WO2023202563A1 - Inhibiteur d'akt en association avec un inhibiteur de kinase pim - Google Patents

Inhibiteur d'akt en association avec un inhibiteur de kinase pim Download PDF

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WO2023202563A1
WO2023202563A1 PCT/CN2023/088917 CN2023088917W WO2023202563A1 WO 2023202563 A1 WO2023202563 A1 WO 2023202563A1 CN 2023088917 W CN2023088917 W CN 2023088917W WO 2023202563 A1 WO2023202563 A1 WO 2023202563A1
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cancer
compound
inhibitor
akt
akt inhibitor
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PCT/CN2023/088917
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English (en)
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Zhenhai SHEN
Kui Lin
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Newbay Technology Development Co., Ltd.
Genentech, 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

Definitions

  • PI3K phosphoinositide 3-kinase
  • mTOR mechanistic target of rapamycin
  • Activation of these isoforms is mediated by recruitment to PtdIns-3, 4-P2 (PI3, 4P2) and PtdIns-3, 4, 5-P3 (PIP3) at the plasma membrane and subsequent phosphorylation of T308 and S473 by 3-phosphoinositide-dependent protein kinase 1 (PDPK1) and mTOR complex 2 (mTORC2) , respectively.
  • PDPK1 3-phosphoinositide-dependent protein kinase 1
  • mTORC2 mTOR complex 2
  • Aberrant activation of AKT in cancer may occur via several mechanisms including mutational activation of the catalytic subunit of PI3K, which generates PIP3 and, indirectly, PI3, 4P2, loss of the PIP3 phosphatase PTEN and, albeit less frequently, activating mutations in AKT.
  • AKT Upon activation, AKT mediates various cellular processes including cell survival, metabolism and proliferation by regulating the activity of downstream proteins including proline-rich AKT substrate of 40 kDa (PRAS40) , glycogen synthase kinase 3 (GSK3) , Forkhead box class O (FoxO) transcription factors, tuberous sclerosis complex 2 (TSC2) , Bcl-2 associated death promoter (BAD) , mTOR complex 1 (mTORC1) , eukaryotic translation inhibition factor 4E-binding protein 1 (4EBP1) , and the S6 ribosomal protein kinase.
  • PRAS40 proline-rich AKT substrate of 40 kDa
  • GSK3 glycogen synthase kinase 3
  • FoxO Forkhead box class O
  • TSC2 tuberous sclerosis complex 2
  • Bcl-2 associated death promoter BAD
  • mTOR complex 1 mTOR complex 1
  • 4EBP1 eukary
  • AKT kinases have emerged as promising therapeutic targets in oncology and both allosteric and ATP-competitive AKT inhibitors have entered clinical investigation.
  • Two main classes of AKT inhibitors (AKTis) have entered clinical investigation in oncology: allosteric inhibitors such as MK-2206 and adenosine 5’-triphosphate (ATP) -competitive inhibitors such as ipatasertib (GDC-0068) . These inhibitors differentially exploit the on-off activity cycle of AKT. In its inactive state, AKT adopts a closed conformation in which the PH domain interacts with the kinase domain, also referred to as the PH-in state.
  • Allosteric inhibitors preferentially bind the inactive PH-in conformation at a cavity formed between the PH and kinase domains, preventing phosphorylation and activation of AKT.
  • ATP-competitive inhibitors selectively target the PH-out conformation, protecting AKT from dephosphorylation at T308 and S473 while simultaneously blocking ATP binding and kinase activity.
  • decreased AKT phosphorylation at both T308 and S473 is typically observed in allosteric inhibitor-treated cells while increased or sustained pAKT at both sites is characteristic of the ATP-competitive inhibitors.
  • AKTis is likely to be the greatest in indications associated with PI3K/AKT pathway activating alterations.
  • One such indication is prostate cancer.
  • Activation of the PI3K/AKT pathway is thought to comprise roughly 50%of metastatic castration-resistant prostate cancer (mCRPC) , frequently via PTEN loss of function.
  • mCRPC metastatic castration-resistant prostate cancer
  • Phase III clinical trials are currently underway to further evaluate ipatasertib as a therapeutic agent in these indications.
  • PIM kinases are family of three highly-related serine and threonine protein kinases encoded by the genes PIM-1, PIM-2, and PIM-3.
  • the gene names are derived from the phrase Proviral Insertion, Moloney, frequent integration sites for murine moloney virus wherein the insertions lead to overexpression of PIM kinases and either de novo T-cell lymphomas, or dramatic acceleration of tumorigenesis in a transgenic Myc-driven lymphoma model. See, e.g., Cuypers et al., Cell (1984) 37: 141-150; Selten et al., EMBO J.
  • PIM kinases show synergy in transgenic mouse models with c-Myc-driven and AKT-driven tumors. See, e.g., Verbeek et al., Mol Cell Biol (1991) 11: 1176-1179; Allen et al. Oncogene (1997) 15: 1133-1141; and Hammerman et al., Blood (2005) 105: 4477-4483.
  • PIM kinases are involved in transforming activity of oncogenes identified in acute myeloid leukemia (AML) including Flt3-ITD, BCR-abl, and Tel-Jak2.
  • MM Multiple myeloma
  • MM is a clonal B-lymphocyte malignancy, which is characterized by the accumulation of terminally differentiated antibody-producing cells in the bone marrow.
  • the present disclosure identifies mechanisms of acquired resistance to both allosteric and ATP-competitive AKTis using an unbiased approach.
  • Systematic analysis of cell lines with acquired AKTi-resistance (AKTi-R) were performed, and potential functional dependencies and combination strategies using a chemical genetics screen were explored.
  • AKT inhibitor resistance could be reversed by co-treatment with PIM kinase inhibitors.
  • PIM kinase inhibitor exhibited synergy against AKT inhibitor resistant cancer.
  • the present disclosure provides a method for treating cancer in a subject in need thereof, comprising administering therapeutically effective amounts of an AKT inhibitor and PIM kinase inhibitor to the subject.
  • the cancer is a resistant cancer, such as AKT inhibitor resistant cancer.
  • the present disclosure provides the use of the combination of an AKT inhibitor and a PIM kinase inhibitor in the treatment of cancer, such as AKT inhibitor resistant cancer.
  • the present disclosure provides the use of the combination of an AKT inhibitor and a PIM kinase inhibitor in the manufacture of a medicament for use in the treatment of cancer, such as AKT inhibitor resistant cancer.
  • the present disclosure provides a combination comprising an AKT inhibitor and a PIM kinase inhibitor.
  • the combination is for use in the treatment of cancer, such as AKT inhibitor resistant cancer.
  • the combination is provided in a pharmaceutical composition.
  • FIG. 1 depicts a schematic for establishing AKT inhibitor resistant (AKTi-R) cell lines. Resistance is established by treatment of the parental (Par) cells with gradually increasing doses of each AKT inhibitor (AKTi) , up to 5 uM. Surviving cell pools and clones were maintained in the presence of AKTi and subject to various analyses.
  • AKTi-R AKT inhibitor resistant
  • FIG. 2 depicts experiments determining the IC 50 values of ATP-competitive AKT inhibitor ipatasertib and allosteric AKT inhibitor MK-2206 in HCT 116 (PTEN WT) colon cancer cell line, LNCaP (PTEN-null) prostate cancer cell line, PC-3 (PTEN-null) prostate cancer cell line, and DU145 (PTEN WT) prostate cancer cell lines, as measured with a 4-day viability assay. Absolute IC 50 values from independent biological repeats are plotted in scatter plots. Error bars represent standard error of the mean (SEM) . As shown, both ipatasertib and MK-2206 are similarly active against PTEN-null LNCaP and PC-3 cell lines, but not PTEN wild type (PTEN-WT) HCT 116 or DU145 cell lines.
  • SEM standard error of the mean
  • FIGS. 3A-3D depict the assessment of viability of ATP-competitive AKT inhibitor ipatasertib and allosteric AKT inhibitor MK-2206 against MK-2206 resistant (M-R) LNCaP cells and ipatasertib resistant (G-R) LNCaP cells.
