents R 10 ;
  • R 11 , R lla , R llb are independently selected from the group consisting of H, Ci-Ce-alkyl, C2-C6- alkenyl and C2-Ce-alkynyl; and wherein n is 0, 1 or 2.
  • R 1 is selected from the group consisting of (iii) H, halogen, CN, NO2, Ci-Ce-alkyl, Ci-Ce-haloalkyl, C2-Ce-alkenyl, C2-C6- haloalkenyl, C2-Ce-alkynyl, C2-Ce-haloalkynyl; wherein each substitutable carbon atom in the aforementioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R 7 ;
  • R 1 is selected from the group consisting of H, halogen, CN, NO2, Ci-C 3 -alkyl,
  • R 2 is selected from the group consisting of H, halogen, CN, NO2, Ci-C2-alkyl, vinyl, Ci-C2-alkoxy and Ci-C2-haloalkoxy; and wherein all other substituents have the meaning as defined above.
  • R 3 is selected from the group consisting of:
  • R 4 is selected from the group consisting of H, halogen, N(R 6a )(R 6b ), Ci-Ce-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, wherein each substitutable carbon atom in the aforementioned moieties is independently unsubstituted or substituted with one or more, same or different R 7 ; and a 5- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic or bicyclic moieties is independently unsubstituted or substituted with one or more, same or different substituents R 8 ; and wherein all other substituents have the meaning as defined above.
  • R 5 , R 6 , R 6a and R 6b are independently from each other selected from the group consisting of H, Ci-Cs-alkyl, C2-Cs-alkenyl, C2-Cs-alkynyl, wherein each substitutable carbon atom in the aforementioned moieties is independently unsubstituted or substituted with one or more, same or different substituents R 9 ; and a 5- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moieties is independently unsubstituted or substituted with one or more, same or different substituents R 10 .
  • R 7 is selected from the group consisting of halogen, CN, NO2, Ci-Cs-alkyl, Ci-Cs-haloalkyl, C2-Cs-alkenyl, C2-Cs-haloalkenyl, C2-Cs-alkynyl, C2-C5- haloalkynyl, OR 6 , N(R 6a )(R 6b ); and a 5- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 8- to 9-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic or bicyclic moieties is independently
  • R 8 is selected from the group consisting of Ci-Cs-alkyl, C2-C3- alkenyl, Ci-Cs-alkylcarbonyl, C2-C3-alkynyl and N(R 6a )(R 6b ).
  • R 9 is selected from the group consisting of halogen, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, N(R lla )(R llb ) and a 5- to 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moiety is independently unsubstituted or substituted with one or more, same or different substituents R 10 .
  • R 10 is selected from the group consisting of halogen, C1-C3- alkyl, C2-C3-alkenyl, Ci-C3-alkylcarbonyl, C2-C3-alkynyl and N(R lla )(R llb ).
  • R 11 , R lla and R llb are independently selected from the group consisting of H, Ci-C3-alkyl, C2-C3-alkenyl and C2-C3-alkynyl.
  • the DYRK1 inhibitor is a compound of formula II, or a salt, stereoisomer, tautomer or N-oxide thereof, wherein
  • R 2 is selected from the group consisting of H, F, or Cl;
  • R 3 is H.
  • the compound of formula II is:
  • the methods of the invention further provide: (c) administering to the subject another cancer therapy, for example, radiation therapy or other cancer treatment.
  • the methods of the invention comprise: administering to a subject in need thereof a therapeutically effective amount of (a) a therapeutic agent of formula I; (b) a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor; and (c) radiation therapy; each therapy being administered sequentially or concomitantly.
  • the subject is first treated with radiation therapy, whereupon the subject is administered a therapeutic agent of Formula I, alone or in combination with a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor.
  • the subject is co-administered (a) the therapeutic agent effective against quiescent cancer cells, (b) a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor and optionally (c) radiation therapy.
  • a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor is a compound that inhibits activity of wild type or one or more mutants in vitro or in vivo, for example, with the IC50 of ⁇ 100 nM, ⁇ 90 nM, ⁇ 80 nM, ⁇ 70 nM, ⁇ 60 nM, ⁇ 50 nM, ⁇ 40 nM, ⁇ 30 nM, ⁇ 20 nM, ⁇ 10 nM, ⁇ 5 nM, or lower in biochemical assays.
  • a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor is selective for the mutants over the wild type.
