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WO2023220355A1 - Protac ciblant pim ayant des fractions de liaison pim sgi-1776, azd-1208 ou pim-447 et une fraction de liaison à l'ubiquitine ligase e3 pour traiter le cancer - Google Patents

Protac ciblant pim ayant des fractions de liaison pim sgi-1776, azd-1208 ou pim-447 et une fraction de liaison à l'ubiquitine ligase e3 pour traiter le cancer Download PDF

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Publication number
WO2023220355A1
WO2023220355A1 PCT/US2023/022017 US2023022017W WO2023220355A1 WO 2023220355 A1 WO2023220355 A1 WO 2023220355A1 US 2023022017 W US2023022017 W US 2023022017W WO 2023220355 A1 WO2023220355 A1 WO 2023220355A1
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Prior art keywords
cancer
compound
vhl
pim
cells
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Inventor
John F. BROGNARD
Rolf E. Swenson
Pedro TORRES-AYUSO
Venkatareddy SABBASANI
Dawid G. MEHLICH
Noel A. WARFEL
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University of Arizona
US Department of Health and Human Services
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University of Arizona
US Department of Health and Human Services
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • PIM Moloney murine leukemia virus
  • the invention further provides a method of treating cancer in a mammal comprising administering to the mammal an effective amount of a compound of formula (I) (i.e., a compound of formula (I) for use in treating cancer in a mammal),
  • X 1 is a residue with an affinity for a Proviral Integration site for Moloney murine leukemia virus (PIM) kinase
  • L is a linker
  • X 2 is a residue with an affinity for a ubiquitin ligase
  • the cancer comprises cancer cells that overexpress a PIM kinase relative to non-cancerous cells of the same tissue type.
  • the cancer can be prostate cancer.
  • FIG. 1 is a chemrcal synthesis of intermediate S4 in an aspect of the invention.
  • FIG. 2 is a chemical synthesis of SGI-1776-VHL-01 in an aspect of the invention.
  • FIG. 3 is a chemical synthesis of SGI-1776-CRBN-01 in an aspect of the invention.
  • FIG. 4 is a chemical synthesis of SGI-1776-IAP-01 in an aspect of the invention.
  • FIG. 5 is a chemical synthesis of intermediate S7 in an aspect of the invention.
  • FIG. 6 is a chemical synthesis of SGI-1776-VHL-02 in an aspect of the invention.
  • FIG. 7 is a chemical synthesis of SGI-1776-VHL-02-epimer in an aspect of the invention.
  • FIG. 8 is a chemical synthesis of intermediate S9 in an aspect of the invention.
  • FIG. 9 is a chemical synthesis of AZD1208-VHL-01 in an aspect of the invention.
  • FIG. 10 is a chemical synthesis of PIM447-VHL-01 in an aspect of the invention.
  • FIG. 11 is a chemical synthesis of intermediate S9-epimer in an aspect of the invention.
  • FIG. 12 is a chemical synthesis of PIM447-VHL-01 -epimer in an aspect of the invention.
  • FIG. 13A is an immunoblot measuring PIM expression and phosphorylation of downstream targets IRS1 and BAD of PC3 cells after treatment with dimethylsulfoxide (DMSO), 3 pm SGI-1776, 3 pm AZD1208, or 1 pm PIM447 for 8 h.
  • FIG. 13B is an immunoblot measuring PIM expression and phosphorylation of downstream targets TRS1 and BAD of LNCaP cells after treatment with dimethylsulfoxide (DMSO), 3 pm SGI-1776, 3 pm AZD1208, or 1 pm PIM447 for 8 h.
  • DMSO dimethylsulfoxide
  • FIG. 13C is an immunoblot measuring PIM expression and phosphorylation of downstream targets IRS1 and BAD of C4-2 cells after treatment with dimethylsulfoxide (DMSO), 3 pm SGI-1776, 3 pm AZD1208, or 1 pm PIM447 for 8 h.
  • DMSO dimethylsulfoxide
  • FIG. 13D is a graph showing the PIM1, PIM2, and PIM3 mRNA levels, as evaluated by immunoblot, exhibited by PC3 cells treated with 3 pm AZD1208 for 4 h.
  • FIG. 14A is an immunoblot in which HA-PIM1 -transfected PC3 cells were incubated with the PIM447 (3 pM) 30 min prior to treatment with MG-132 (10 pM) for the times indicated and PIM1 immunoprecipitated. PIM1 ubiquitination was evaluated by immunoblot on the immunoprecipitation fractions.
  • FIG. 15A is an immunoblot in which PC3 cells transfected with wild-type (WT) or kinase-dead (K67M) HA-PIM were treated with cycloheximide (CHX, 10 pM) with or without AZDI 208 (3 pM) for the times specified and cells collected to evaluate PIM1 degradation by immunoblot. Where indicated, cells were pre-treated with AZD1208 (concentration, time) before incubating with CHX.