  • FIGS. 3A-3B reveals that the M-R cells display substantial resistance specifically to the allosteric AKT inhibitor (FIG. 3A) compared to the ATP-competitive AKT inhibitor (FIG. 3B) .
  • FIGS. 3C-3D reveals that the G-R cells are resistant to both the allosteric AKT inhibitor (FIG. 3C) and ATP-competitive AKT inhibitor (FIG.
  • MK-2206-resistant cell pools are denoted as M-Rpool
  • G-Rpool ipatasertib-resistant cell pools
  • Individual AKTi-R clones were assigned numbers (e.g., -3, -5, -7) , which are indicated following the M-R or G-R prefix.
  • FIGS. 4A-4E depict the impact of AKT Inhibitor Withdrawal (IW) for 11 passages assessed in M-R and G-R LNCaP cells.
  • 4E depicts representative images from day 4, comparing G-R1 LNCaP cells to G-R1 IW LNCaP cells upon treatment with ipatasertib, showing upon partial reversion of AKTi resistance that the cellular morphology is altered in G-R1 cells (compared to Par cells) .
  • the partial reversion of resistance in G-R IW cells may be associated with a restored ability of ipatasertib to suppress mTORC1 signaling.
  • M-R LNCaP cells are specific to allosteric AKT inhibition, irreversible, and associated with impaired MK-2206-mediated suppression of AKT signaling, while the resistance of ipatasertib resistant (G-R) LNCaP cells is AKTi class independent and partially reversible.
  • FIGS. 5A-5C depict the screening procedure studying the effects of the PIM inhibitor (PIMi) in LNCaP parental (Par) cells plated in DMSO-control medium or in LNCaP G-R cells plated in 5 uM ipatasertib-containing medium using a 4-day viability assay (FIG. 5A) , and the resulting scatter plots of the average IC 50 log2 fold change (AVG IC 50 log2 FC) (FIG. 5B) or average mean viability difference (Avg Delta MV) (FIG. 5C) of G-R cells versus parental (Par) cells from the screen.
  • PIM inhibitor PIM inhibitor
  • FIGS. 5A-5C depict the screening procedure studying the effects of the PIM inhibitor (PIMi) in LNCaP parental (Par) cells plated in DMSO-control medium or in LNCaP G-R cells plated in 5 uM ipatasertib-containing medium using a 4-day viability assay (FI
  • FIGS. 6A-6C depict data relating to the PIMi GDC-0570 in combination with the AKTi ipatasertib.
  • FIG. 6A shows the dose response of GDC-0570 alone against LNCaP parental (Par) cells, GDC-0570 alone against G-R3 cells, and GDC-0570 plated in 5 uM ipatasertib-containing medium against G-R3 cells, assessed using a 4-day viability assay.
  • the data shows combination has a larger effect on killing cancer cells than the single agent.
  • FIG. 6B is a summary of the IC 50 of ipatasertib alone, GDC-0570 alone, their combination, and the delta mean viability (MV) difference, which is the difference between the area under the curve of GDC-0570 + 5 uM ipatasertib (G-R3 cells) and GDC-0570 alone (Par cells) .
  • the negative delta MV indicates G-R3 cells in the presence of ipatasertib is more sensitive to GDC-0570 than the LNCaP parental cells.
  • FIG. 6C shows the effects of ipatasertib (ipat) and GDC-0570 on G-R3 cell line viability, demonstrating a strong synergistic effect in their combination (BLISS score >15) .
  • FIGS. 7A-7B depict data relating to the dose response of the PIMi AZD1208 in combination with the AKTi ipatasertib.
  • FIG. 7A shows the dose response of AZD1208 alone against LNCaP parental (Par) cells, AZD1208 alone against G-R3 cells, and AZD1208 plated in 5 uM ipatasertib-containing medium against G-R3 cells, assessed using a 4-day viability assay.
  • the data shows combination has a larger effect on killing cancer cells than the single agent.
  • FIG. 7B shows the effects of ipatasertib (ipat) and AZD1208 on G-R3 cell line viability, demonstrating a strong synergistic effect in their combination (BLISS score > 15) .
  • FIGS. 8A-8B depict data relating to the dose response of the PIMi LGH447 in combination with the AKTi ipatasertib.
  • FIG. 8A shows the response of LGH447 alone against LNCaP parental (Par) cells, AZD1208 alone against G-R3 cells, and LGH447 plated in 5 uM ipatasertib-containing medium against G-R3 cells, assessed using a 4-day viability assay.
  • the data shows combination has a larger effect on killing cancer cells than the single agent.
  • FIG. 8B shows the effects of ipatasertib (ipat) and LGH447 on G-R3 cell line viability, demonstrating a strong synergistic effect in their combination (BLISS score > 15) .
  • FIGS 9A-9H depict data relating to the PIMi GNE-1571 in combination with the AKTi ipatasertib (FIGS. 9A-9F) or MK2206 (FIGS. 9G-9H) .
  • FIG. 9A shows the dose response of GNE-1571 alone against LNCaP parental (Par) cells or GNE-1571 plated in 5 uM ipatasertib-containing medium against G-R3 cells, assessed using a 4-day viability assay.
  • FIG. 9B-9C depict the cellular response of G-Rpool, G-R1, and G-R3 cells (maintained in the presence of 5 uM ipatasertib-containing medium) or Par cells to GNE-1571 using a 4-day viability assay.
  • IC 50 values are depicted in the scatter plots.
  • FIG. 9D is a summary of the IC 50 of ipatasertib alone, GNE-1571 alone, their combination, and the delta mean viability (MV) difference, which is the difference between the area under the curve of GNE-1571 + 5 uM ipatasertib (G-R3 cells) and GNE-1571 alone (Par cells) .
  • MV delta mean viability
  • FIG. 9E depicts heatmaps showing percent viability inhibition, BLISS or HSA scores associated with each dose combination treatment of Par or G-R3 cells with ipatasertib and/or GNE-1571.
  • FIG 9F depicts the scatter plots of mean BLISS sum values from independent biological replicates, with the mean BLISS sum and mean HSA average calculated from these experiments, demonstrating a strong synergistic effect in their combination (BLISS Sum > 100; HSA Avg > 0) .
  • FIG. 9E depicts heatmaps showing percent viability inhibition, BLISS or HSA scores associated with each dose combination treatment of Par or G-R3 cells with ipatasertib and/or GNE-1571.
  • FIG 9F depicts the scatter plots of mean BLISS sum values from independent biological replicates, with the mean BLISS sum and mean HSA average calculated from these experiments, demonstrating a strong synergistic effect in their combination (BLISS Sum > 100; HSA Avg > 0) .
  • FIG 9G depicts heatmaps showing percent viability inhibition, BLISS or HSA scores associated with each dose combination treatment of Par or G-R3 cells with MK-2206 and/or GNE-1571.
  • FIG 9H depicts the scatter plots of mean BLISS sum values from independent biological replicates, with the mean BLISS sum and mean HSA average calculated from these experiments, demonstrating a strong synergistic effect in their combination (BLISS Sum > 100; HSA Avg > 0) .
  • FIGS. 10A-10J depict data relating to the PIMi GDC-0339 in combination with the AKTi ipatasertib (FIGS. 10A-10H) or MK-2206 (FIGS. 10I-10J) .
  • FIG. 10A shows the dose response of GDC-0339 alone against LNCaP parental (Par) cells or GDC-0339 plated in 5 uM ipatasertib-containing medium against G-R3 cells, assessed using a 4-day viability assay.
  • FIGS. 10A shows the dose response of GDC-0339 alone against LNCaP parental (Par) cells or GDC-0339 plated in 5 uM ipatasertib-containing medium against G-R3 cells, assessed using a 4-day viability assay.
  • FIG. 10B-10C depict the cellular response of G-Rpool, G-R1, and G-R3 cells (maintained in the presence of 5 uM ipatasertib-containing medium) or Par cells to GDC-0339 using a 4-day viability assay.