  • a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor is effective for the treatment of prevention of a neoplasm, including but not limited to, all such compounds approved for the treatment of cancer, compounds in clinical trials for the treatment of cancer, compounds that otherwise demonstrate efficacy in treating cancer in a mammalian subject (e.g., mouse, rats, dogs, monkeys, humans), and compounds that demonstrate efficacy against neoplastic cells in vitro. Many such compounds are known.
  • the MAPK pathway inhibitor is a MEK inhibitor, either MEK1 or MEK2.
  • the MEK-RAS-MAPK pathway inhibitor is an inhibitor of b-Raf and an inhibitor of b-Raf with a V600E mutation, such as, for example, vemurafenib, dabrafenib, encorafenib, or sorafenib.
  • MEK-RAS-MAPK pathway inhibitor is an inhibitor of wild type or mutated (mutant) KRAS, including but not limited to KRAS mutants on codons 12, 13, and 61, such as G12C, G12D, G12V, G13D, and Q61H.
  • a MEK inhibitor is, for example, trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CH5126766 (RO5126766), or CI-1040.
  • a KRAS-mutant inhibitor is a pan-RAS inhibitor such as BI 1701963 or BBP-454, affecting this inhibition by means of inhibiting the formation or function of a KRAS-SOS1 complex or by any other means, or an inhibitor of certain mutant KRAS proteins, such as sotorasib (AMG 510), MRTX849, MRTX1257, ARS-853, ARS-3248 (JNJ 74699157).
  • the MEK-RAS- MAPK pathway inhibitor is a combination of two or more inhibitors of MEK, b-Raf, and KRAS.
  • the neoplasm being treated is a cancer, for example, colon, colorectal, breast, brain, prostate, pancreatic or ovarian cancers, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), juvenile myelomonocytic leukemia (JMML), nonsmall cell lung cancer (NSCLC), small cell lung cancer (SCLC), lymphoma, melanoma, or myeloproliferative syndrome (MPS), osteosarcoma, neuroblastoma or glioblastoma.
  • the cancer is primary or metastatic.
  • the cancer is of the type represented by the cell line types shown in the Examples.
  • the subject having cancer possesses a mutation in the MEK and/or b-RAF, and/or KRAS gene(s) associated with an increased risk of cancer and/or resistance to certain anti-cancer treatments.
  • the disclosed combinations and methods may afford one or more of the improvements as defined in the Glossary relative to the use of each individual components or existing single and combination treatments. Also, the disclosed combinations and methods may permit reduction in doses and/or frequency of administration of therapeutic agents and radiation to achieve the same improvements as a result of treatment relative to what is possible using individual components or existing single and combination treatments.
  • the disclosed combinations need not be synergistic or even result in a significant reduction in ECso values to yield a significant improvement in the effectiveness of treatment relative to single therapy with a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor.
  • quiescent cancer cells are inherently less susceptible to anti-cancer therapeutics, including MEK inhibitors, b-RAF inhibitors, or KRAS inhibitors, and even a small fraction of quiescent cells that survives posttreatment can lead to recurrence.
  • eradicating the resistant, quiescent cell populations in a neoplasm may or may not yield a synergistic reduction in EC50 values, yet may yield a significant improvement in cancer elimination, recurrence rate and appearance of metastatic neoplasms.
  • the administration routes and regimen of the disclosed combination may well vary depending on the neoplastic condition treated, extent of progression of the neoplasm, age and physical condition of the subject, exact combination selected, and other factors.
  • Administration regimen may include multiple doses per period of time, the treatments administered concurrently or sequentially, etc.
  • DYRK1 inhibitor may be administered before a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor.
  • the DYRK1 inhibitor may be administered 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours before a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor.
  • the DYRK1 inhibitor may be administered at the same time (concomitantly) as a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor.
  • the DYRK1 inhibitor may be administered 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours after a MEK inhibitor or a b-RAF inhibitor, or a KRAS inhibitor.
  • the DYRK1 inhibitor may be administered at a different schedule regiment including but not limited to daily, every two days, every three days, every four days, biweekly (twice per week), once weekly, once every two weeks, once per month by oral (PO), intravenous (IV), intraperitoneal (IP), subcutaneous (SC), intratumoral (IT), intrathecal, or other routes of administration.
  • schedule regiment including but not limited to daily, every two days, every three days, every four days, biweekly (twice per week), once weekly, once every two weeks, once per month by oral (PO), intravenous (IV), intraperitoneal (IP), subcutaneous (SC), intratumoral (IT), intrathecal, or other routes of administration.
  • the combinations may be administered to subjects who are naive to treatment (have not been treated), or subjects who underwent previous treatments with first-line, second-line, third- line, or other therapies, radiation treatments, or have undergone surgical resection or de-bulking of a solid tumor, or subjects whose cancers relapsed, or subjects whose cancers are non-metastatic or metastatic.
  • Example 1 Determination of fraction of quiescent cancer cells within a population
  • the following cell lines were obtained from ATCC and cultured according to the ATCC recommendations: H2122 - non-small cell lung cancer cell line harboring G12C KRAS mutation; A549 - non-small cell lung cancer cell line harboring G12S KRAS mutation; H23 - non-small cell lung cancer cell line harboring G12C KRAS mutation; H358 - non-small cell lung cancer cell line harboring G12C KRAS mutation; OVCAR - ovarian cancer cell line wild type KRAS, H1975 - non-small cell lung cancer cell line wild-type KRAS, SW620 - colon cancer cell line harboring G12V KRAS mutation.
  • Cell cultures of these lines were seeded into 6-well plates at 3* 10 5 - 6* 10 5 cells/well; the plated number of cells depended on cell size and rate of proliferation, aiming for approximately 50% confluency. After seeding, the cells were allowed to attach for 24 hours while incubated at 37 °C in a humidified 5% CO2 atmosphere, and then treated with compounds for desired amount of time (usually 24 hours) incubating under same conditions. Then the cells were harvested by trypsinization, pooled with the floating cells, washed in PBS, and fixed in 70% ice-cold ethanol overnight.
  • AO staining For Acridine Orange (AO) staining, fixed cells were washed once with ice-cold PBS, re-suspended in 100 pL PBS, followed by addition of 200 pL of permeabilizing solution and 600 pL AO staining solution. The measurements were performed with Guava easyCyte HT flow cytometer (EMD Millipore) using the blue laser for excitation at 488 nm, monitoring emission of the AO-DNA complex at 526 nm and AO-RNA complex at 650 nm. The complete protocol and composition of buffers are described in the literature (Darzynkiewicz Z, Juan G, and Srour EF (2004) Differential Staining of DNA and RNA (2004). Current Protocols in Cytometry, Chapter 7:Unit 7.3).
  • cells were seeded into 96-well plates at 2* 10 3 - 6* 10 3 cells/well; depending on cell size and rate of proliferation aiming for approximately 50% confluency.
  • Cells were allowed to attach for 24 hours incubated at 37 °C in a humidified 5% CO2 atmosphere. The treatments were performed using at least 6 different concentrations of a compound in 1 :3 serial dilutions. Before reading the results cells were incubated for 96 hours in 5% CO2 incubator at 37 °C. Each treatment was performed in triplicate. Results were analyzed by CellTiter-GloTM Luminescent Cell Viability Assay (Promega, cat. # G7571) according to the manufacturer’s instructions using SpectraMAX Gemini Spectrophotometer (Molecular Devices).
  • cells were seeded into 96-well ULA (ultra-low attachment) plates (Corning #4515) at 5* 10 3 - 6* 10 3 cells/well depending on cell size and rate of proliferation aiming for spheroid formation with diameter of 400-600 pM at the beginning of treatment.
  • Cells were incubated for 2-3 days (depending on the cell line) at 37 °C in a humidified 5% CO2 atmosphere allowing for tight spheroid formation.
  • 50 pL of media was removed from each well and replaced with fresh media with compounds. The treatments were performed using at least 6 different concentrations of a compound in 1 :3 serial dilutions.
  • A549 cells were cultured and treated as described in Examples 1 and 2.
  • the highest concentration of selumetinib used in this assay was 10 pM and the concentrations of Compound 1-7 were 3 pM and 6 pM.
  • the observed EC50 values for selumetinib were 2.35 pM when Compound 1-7 was not present, 0.92 pM when Compound 1-7 was present at a concentration of 3 pM, and 0.01 pM when Compound 1-7 was present at a concentration of 6 pM. See FIG. 3.
  • OVCAR cells were cultured and treated as described in Examples 1 and 2.
  • the highest concentration of selumetinib used in this assay was 50 pM and the concentrations of Compound 1-7 were 1 pM and 3 pM, respectively.
  • the EC50 values observed for selumetinib were 238 pM when Compound 1-7 was not present, 173 pM when Compound 1-7 was present at a concentration of 1 pM, and ⁇ 0.1 pM when Compound 1-7 was present at a concentration of 3 pM. See FIG. 4.