  • IC 50 values are depicted in the scatter plots.
  • FIG. 10D is a summary of the IC 50 of ipatasertib alone, GDC-0339 alone, their combination, and the delta mean viability (MV) difference, which is the difference between the area under the curve of GDC-0339 + 5 uM ipatasertib (G-R3 cells) and GDC-0339 alone (Par cells) .
  • MV delta mean viability
  • FIG. 10E depicts heatmaps showing percent viability inhibition, BLISS or HSA scores associated with each dose combination treatment of Par or G-R3 cells with ipatasertib and/or GDC-0339.
  • FIG. 10F depicts the scatter plots of mean BLISS sum values from independent biological replicates from the LNCaP Par and G-R3 cell lines studies, with the mean BLISS sum and mean HSA average calculated from these experiments, demonstrating a strong synergistic effect in their combination (BLISS Sum > 100; HSA Avg > 0) .
  • FIG. 10E depicts heatmaps showing percent viability inhibition, BLISS or HSA scores associated with each dose combination treatment of Par or G-R3 cells with ipatasertib and/or GDC-0339.
  • FIG. 10F depicts the scatter plots of mean BLISS sum values from independent biological replicates from the LNCaP Par and G-R3 cell lines studies, with the mean BLISS sum and mean HSA average calculated from
  • FIG 10G depicts heatmaps showing percent viability inhibition and FIG 10H provides the BLISS Sum and HSA average scores associated with the treatment of 22RV1 cells with the combination of ipatasertib and GDC-0339, demonstrating a strong synergistic effect in their combination (BLISS Sum >100; HSA Avg > 0) .
  • 22RV1 cells are a human prostate carcinoma epithelial cell line derived from a xenograft serially propagated in mice after castration-induced regression and relapse of the parental, androgen-dependent CWR22 xenograft, and is an example of a cell line with intrinsic AKT resistance.
  • FIG. 10I depicts heatmaps showing percent viability inhibition, BLISS or HSA scores associated with each dose combination treatment of Par or G-R3 cells with MK-2206 and/or GDC-0339.
  • FIG 10J depicts the scatter plots of mean BLISS sum values from independent biological replicates, with the mean BLISS sum and mean HSA average calculated from these experiments, demonstrating a strong synergistic effect in their combination (BLISS Sum > 100; HSA Avg > 0) .
  • FIGS. 11A-11B depict data relating to the PIMi GNE-5775 in combination with the AKTi ipatasertib.
  • FIG. 11A shows the dose response of GNE-5775 alone against LNCaP parental (Par) cells or GNE-5775 plated in 5 uM ipatasertib-containing medium against G-R3 cells, assessed using a 4-day viability assay.
  • FIG. 11A shows the dose response of GNE-5775 alone against LNCaP parental (Par) cells or GNE-5775 plated in 5 uM ipatasertib-containing medium against G-R3 cells, assessed using a 4-day viability assay.
  • 11B is a summary of the IC 50 of ipatasertib alone, GNE-5775 alone, their combination, and the delta mean viability (MV) difference, which is the difference between the area under the curve of GNE-5775 + 5 uM ipatasertib (G-R3 cells) and GNE-5775 alone (Par cells) .
  • the negative delta MV indicates G-R3 cells in the presence of ipatasertib is more sensitive to GNE-5775 than the LNCaP parental cells.
  • FIGS. 12A-12B depict data relating to the PIMi GNE-5652 in combination with the AKTi ipatasertib.
  • FIG. 12A shows the dose response of GNE-5652 alone against LNCaP parental (Par) cells or of GNE-5652 plated in 5 uM ipatasertib-containing medium against G-R3 cells, assessed using a 4-day viability assay.
  • IC 50 is the difference between the area under the curve of GNE-5652 + 5 uM ipatasertib (G-R3 cells) and GNE-5652 alone (Par cells) ;
  • ND IC 50 not determined.
  • GNE-5652 demonstrated significant reduction of cell viability in G-R3 cells maintained in the presence of ipatasertib compared to GNE-5652 alone in Par cells as shown by delta MV analysis, although it did not reach 50%inhibition of viability in the fitted curve in G-R3 cells and therefore the IC 50 values were not determined.
  • FIGS. 13A-13D demonstrate that the combined treatment with a PIMi overcomes resistance in ipatasertib-resistant in vivo models.
  • FIGS. 13A-13B depict tumor xenografts derived from the LNCaP Par cells and ipatasertib-resistant G-R3 cells (which are cells established through in vitro selection) .
  • FIG. 13C schematic depicts ipatasertib-resistant tumor models directly established in vivo. Mice bearing LNCaP parental xenograft tumors were exposed to prolonged ipatasertib treatment and surviving tumors were excised and adapted in vitro to establish the resistant line R0068 X1.2.
  • FIGS. 13D depicts R0068 X1.2 tumors grown in vivo when re-implanted into male NOD scid gamma (NSG) mice.
  • Mice bearing the indicated tumors in FIGS. 13A, 13B and 13D were treated as the following groups: Group 1-vehicle; Group 2-ipatasertib (ipat) monotherapy (25 mg/kg PO QD) ; Group 3-GDC-0339 monotherapy (100 mg/kg PO QD) ; and Group 4-Combination of ipatasertib (ipat) (25 mg/kg PO QD) and GDC-0339 (100 mg/kg PO QD) .
  • TGI Tumor growth inhibition
  • FIG. 14 Effect of GDC-0570 and GDC-0068 combination on tumor volume.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) .
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • terapéuticaally effective amount means a combined amount of the AKT inhibitor and PIM inhibitor that (i) treats the cancer, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the cancer, and/or (iii) prevents or delays the onset of one or more symptoms of the cancer, wherein the combined amount has demonstrated an improvement in (i) , (ii) , or (iii) compared to single agent therapy.
  • the therapeutically effective amount of the combination may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
  • the combination may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic.
  • efficacy can be measured, for example, by assessing the time to disease progression (TTP) and/or determining the response rate (RR) .
  • the term “synergistic” refers to the effect achieved when the AKT inhibitor and PIM inhibitor used together is greater than the expected mathematical sum of the effects that results from using the AKT inhibitor and PIM inhibitor separately. Synergy may be evaluated using a BLISS independence model. See, e.g., Lehar et al., Molecular Systems Biology (2007) 3: 80 1-14 and Borisy, et al., Proceedings of the National Academy of Sciences of the United States of America (2003) 100: 7977-7982.
  • a Bliss Sum or Bliss score 0 indicates that the combination treatment is additive (as expected for independent pathway effects) ; a Bliss Sum or Bliss Score >0 indicates activity greater than additive (synergy) ; and a Bliss Sum or Bliss score ⁇ 0 indicates the combination is less than additive (antagonism) .
  • HSA or “highest single agent” score is calculated at each dose matrix point based on the excess loss of viability in the combination in comparison to the highest single drug response. See, e.g., Lehar et al., Molecular Systems Biology (2007) 3: 80 1-14; Berenbaum, Pharmacol Rev (1989) 41: 93-141; Lehar et al. Nature Biotechnology (2009) 27: 659-666 (2009) ; and Wallin et al., Clinical cancer research (2012) 18: 3901-3911) .
  • An HSA score >0 suggests a combination effect greater than the maximum of the single agent responses at corresponding concentrations.
  • HSA Avg is the average of HSA for each pair (e.g., as shown on a heatmap) .
  • Resistant cancer or “refractory cancer” is used interchangeably herein, and refers to a cancer that is not responsive to therapeutic treatment. Resistant cancer may have intrinsic resistance or acquired resistance. “Intrinsic resistance” means a lack of tumor response to initial therapy. “Acquired resistance” refers to tumors that initially respond to treatment and later relapsed.
  • AKT resistant cancer comprises cancers that have acquired resistance to one or more AKT inhibitors by prior treatment with one or more AKT inhibitors, or may comprise cancers with intrinsic resistance to one or more AKT inhibitors, such as cancers having an activated PIM kinase. The resistant cancer may be resistant at the beginning of treatment, or it may become resistant during treatment.