  • H1975 cells were cultured and treated as described in Examples 1 and 2.
  • the highest concentration of selumetinib used in this assay was 20 pM and the concentrations of Compound II- 1 were 1 pM.
  • the EC 50 values observed for selumetinib were 59 pM when Compound II- 1 was not present, 0.13 pM when Compound II- 1 was present at a concentration of 1 pM. See FIG. 17.
  • A549 cells were cultured and treated as described in Examples 1 and 2.
  • the highest concentration of trametinib used in this assay was 0.5 pM and the concentrations of Compound 1-7 were 2.2 pM and 6.73 pM, respectively.
  • the EC50 values observed for trametinib were 16.2 nM when Compound 1-7 was not present, 16 nM when Compound 1-7 was present at a concentration of 2.2 pM, and 3.2 nM when Compound 1-7 was present at a concentration of 6.73 pM. See FIG. 5.
  • H23 cells were cultured and treated as described in Examples 1 and 2.
  • the highest concentration of trametinib used in this assay was 100 nM and the concentrations of Compound 1-7 were 0.12 pM and 3.3 pM, respectively.
  • the EC50 values observed for trametinib were 19.2 nM when Compound 1-7 was not present, 15.5 nM when Compound 1-7 was present at a concentration of 0.12 pM, and 11.8 nM when Compound 1-7 was present at a concentration of 3.3 pM. See FIG. 6.
  • Example 6 Combination of a DYRK1 inhibitor with trametinib in 3D cell culture H23 cells were cultured and treated as described in Examples 1 and 5.
  • the highest concentration of trametinib used in this assay was 6 nM and the concentrations of Compound 1-7 were 5 pM and 10 pM, respectively.
  • the ECso values observed for trametinib were 1.7 nM when Compound 1-7 was not present, 1.2 nM when Compound 1-7 was present at a concentration of 5 pM, and ⁇ 0.01 nM when Compound 1-7 was present at a concentration of 10 pM. See FIG. 7.
  • Example 7 Combination of a DYRK1 inhibitor with KRAS G12C mutant inhibitor MRTX-849 or KRAS G12C mutant inhibitor AMG-510
  • H2122 cells were cultured and treated as described in Examples 1 and 2.
  • the highest concentration of MRTX-849 used in this assay was 1 pM and the concentrations of Compound I- 7 were 2.5 pM and 5 pM.
  • the ECso values observed were 0.4 pM when Compound 1-7 was not present, 0.1 pM when Compound 1-7 was present at a concentration of 2.5 pM, and 0.018 pM when Compound 1-7 was present at a concentration of 5 pM. See FIG. 8.
  • H2122 cells were cultured and treated as described in Examples 1 and 2.
  • the highest concentration of AMG-510 used in this assay was 1 pM and the concentrations of Compound 1-7 were 2.5 pM and 5 pM.
  • the ECso values observed were > 1 pM when Compound 1-7 was not present, 0.9 pM when Compound 1-7 was present at a concentration of 2.5 pM, and 0.024 pM when Compound 1-7 was present at a concentration of 5 pM. See FIG. 9.
  • H358 cells were cultured and treated as described in Examples 1 and 2.
  • the highest concentration of AMG-510 used in this assay was 2 pM and the concentrations of Compound II- 1 was 0.25 pM.
  • the ECso values observed were 2 nM when Compound II- 1 was not present, 0.53 nM when Compound II- 1 was present at a concentration of 0.25 pM. See FIG. 14.
  • H358 cells were cultured and treated as described in Examples 1 and 2.
  • the highest concentration of MRTX-849 used in this assay was 0.2 pM and the concentration of Compound II-l were 0.25 pM.
  • the EC50 values observed were 4 nM when Compound II-l was not present, ⁇ 0.5 nM when Compound II-l was present at a concentration of 0.25 pM. See FIG. 15.
  • Example 8 Cell cycle effects and cytotoxicity of trametinib and combination of a DYRK1 inhibitor and trametinib
  • SW620 cells were cultured, treated, and analyzed as described in Example 1. The results when different concentrations of trametinib, Compound 1-7, or both trametinib and Compound I- 7 are present are shown in FIG. 10.
  • the H2122 cells were cultured and treated as described in Example 1. The results when cells were treated with MRTX-849, Compound 1-7, or both MRTX-849 and Compound 1-7 are present are shown in FIG. 11.
  • Example 10 Cell cycle effects and cytotoxicity of AMG-510 and combination of DYRK1 inhibitor with AMG-510
  • the H2122 cells were cultured, treated, and analyzed as described in Examples 1 and 2. The results when cells were treated with AMG-510, Compound 1-7, or both AMG-510 and Compound 1-7 are present are shown in FIG. 12.
  • H2122 cells were incubated for 24 hours under normal growth medium (FBS+) with or without treatment. Under these conditions, exposure to AMG-510 led to an increase in fraction of cells in quiescent state (Go). When cells were co-treated with combination of AMG-510 and Compound 1-7 no such increase in proportion of quiescent cells was observed and a large increase in cytotoxicity of AMG-510 was observed, as judged by the large increase in apoptotic cells as determined by sub-Go fraction.
  • FBS+ normal growth medium
  • Example 11 Induction of DYRK1B upon treatment of SW620 cells with trametinib, MEK inhibitor
  • SW620 cells were cultured and treated as described in Examples 1 and 2.
  • Western Blot analysis cells were seeded into 6-well plates at 5* 10 5 - 9* 10 5 cells/well (depending on the cell size and rate of proliferation), allowed to attach for 24 hours, then treated with compounds for 24 hours, and harvested. Immunoblotting was performed using conventional techniques, as described in Cell Signaling Technologies Western Blotting protocol (www.cellsignal.com).
  • Antibodies used for blotting were from Cell Signaling Technology (CST): DYRK1B (D40D1) Rabbit mAb #5672; P-Actin (13E5) Rabbit mAb #4970; Anti-rabbit IgG, HRP -linked Antibody #7074.
  • CST Cell Signaling Technology
  • the Primary Antibody Dilution Buffer IX TBST with 5% BSA (CST #9998) was used.
  • SignalFireTM ECL Reagent was used for detection.
  • the expression levels of DYRK1B, ph-t202 MAPK, total MAPK, ph-SlO p27, total p27 and P-actin in SW620 cells following the 24 hours treatment with trametinib or combination of trametinib and compound 1-7 as observed by Western blot analysis are shown in FIG. 13.
  • the expression of DYRK1B protein was compared to that in untreated cells incubated in regular growth medium containing FBS (FBS+) or serum free medium (FBS-), single treatment with trametinib to the treatment with combination of trametinib and compound 1-7.
  • cells were seeded into 96-well ULA (ultra-low attachment) plates (Corning #4515) at 5* 10 3 - 6* 10 3 cells/well depending on cell size and rate of proliferation aiming for spheroid formation with diameter of 400-600 pM at the beginning of treatment.
  • Cells were incubated for 2-3 days (depending on the cell line) at 37 °C in a humidified 5% CO2 atmosphere allowing for tight spheroid formation.
  • 50 pL of media was removed from each well and replaced with fresh media with compounds. The treatments were performed using at least 6 different concentrations of a compound in 1 :3 serial dilutions.

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Abstract

La présente invention concerne des compositions et des méthodes destinées au traitement de néoplasmes, en particulier, par ciblage de cellules cancéreuses quiescentes et proliférantes à l'aide d'un inhibiteur de DYRK1 en association avec d'autres traitements efficaces contre certaines affections néoplasiques, en particulier, un traitement anticancéreux faisant appel à un inhibiteur de MEK ou un inhibiteur de b-RAF, ou un inhibiteur de KRAS.
PCT/US2022/013081 2022-01-20 2022-01-20 Polythérapie anticancéreuse associant des inhibiteurs de dyrk1 et des inhibiteurs de la voie ras-raf-mek-erk (mapk) WO2023140846A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150292032A1 (en) * 2012-10-10 2015-10-15 Felicitex Therapeutics, Inc. Treatment of cancer by targeting quiescent cancer cells
US9446044B2 (en) * 2011-08-19 2016-09-20 Diaxonhit DYRK1 inhibitors and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9446044B2 (en) * 2011-08-19 2016-09-20 Diaxonhit DYRK1 inhibitors and uses thereof
US20150292032A1 (en) * 2012-10-10 2015-10-15 Felicitex Therapeutics, Inc. Treatment of cancer by targeting quiescent cancer cells

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BONI JACOPO, RUBIO-PEREZ CARLOTA, LÓPEZ-BIGAS NURIA, FILLAT CRISTINA, DE LA LUNA SUSANA: "The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities", CANCERS, vol. 12, no. 8, pages 2106, XP093081950, DOI: 10.3390/cancers12082106 *

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