  • PTEN loss of function refers to cancer that has been characterized (such as by next-generation sequencing (NGS) , immunohistochemistry (IHC) , or fluorescence in situ hybridization (FISH) ) as having PTEN loss or PTEN null (no PTEN) by genomic deletion or insertion, PTEN mutation, promotor methylation, PTEN copy number loss, or loss of PTEN protein expression.
  • NGS next-generation sequencing
  • IHC immunohistochemistry
  • FISH fluorescence in situ hybridization
  • Exemplary cancers with PTEN loss of function include but are not limited to prostate, uterine, ovarian and brain cancers.
  • PI3K altered cancer refers to cancer that has been characterized (such as by next-generation sequencing (NGS) , polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) ) as having an activating mutation or amplification of PI3K (phosphatidylinositol-3 kinase) , thereby promoting oncogenic activity.
  • NGS next-generation sequencing
  • PCR polymerase chain reaction
  • FISH fluorescence in situ hybridization
  • the PIK3CA gene encoding the p110 ⁇ catalytic subunit of PI3K
  • the mutations E542K, E545K, and H1047R have also been found to be activating mutations.
  • Exemplary cancers with PI3K oncogenic alterations include ovarian, lung, stomach, and brain cancers.
  • AKT altered cancer refers to cancer that has been characterized (such as by next-generation sequencing (NGS) , polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) ) as having an activating mutation or amplification of AKT, thereby promoting oncogenic activity.
  • AKT activating mutations can occur in AKT1, AKT2, or AKT3 isoforms.
  • activating AKT1 mutations such as E17K, have been found in head and neck, colorectal, endometrial, lung, melanoma, and ovarian cancers.
  • the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is an adult human subject. In some embodiments, the subject is a human male subject. In some embodiments, the subject is a human female subject. “Subject” and “patient” and “individual” are also used interchangeably herein.
  • phrases "pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • phrases “pharmaceutically acceptable salt” refers to pharmaceutically acceptable organic or inorganic salts of a compound.
  • Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate” , ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1, 1'-methylene-bis - (2-hydroxy-3-
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the
  • Acids which are generally considered suitable for the formation of pharmaceutically useful or acceptable salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds. ) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1 19; P. Gould, International J. of Pharmaceutics (1986) 33 201 217; Anderson et al, The Practice of Medicinal Chemistry (1996) , Academic Press, New York; Remington's Pharmaceutical Sciences, 18th ed., (1995) Mack Publishing Co., Easton PA; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website) .
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the present disclosure is generally related to the combination of an AKT inhibitor and a PIM kinase inhibitor as described herein, e.g., for use in the treatment of cancer.
  • the AKT inhibitor is selected from the group consisting of allosteric AKT inhibitors and ATP-competitive AKT inhibitors. In some embodiments, the AKT inhibitor is an allosteric AKT inhibitor.
  • An “allosteric AKT inhibitor” refers to a substance that inhibits AKT by preferentially binding the inactive PH-in conformation, e.g., for example, at a cavity formed between the PH and kinase domains, preventing phosphorylation and activation of AKT.
  • Exemplary allosteric AKT inhibitors include, but are not limited to, miransertib (ARQ 092) , vevorisertib (ARQ 751) , BAY1125976, perifosine (KRX-0401) , triciribine, TAS-117, and pharmaceutically acceptable salts thereof, the structures of which are provided below:
  • the allosteric AKT inhibitor is MK-2206 or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of MK-2206 is the dihydrochloride salt.
  • the AKT inhibitor is an ATP-competitive AKT inhibitor.
  • An “ATP-competitive AKT inhibitor” refers to a substance that inhibits AKT by selectively targeting the PH-out conformation, e.g., for example, by protecting AKT from dephosphorylation at T308 and S473 while simultaneously blocking ATP binding and kinase activity.
  • Exemplary ATP-competitive AKT inhibitors include, but are not limited to, ipatasertib (GDC-0068) , capivasertib (AZD 5363) , Afuresertib (GSK2110183) , uprosertib (GSK2141795) , MSC2363318A, cenisertib (R763/AS703569) , and pharmaceutically acceptable salts thereof, the structures of which are provided below:
  • the ATP-competitive AKT inhibitor is ipatasertib (GDC-0068) , also known as (S) -2- (4-chlorophenyl) -1- (4- ( (5R, 7R) -7-hydroxy-5-methyl-6, 7-dihydro-5H-cyclopenta [d] pyrimidin-4-yl) piperazin-1-yl) -3- (isopropylamino) prop an-1-one, or a pharmaceutically acceptable salt thereof, which is described in Example 14 of WO2008/006040.
  • the pharmaceutically acceptable salt of ipatasertib is the monohydrochloride salt.
  • the pharmaceutically acceptable salt of ipatasertib is the amorphous monohydrochloride salt.
  • the PIM kinase inhibitor is a PIM-1 kinase inhibitor, PIM-2 kinase inhibitor, or PIM-3 inhibitor. In some embodiments, the PIM kinase inhibitor is a pan-PIM kinase inhibitor, which exhibits potent activity against PIM-1, PIM-2 and/or PIM-3 inhibitor.
  • Exemplary PIM kinase inhibitors include, but are not limited to, AZD1208, LGH447, and the compounds disclosed in WO2014048939, US20110059961 or US20130079321 (such as GDC-0570, GNE-1571, GNE-5775, GDC-0339 and GNE-5652) , and pharmaceutically acceptable salts thereof, the structures of which are provided below:
  • the PIM kinase inhibitor is selected from the group consisting of GDC-0570, GNE-1571, GNE-5775, GDC-0339, GNE-5652, and pharmaceutically acceptable salts thereof.
  • the PIM kinase inhibitor is GDC-0570, also known as N- (5- ( (2S, 5R, 6S) -5-amino-6-fluorooxepan-2-yl) -l-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
  • GDC-0570 is Compound 321 in WO2014048939.
  • the PIM kinase inhibitor is GNE-1571, also known as N- (5- ( (2S, 5R, 6S) -5-amino-6-fluorooxepan-2-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2-fluorophenyl) thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
  • GNE-1571 is Compound 322 in WO2014048939.
  • the PIM kinase inhibitor is GNE-5775, also known as N- (5- ( (2S, 5R, 6S) -5-amino-6-fluorooxepan-2-yl) -1 -methyl-1 H-pyrazol-4-yl) -2- (3-methylpyridin-2-yl) thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
  • GNE-5775 is Compound 231 in WO2014048939.
  • the PIM kinase inhibitor is GDC-0339, also known as 5-amino-N- (5- ( (4R, 5R) -4-amino-5-fluoroazepan-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluo rophenyl) thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
  • GDC-0339 is the compound of Example 139 in US20130079321.
  • the PIM kinase inhibitor is GNE-5652, also known as (S) -5-amino-N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (2, 6-difluorophenyl) thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
  • GNE-5652 is the compound of Example 3 in US20110059961.
  • the AKT inhibitor and the PIM kinase inhibitor may exist as isotopically-labeled compounds which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • Exemplary isotopes that can be incorporated into compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl 123 I and 125 I.
  • Certain isotopically-labeled compounds e.g., those labeled with 3 H and 14 C
  • Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability.
  • isotopes such as deuterium ( 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • the AKT inhibitor is ipatasertib or pharmaceutically acceptable salt thereof, and the PIM kinase inhibitor is GDC-0570, GNE-1571, GNE-5775, GDC-0339, or GNE-5652, or a pharmaceutically acceptable salt thereof.
  • the AKT inhibitor is ipatasertib or pharmaceutically acceptable salt thereof, and the PIM kinase inhibitor is GDC-0570 or pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for treating cancer to a subject in need thereof, such as an AKT inhibitor resistant cancer, preferably ATP-competitive AKT inhibitor resistant cancer, and more preferably ipatasertib resistant cancer, comprising administering a therapeutically effective amount of an AKT inhibitor and a therapeutically effective amount of an PIM kinase inhibitor to the subject.
  • a subject in need thereof such as an AKT inhibitor resistant cancer, preferably ATP-competitive AKT inhibitor resistant cancer, and more preferably ipatasertib resistant cancer
  • the present disclosure provides the use of the combination of an AKT inhibitor and a PIM kinase inhibitor in the treatment of cancer, such as AKT inhibitor resistant cancer, preferably ATP-competitive AKT inhibitor resistant cancer, and more preferably ipatasertib resistant cancer.
  • cancer such as AKT inhibitor resistant cancer, preferably ATP-competitive AKT inhibitor resistant cancer, and more preferably ipatasertib resistant cancer.
  • the present disclosure provides the use of the combination of an AKT inhibitor and a PIM kinase inhibitor in the manufacture of a medicament for use in the treatment of cancer, such as AKT inhibitor resistant cancer, preferably ATP-competitive AKT inhibitor resistant cancer, and more preferably ipatasertib resistant cancer.
  • cancer such as AKT inhibitor resistant cancer, preferably ATP-competitive AKT inhibitor resistant cancer, and more preferably ipatasertib resistant cancer.
  • Tumor and “cancer” are used interchangeably herein, and refer to the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • cancers include breast cancer, squamous cell cancer (e.g., epithelial squamous cell cancer) , lung cancer including small-cell lung cancer, non-small cell lung cancer ( "NSCLC” ) , adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
  • Gastric cancer includes stomach cancer, which can develop in any part of the stomach and may spread throughout the stomach and to other organs.
  • the cancer is selected from the group consisting of breast, multiple myeloma, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC) , small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, pancreatic, lymphoma, myeloid disorders, leukemia, myeloid leukemia, non-Hodgkin lymphoma, Hodgkin's lymphoma, acute myelogenous le
  • the cancer is breast cancer.
  • the breast cancer is selected from the group consisting of hormone receptor positive/ERBB2 negative breast cancer, ERBB2 positive breast cancer, and triple-negative breast cancer, preferably triple-negative breast cancer.
  • the cancer is a resistant cancer. In certain embodiments, the cancer is an AKT inhibitor resistant cancer. In certain embodiments, the cancer is an ATP-competitive AKT inhibitor resistant cancer. In certain embodiments, the cancer is an ipatasertib resistant cancer.
  • the cancer is characterized by one or more of: having PTEN loss of function, is a PI3K altered cancer, and/or is an AKT altered cancer. In certain embodiments, the cancer is characterized by having PTEN loss of function. In certain embodiments, the cancer is characterized as a PI3K altered cancer. In certain embodiments, the cancer is characterized as an AKT altered cancer. In certain embodiments, the cancer is characterized as a PI3K or AKT altered cancer. In certain embodiments, the cancer which is characterized by one or more of: having PTEN loss of function, is a PI3K altered cancer, and/or is an AKT altered cancer, is also an AKT inhibitor resistant cancer.
  • the cancer which is characterized by one or more of: having PTEN loss of function, is a PI3K altered cancer, and/or is an AKT altered cancer is also an ATP-competitive AKT inhibitor resistant cancer.
  • the cancer which is characterized by one or more of: having PTEN loss of function, is a PI3K altered cancer, and/or is an AKT altered cancer is also an ipatasertib resistant cancer.
  • the cancer is prostate cancer. In some embodiments, the cancer is castration-resistant prostate cancer. In some embodiments, the cancer is metastatic castration-resistant prostate cancer. In some embodiments, the cancer is prostate cancer with PTEN loss of function. In certain embodiments, the prostate cancer is AKT inhibitor resistant cancer. In certain embodiments, the prostate cancer is ATP-competitive AKT inhibitor resistant cancer. In some embodiments, the prostate cancer is ipatasertib resistant cancer.
  • the subject has previously been subjected to a therapy comprising administering the AKT inhibitor, thereby acquiring AKT inhibitor resistant cancer. In some embodiments, the subject has previously been subjected to a therapy comprising administering the ATP-competitive AKT inhibitor. In some embodiments, the subject has been subjected to a therapy comprising administering ipatasertib. In some embodiments, the subject has been subjected to ipatasertib monotherapy.
  • the subject has AKT inhibitor resistant cancer. In certain embodiments, the subject has ATP-competitive AKT inhibitor resistant cancer. In certain embodiments, the subject has ipatasertib resistant cancer.
  • the PIM kinase inhibitor and the AKT inhibitor are each administered in amounts that, in combination, are therapeutically effective.
  • the molar ratio of the AKT inhibitor and the PIM kinase inhibitor is about 1: 0.001, about 1: 0.01, about 1: 0.1, about 1: 1, or about 1: 2. In some embodiments, the molar ratio of the AKT inhibitor and the PIM kinase inhibitor is about 1: 1000, about 1: 100, about 1: 10, or about 1: 5. In some embodiments, the molar ratio of the AKT inhibitor and the PIM kinase inhibitor is about 1: 0.001 to about 1: 1000, about 1: 0.01 to about 1: 100, about 1: 0.1 to about 1: 10, or about 1: 1 to about 1: 5.
  • the weight ratio of AKT inhibitor and PIM kinase inhibitor is from about 10: 1-1: 10, preferably about 3: 1-1: 3, 3: 1, 2: 1, 1: 1, 1: 2 or 1: 3.
  • the method further comprises administering a third therapeutic agent.
  • the AKT inhibitor and the PIM kinase inhibitor are administered simultaneously. In some embodiments, the AKT inhibitor and the PIM kinase inhibitor are administered sequentially. When administered sequentially, the combination may be administered in two or more administrations. The combined administration includes co-administration, using separate formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities.
  • Suitable dosages for any of the above co-administered agents are those presently used and may be lowered due to the combined action (synergy) of the newly identified agent and other chemotherapeutic agents or treatments, such as to increase the therapeutic index or mitigate toxicity or other side-effects or consequences.
  • the method may further comprise surgical therapy and/or radiotherapy.
  • the amounts of the PIM kinase inhibitor, the AKT inhibitor and the other pharmaceutically active chemotherapeutic agent (s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the present disclosure provides a combination comprising an AKT inhibitor and a PIM kinase inhibitor.
  • the combination is for use in the treatment of cancer, such as AKT inhibitor resistant cancer, preferably ATP-competitive AKT inhibitor resistant cancer, and more preferably ipatasertib resistant cancer.
  • the combination is provided in a single pharmaceutical composition along with a pharmaceutically acceptable excipient.
  • the combination is provided in two pharmaceutical compositions, one comprising an AKT inhibitor and pharmaceutically acceptable excipient, and another comprising a PIM kinase inhibitor and a pharmaceutically acceptable excipient, administered together in combination.
  • pharmaceutically acceptable excipient refers to a substance that assists in the in vivo delivery and/or manufacture of a pharmaceutical composition containing the active agent or agents as described herein.
  • Pharmaceutically acceptable excipients are inert.
  • Non-limiting examples of pharmaceutically acceptable excipients include pharmaceutically acceptable polymers, water, NaCl, normal saline solutions, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, surfactants, coatings, sweeteners, flavors, salt solutions, alcohols, oils, gelatins, carbohydrates, colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like.
  • Pharmaceutically acceptable excipients are described in the Handbook of Pharmaceutical Excipients, 8 th Edition, published by the Pharmaceutical Press (2017) , and in the United States Food and Drug Administration Inactive Ingredient Database (July 2017) , the disclosures of which are incorporated by reference herein.
  • the pharmaceutical composition may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass) , sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • compositions may be prepared for various routes and types of administration.
  • the pharmaceutical compositions will be dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the pharmaceutical composition is formulated for oral delivery.
  • Formulations of the AKT inhibitor and/or the PIM kinase inhibitor suitable for oral administration may be prepared as discrete units such as pills, hard or soft e.g., gelatin capsules, cachets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, syrups or elixirs each containing a predetermined amount of the AKT inhibitor and/or the PIM kinase inhibitor.
  • the amount of compound of the AKT inhibitor and the PIM kinase inhibitor may be formulated in a pill, capsule, solution or suspension as a combined formulation.
  • the AKT inhibitor and the PIM kinase inhibitor may be formulated separately in a pill, capsule, solution or suspension for administration by alternation.
  • the pharmaceutical composition is a solid dosage form, such as a tablet, capsule, or pill, administered orally.
  • the solid dosage form is a tablet.
  • a dose may be administered once a day (QD) , twice per day (BID) , or more frequently, depending on the pharmacokinetic (PK) and pharmacodynamic (PD) properties, including absorption, distribution, metabolism, and excretion of the particular compound.
  • PK pharmacokinetic
  • PD pharmacodynamic
  • toxicity factors may influence the dosage and administration dosing regimen.
  • the pill, capsule, or tablet may be ingested twice daily, daily or less frequently such as weekly or once every two or three weeks for a specified period of time. The regimen may be repeated for a number of cycles of therapy.
  • the total daily dose may be administered in a range of about 100 to about 600 mg of ipatasertib free base equivalent.
  • the pharmaceutical composition in this instance may comprise 100 mg, 200 mg, 300 mg, 400 mg, or any amount of the ipatasertib free base in order to allow for administration of the total daily dose.
  • a total daily dose of about 200 mg of ipatasertib free base equivalent is administered, and the pharmaceutical composition may comprise 100 mg (administered twice) or 200 mg.
  • a total daily dose of about 400 mg of ipatasertib free base equivalent is administered, and the pharmaceutical composition may comprise 100 mg (administered 4 times) , 200 mg (administered twice) , or 400 mg.
  • “Free base equivalent” refers to the amount of free base of ipatasertib, e.g., for example, a “total daily dose of about 400 mg of ipatasertib” means administering about 400 mg of ipatasertib free base, which is equivalent to about 431.88 mg of ipatasertib mono-hydrochloride salt.
  • Embodiment 1 provided herein is a method for treating AKT inhibitor resistant cancer in a human subject in need thereof, comprising administering a therapeutically effective amount of an AKT inhibitor and a PIM kinase inhibitor to the subject, or a combination comprising a therapeutically effective amount of an AKT inhibitor and a PIM kinase inhibitor, for use in treating AKT inhibitor resistant cancer in a subject in need thereof; or use of a combination comprising a therapeutically effective amount of an AKT inhibitor and a PIM kinase inhibitor in the manufacture of the medicament in the treatment of AKT inhibitor resistant cancer in a subject in need thereof.
  • Embodiment 2 The method or the compound or the use of Embodiment 1, wherein the cancer is ATP-competitive AKT inhibitor resistant cancer.
  • Embodiment 3 The method or the compound or the use of Embodiment 3, wherein the cancer is ipatasertib resistant cancer.
  • Embodiment 4 The method or the compound or the use of any one of Embodiments 1-3, wherein the AKT inhibitor is selected from the group consisting of allosteric AKT inhibitors and ATP-competitive AKT inhibitors.
  • Embodiment 5 The method or the compound or the use of Embodiment 4, wherein the AKT inhibitor is an allosteric AKT inhibitor.
  • Embodiment 6 The method or the compound or the use of Embodiment 5, wherein the allosteric AKT inhibitor is selected from the group consisting of miransertib (ARQ 092) , vevorisertib (ARQ 751) , BAY1125976, perifosine (KRX-0401) , triciribine, TAS-117, and pharmaceutically acceptable salts thereof.
  • the allosteric AKT inhibitor is selected from the group consisting of miransertib (ARQ 092) , vevorisertib (ARQ 751) , BAY1125976, perifosine (KRX-0401) , triciribine, TAS-117, and pharmaceutically acceptable salts thereof.
  • Embodiment 7 The method or the compound or the use of Embodiment 4, wherein the AKT inhibitor is an ATP-competitive AKT inhibitor.
  • Embodiment 8 The method or the compound or the use of Embodiment 5, wherein the ATP-competitive AKT inhibitor is selected from the group consisting of ipatasertib (GDC-0068) , capivasertib (AZD 5363) , Afuresertib (GSK2110183) , uprosertib (GSK2141795) , MSC2363318A, cenisertib (R763/AS703569) , and pharmaceutically acceptable salts thereof.
  • the ATP-competitive AKT inhibitor is selected from the group consisting of ipatasertib (GDC-0068) , capivasertib (AZD 5363) , Afuresertib (GSK2110183) , uprosertib (GSK2141795) , MSC2363318A, cenisertib (R763/AS703569) , and pharmaceutically acceptable salts thereof.
  • Embodiment 9 The method or the compound or the use of any one of Embodiments 1-8, wherein the PIM kinase inhibitor is a PIM-1 kinase inhibitor, PIM-2 kinase inhibitor, or PIM-3 inhibitor.
  • Embodiment 10 The method or the compound or the use of Embodiment 9, wherein the PIM kinase inhibitor is a pan-PIM kinase inhibitor.
  • Embodiment 11 The method or the compound or the use of Embodiment 9, wherein the PIM kinase inhibitor is selected from the group consisting of AZD1208, LGH447, GDC-0570, GNE-1571, GNE-5775, GDC-0339, GNE-5652, and pharmaceutically acceptable salts thereof.
  • Embodiment 12 The method or the compound or the use of Embodiment 11, wherein the PIM kinase inhibitor is selected from the group consisting of GDC-0570, GNE-1571, GNE-5775, GDC-0339, GNE-5652 and pharmaceutically acceptable salts thereof.
  • Embodiment 13 The method or the compound or the use of Embodiment 12, wherein the PIM kinase inhibitor is selected from the group consisting of GDC-0570, GNE-1571, GNE-5775, GDC-0339 and GNE-5652, and pharmaceutically acceptable salts thereof, and the AKT inhibitor is ipatasertib or pharmaceutically acceptable salt thereof.
  • the PIM kinase inhibitor is selected from the group consisting of GDC-0570, GNE-1571, GNE-5775, GDC-0339 and GNE-5652, and pharmaceutically acceptable salts thereof
  • the AKT inhibitor is ipatasertib or pharmaceutically acceptable salt thereof.
  • Embodiment 14 The method or the compound or the use of any one of Embodiments 1-13, wherein the cancer selected from the group consisting of is selected from the group consisting of breast, multiple myeloma, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC) , small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, pancreatic, lymphoma, myeloid disorders, leukemia, myeloid leukemia,
  • Embodiment 15 The method or the compound or the use of Embodiment 14, wherein the cancer is breast cancer.
  • Embodiment 16 The method or the compound or the use of Embodiment 15, wherein the breast cancer is selected from the group consisting of hormone receptor positive/ERBB2 negative breast cancer, ERBB2 positive breast cancer, and triple-negative breast cancer, preferably triple-negative breast cancer.
  • Embodiment 17 The method or the compound or the use of Embodiment 14, wherein the cancer is prostate cancer.
  • Embodiment 18 The method or the compound or the use of Embodiment 17, wherein the cancer is castration-resistant prostate cancer.
  • Embodiment 19 The method or the compound or the use of Embodiment 18, wherein the cancer is metastatic castration-resistant prostate cancer.
  • Embodiment 20 The method or the compound or the use of any one of Embodiments 1-19, wherein the cancer is characterized by one or more of: having PTEN loss of function, is a PI3K altered cancer, and/or is an AKT altered cancer.
  • Embodiment 21 The method or the compound or the use of any one of Embodiments 1-20, wherein the subject has previously been subjected to a therapy comprising administering an AKT inhibitor, thereby acquiring AKT inhibitor resistant cancer.
  • Embodiment 22 The method or the compound or the use of Embodiment 21, wherein the subject has previously been subjected to therapy comprising administering ipatasertib.
  • Embodiment 23 The method or the compound or the use of any one of Embodiments 1-22, wherein the subject is a human subject.
  • Embodiment 24 The method or the compound or the use of any one of Embodiments 1-23, wherein the method further comprises administering a third therapeutic agent.
  • Embodiment 25 The method or the compound or the use of any one of Embodiments 1-24, wherein the combination provides a synergistic therapeutic effect compared to administration of the AKT inhibitor or the PIM kinase inhibitor alone.
  • Embodiment 26 The method or the compound or the use of any one of Embodiments 25, wherein the molar ratio of the AKT inhibitor and the PIM kinase inhibitor is about 1: 0.001, about 1: 0.01, about 1: 0.1, about 1: 1, or about 1: 2.
  • Embodiment 27 The method or the compound or the use of any one of Embodiments 25, the molar ratio of the AKT inhibitor and the PIM kinase inhibitor is about 1: 1000, about 1: 100, about 1: 10, or about 1: 5.
  • Embodiment 28 The method or the compound or the use of any one of Embodiments 25, the molar ratio of the AKT inhibitor and the PIM kinase inhibitor is about 1: 0.001 to about 1: 1000, about 1: 0.01 to about 1: 100, about 1: 0.1 to about 1: 10, or about 1: 1 to about 1: 5.
  • Embodiment 29 The method or the compound or the use of any one of Embodiments 25, wherein the weight ratio of AKT inhibitor and PIM kinase inhibitor is from about 10: 1-1: 10.
  • Embodiment 30 The method or the compound or the use of any one of Embodiments 25, wherein the weight ratio of AKT inhibitor and PIM kinase inhibitor is from about 3: 1-1: 3.
  • Embodiment 31 The method or the compound or the use of any one of Embodiments 25, wherein the weight ratio of AKT inhibitor and PIM kinase inhibitor is about 3: 1, 2: 1, 1: 1, 1: 2 or 1: 3.
  • Embodiment 32 provided is a pharmaceutical composition comprising an AKT inhibitor and a PIM kinase inhibitor, and a pharmaceutically acceptable excipient.
  • LNCaP is an approximately tetraploid epithelial line derived from a prostate adenocarcinoma metastasis. See, e.g., Horoszewicz et al., Progress in clinical and biological research (1980) 37: 115-132; and Horoszewicz, et al. Cancer Res (1983) 43: 1809-1818.
  • LNCaP cells harbor a frameshift mutation (K6fs*4) (COSMIC # COSM4929) and loss of heterozygosity (LOH) in PTEN. See, e.g., Spans, The Prostate (2012) 72: 1317-1327 and Vlietstra et al., Cancer Res (1998) 58: 2720-2723. The presence of both alterations was confirmed in the LNCaP line in-house via exome sequencing and SNP array.
  • FIG. 2 depicts experiments determining the IC 50 values of ATP-competitive AKT inhibitor ipatasertib and allosteric AKT inhibitor MK-2206 in HCT 116 (PTEN WT) colon cancer cell line, LNCaP (PTEN-null) prostate cancer cell line, PC-3 (PTEN-null) prostate cancer cell line, and DU145 (PTEN WT) prostate cancer cell lines, as measured with a 4-day viability assay. Absolute IC 50 values from independent biological repeats are plotted in scatter plots. Error bars represent standard error of the mean (SEM) . As shown, both ipatasertib and MK-2206 are similarly active against PTEN-null LNCaP and PC-3 cell lines, but not PTEN wild type (PTEN-WT) HCT 116 and DU145 cell lines.
  • SEM standard error of the mean
  • AKTi-resistant (AKTi-R) cell lines were established by treating the parental (Par) LNCaP cells with gradually escalating doses of MK-2206 or ipatasertib until reaching a maximum dose of 5 ⁇ M of AKTi. See, e.g., schematic provided in FIG. 1.
  • MK-2206-resistant (M-R) and ipatasertib-resistant (G-R) cell pools were then subjected to single cell sorting using FACS Aria instrumentation and software (BD Biosciences) and surviving clones were expanded in the presence of AKTi at the maximum doses indicated above.
  • MK-2206-resistant cell pools are denoted as M-Rpool
  • G-Rpool ipatasertib-resistant cell pools
  • Individual AKTi-R clones were assigned numbers (e.g., -3, -5, -7) , which are indicated following the M-R or G-R prefix. All cell lines were maintained at 37°C/5%CO 2 in Roswell Park Memorial Institute medium (RPMI) 1640 supplemented with 10%fetal bovine serum (FBS) (Sigma) , 2 mM L-Glutamine, and 0.01 M HEPES, pH 7.2. Growth medium for AKTi-R cell lines was additionally supplemented with AKTi at the indicated concentration for cell line maintenance.
  • RPMI Roswell Park Memorial Institute medium
  • FIGS. 3A-3D depict the assessment of viability of ATP-competitive AKT inhibitor ipatasertib and allosteric AKT inhibitor MK-2206 against M-R cells and ipatasertib resistant G-R cells.
  • FIGS. 3A-3B reveal that the M-R cells display substantial resistance specifically to the allosteric AKT inhibitor (FIG. 3A) compared to the ATP-competitive AKT inhibitor (FIG. 3B) .
  • FIGS. 3C-3D reveal that the G-R cells are resistant to both the allosteric AKT inhibitor (FIG. 3C) and ATP-competitive AKT inhibitor (FIG. 3D) .
  • Error bars represent standard error of the mean (SEM) .
  • FIGS. 4A-4E depict the impact of AKT inhibitor withdrawal for 11 passages (IW) was assessed in M-R and G-R LNCaP cells.
  • MK MK-2206
  • ipat ipatasertib
  • FIG. 4A to FIG. 4B Images were subjected to confluence analysis and percent confluence values from 8 replicates per conditions were averaged. Scatter plots depict percent confluence over time, with error bars indicating standard deviations. As shown, partial reversion of AKTi resistance is noted in G-R cells that were subjected to ipatasertib withdrawal (compare FIG. 4A to FIG. 4B) , but not in M-R cells subjected to MK-2206 withdrawal (compare FIG. 4C to FIG. 4D) .
  • FIG. 4E depicts representative images from day 4, comparing G-R LNCaP cells to G-R1 IW LNCaP cells upon treatment with ipatasertib, showing partial reversion of AKTi resistance, and that the cellular morphology is altered in G-R1 cells compared to Par cells.
  • the partial reversion of resistance in G-R IW cells may be associated with a restored ability of ipatasertib to suppress mTORC1 signaling.
  • a library of small molecules including chemotherapeutics and compounds targeting a range of molecular mechanisms were screened against parental cells plated in DMSO-containing medium or G-R cells plated in ipatasertib. Both ipatasertib and MK-2206 were included in the library and as expected, they were identified among the top compounds associated with enhanced resistance in G-R cells.
  • FIGS. 5A-5C depict the screening procedure studying the effects of the PIM inhibitor in LNCaP parental (Par) cells plated in DMSO-control medium or in LNCaP G-R cells plated in 5 uM ipatasertib-containing medium using a 4-day viability assay (FIG. 5A) , and the resulting scatter plots of the average IC 50 log2 fold change (AVG IC 50 log2 FC) (FIG. 5B) or average mean viability difference (Avg Delta MV) (FIG. 5C) of G-R cells versus parental (Par) cells from the screen.
  • AVG IC 50 log2 FC average mean viability difference
  • FIGS. 5C Average mean viability difference
  • Par or G-R cells were plated in black/clear bottom 384 well plates (BD Falcon) and incubated at 37°C under 5%CO 2 and 24 hours later were treated with a 9-point dose titration of ipatasertib, a second inhibitor, or a combination of the two. All conditions were tested in quadruplicate within each experiment. Treated cells were then incubated for 4 days and cellular viability was assessed using the CellTiter-GloR (Promega) luminescent assay according to the manufacturer’s instructions. Total luminescence was measured on a Wallac Multilabel Reader (PerkinElmer) and was considered to represent cellular viability.
  • Dose response curves depict mean %viability (%DMSO control) , with error bars representing standard error of the mean (SEM) , from quadruplicate samples (y-axis) versus concentration of inhibitor (x-axis) from a single representative experiment.
  • the inhibitor concentration resulting in the half maximum inhibitor effect (IC 50 ) was calculated from %viability values from quadruplicate wells using a 4-parameter curve analysis (XLfit, IDBS software) . See, e.g., Lin et al. Clinical cancer research (2013) 19: 1760-1772.
  • Ipatasertib and GDC-0339 were formulated in 0.5%methylcellulose/0.2%Tween-80 (MCT) and were administered once daily (QD) via oral formulation (per os; PO) at 25 and 100 mg/kg, respectively for 21 days.
  • Tumor volumes were determined using digital calipers (Fred V. Fowler Company, Inc, Newton MA) using the formula (L x W x W) /2. Tumor volumes and body weights were recorded twice weekly over the course of the study. Mice with tumor volumes >2000 mm3 or recorded body weight loss of >20%from their start of treatment were euthanized per Institutional Animal Care and Use Committee guidelines.
  • a generalized additive mixed model was then applied to describe the change of transformed tumor volumes over time using regression splines with auto-generated spline bases as this approach addresses both repeated measurements from the same study subjects and moderate dropouts before study end.
  • GMM generalized additive mixed model
  • group-level efficacy were obtained by calculating a growth contrast, the difference in AUC-based growth rates (i.e., eGaIT) between the treatment and reference group fits.
  • group AUC values are corrected for starting tumor burden and then subjected to slope equivalence “normalization” .
  • Slope equivalence “normalization” of AUC results in the actual slope of a fit on the natural log (LN) scale in cases of log-linear growth.
  • FIGS. 13A-13D demonstrate that the combined treatment with a PIMi overcomes resistance in ipatasertib-resistant in vivo models.
  • FIGS. 13A-13B depict tumor xenografts derived from the LNCaP Par cells and ipatasertib-resistant G-R3 cells (which are cells established through in vitro selection) .
  • FIG. 13C schematic depicts ipatasertib-resistant tumor models directly established in vivo. Mice bearing LNCaP parental xenograft tumors were exposed to prolonged ipatasertib treatment and surviving tumors were excised and adapted in vitro to establish the resistant line R0068 X1.2.
  • FIGS. 13D depicts R0068 X1.2 tumors grown in vivo when re-implanted into male NOD scid gamma (NSG) mice.
  • Mice bearing the indicated tumors in FIGS. 13A, 13B and 13D were treated as the following groups: Group 1-vehicle; Group 2-ipatasertib (ipat) monotherapy (25 mg/kg PO QD) ; Group 3-GDC-0339 monotherapy (100 mg/kg PO QD) ; and Group 4-Combination of ipatasertib (ipat) (25 mg/kg PO QD) and GDC-0339 (100 mg/kg PO QD) .
  • TGI Tumor growth inhibition
  • Example 4 Combined Drug Treatment for breast cancer using AKT inhibitor ipatasertib in combination with PIM kinase inhibitor GDC-0570
  • Tumor-bearing mice were divided into 6 dose groups, including vehicle group, GDC-0570 at 50 mg/kg, GDC-0570 at 100 mg/kg, GDC-0570 at 150 mg/kg, ipatasertib at 50mg/kg and GDC-0570 (50 mg/kg) combination with ipatasertib (50 mg/kg) groups. Dosing solutions were administrated orally every day. The duration of the study was 21 days. Tumor volumes were measured twice a week. Body weights were measured each day before dosing.
  • mice 120 female BALB/c nude mice, 7-8 weeks old with average body weight of 20 g ⁇ 20%, were used for tumor fragment implantation. Among them, 60 mice were selected for administration of test articles.
  • the PDX model was established for pre-clinical efficacy study. This PDX model was derived from a 55-year-old male Chinese TNBC patient.
  • GDC-0570 vehicle 0.5%MC and 0.2%Tween 80 kept at 2-8°C
  • GDC-0570 dosing solutions The required amount of GDC-0570 powder was weighed and added into appropriate amount of 0.5%MC0.2%Tween 80 solution to create a formulation at 30mg/ml, and then mixed via vortex and sonication until becoming homogeneous. It was then diluted with MCT to other concentrations (10mg/ml, 20mg/ml and 30mg/ml) . Dosing suspension was stored at 2-8°C for up to a week.
  • Ipatasertib vehicle 0.5%MC and 0.2%Tween 80 kept at 2-8°C
  • Ipatasertib dosing solutions The required amount of ipatasertib powder was weighed and added into appropriate amount of 0.5%MC, 0.2%Tween 80 solution to create a formulation at 10mg/ml, and then mixed via vortex and sonication until becoming homogeneous. Dosing suspension was stored at 2-8°C for up to a week.
  • Tumor sizes were measured twice a week while body weights were measured daily before dosing. Clinical sign was observed on a daily basis. All animals were euthanized on day 20 after tumor size calibration. After animal euthanization, tumor samples were collected.
  • Tumor Volume (TV) (Length ⁇ Width 2 ) /2
  • Relative Tumor Volume (RTV) TV f /TV 0 , where TV 0 and TV f are the tumor volume measured on day 0 and day 20, respectively;
  • T/C Ratio (%) (RTV of the treatment group/RTV of the vehicle control group) ⁇ 100%;
  • TGI Tumor Growth Inhibition Rate
  • TVt f was the group mean tumor volume (TV) of treatment group at final treatment day
  • TVt 0 was the group mean TV of treatment group at treatment day 0
  • TVc f was the group mean TV of control group at final treatment day
  • TVc 0 was the group mean TV of control group at treatment day 0
  • Percent of tumor regression 100 ⁇ (TV 0 -TV f ) /TV 0
  • TV 0 was the group mean TV in the same group but measured at the treatment day 0
  • TV f was the group mean TV in the same group but measured at the last treatment day
  • Tumor growth curve was plotted using tumor volume as Y axis and time as X axis; Body weight change curve was plotted using animal body weight as Y axis and time as X axis. Data on tumor volume and body weight change in percentage were analyzed using the One Way. Analysis of Variance (One Way-ANOVA) method, followed by a significance test using the Bartlett’s test (p ⁇ 0.05) .
  • Non-significant tumor inhibition effect TGI (%) ⁇ 60%, or P>0.05
  • the ulcer is greater than 5mm in diameter, and becomes cavitated or develops signs of infection/bleeding, and does not heal or form a scab within 1 week; or if animal shows signs of discomfort.
  • Table 1 shows the effect of GDC-0570 and ipatasertib on tumor growth.
  • Table 1 Effect of GDC-0570 and ipatasertib on tumor volume in TNBC PDX model
  • Table 2 Effect of GDC-0570 and ipatasertib on T/C Ratio and TGI in TNBC PDX model
  • Example 5 Combined drug treatment for breast cancer using AKT inhibitor ipatasertib in combination with PIM kinase inhibitor GDC-0571 or GNE-5775
  • Tumor-bearing mice are divided into 6 dose groups, including vehicle group, GDC-0571 or GNE-5775 at 50 mg/kg, GDC-0571 or GNE-5775at 100 mg/kg, GDC-0571 or GNE-5775 at 150 mg/kg, ipatasertib at 50mg/kg and GDC-0571 or GNE-5775 (50 mg/kg) combination with ipatasertib (50 mg/kg) groups.
  • Dosing solutions are administrated orally to the xenograft mice every day. The duration of the study is 21 days. Tumor volumes are measured twice a week. Body weights are measured each day before dosing.

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Abstract

L'invention concerne une combinaison associant un inhibiteur d'AKT et un inhibiteur de kinase PIM, destinée à être utilisée dans le traitement du cancer, tel que le cancer résistant à l'inhibiteur d'AKT, chez un sujet nécessitant un tel traitement. L'invention concerne également une composition la comprenant.
PCT/CN2023/088917 2022-04-18 2023-04-18 Inhibiteur d'akt en association avec un inhibiteur de kinase pim WO2023202563A1 (fr)

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