  • WT wild-type
  • K67M kinase-dead
  • FIG. 16A is an immunoblot in which PC3 cells were pre-incubated with dimethylsulfoxide (DMSO) or PIM447 (3 pM) 30 min prior to treatment with cycloheximide (CHX, 10 pM) for the times indicated. Lysates were collected to evaluate PIM1 degradation and PIM1 inhibition was assessed as reduced IRS-Serl lOl phosphorylation.
  • DMSO dimethylsulfoxide
  • PIM447 3 pM
  • CHX cycloheximide
  • FIG. 16C is an immunoblot in which PC3 cells transfected with wild-type (WT) or kinase-dead (K67M) HA-PIM1 were pretreated with PIM447 (3 pM) 30 min prior to treatment with cycloheximide (CHX, 10 pM) for the times indicated. Lysates were collected to evaluate PIM1 degradation.
  • WT wild-type
  • K67M kinase-dead
  • CHX cycloheximide
  • FIG. 17A is an immunoblot in which PC3-LN4 cells with PIM1 knocked out (KO) were reconstituted with wild-type (WT) or kinase-dead (K67M) PIM1. PIM1 levels and BAD-Serl lOl phosphorylation were evaluated.
  • FIG. 17B is a graph showing the relative cell viability of PC3-LN4 cells with PIM1 knocked out (KO) reconstituted with wild-type (WT) or kinase-dead (K67M) PIM1 as a function of docetaxel concentration.
  • FIG. 18A is an immunoblot of PIM1 expression of transfected cells.
  • FIGs. 19A-19C are immunoblots of doxycycline-inducible PIM1 (PC3-dox-PIMl) expression by PIM PROTACs of formula (I) in PC3 cells.
  • PIM1 was induced with doxycycline (1 pg/ml, 24 h), and SGI-1776-VHL-01 (FIG. 19A), SGI-1776-IAP-01 (FIG. 19B), or SGI- 1776-CRBN-01 (FIG. 19C) were added at the indicated concentrations (24 h).
  • Cells were lysed, and PIM1 expression was analyzed by immunoblot. The experiments were conducted twice.
  • FIGs. 20A-20H are immunoblots showing PIM PROTACs in PC3 cells with doxycycline-inducible PIM1 (PC3-dox-PIMl) expression.
  • PIM1 was induced with doxycycline (1
  • Cells were lysed, and PIM1 expression was analyzed by immunoblot.
  • PIM1 was induced with doxycycline (1 pg/ml, 24 h).
  • Cells were then pre-treated for 30 minutes with the indicated inhibitors: MG-132 (10 pM), MLN4924 (3 pM), and VH-298 (50 pM).
  • the SGI-1776-VHL-02 (FIG 20C) or PIM447-VHL-01 (FIG. 20D) PROTACs were then added (0.75 pM, 4 h). Cells were lysed and PIM1 levels evaluated by immunoblot.
  • FIGs. 20E and 20F PIM1 was induced with doxycycline (1 pg/ml, 24 h).
  • Cells were PROTACs (SGI-1776-VHL-02 (FIG. 20E) or PIM447-VHL-01 (FIG. 20F)), or their corresponding epimer controls (SGI-1776-cA-VHL-02 or PIM447-cA-VHL-01) and were added at the indicated concentrations for 24 h. Cells were then lysed, and PIM1 expression was analyzed. In FIGs. 20G and 20H, PIM1 was induced with doxycycline (1 pg/ml, 24 h). DMSO or PROTACs (SGI-1776-VHL-02 (FIG. 20G) or PIM447-VHL-01 (FIG. 20H), at 0.75 pM) were added for the times indicated, and PIM1 degradation was assessed by immunoblot. All experiments were conducted twice.
  • FIGs. 21A-21H are immunoblots showing that PIM PROTACs efficiently degrade endogenous PIM1 in PC3 cells.
  • PC3 cells were incubated under normoxic or hypoxic (1% O2) conditions for 24 h.
  • SGI-1776-VHL-02 (FIG. 21A) or PIM447-VHL-01 (FIG. 21B) were added at the indicated concentrations (24 h); cells were lysed, and PIM1 degradation was analyzed by immunoblot.
  • FIGs. 21C and 21D PC3 were cultured in normoxia or hypoxia for 24 h.
  • PROTACs SGI-1776-VHL-02 (FIG. 21E) or PIM447-VHL-01 (FIG. 21F), at 0.75 pM) or DMSO were added for the times indicated, and endogenous PIM1 degradation was assessed by immunoblot.
  • FIGs. 21G and 21H PC3 cells were incubated in normoxia or hypoxia for 24 h, followed by incubation with DMSO or PROTACs (SGI-1776-VHL-02 (FIG. 21G) or PIM447-VHL-01 (FIG. 21H), each at 0.75 pM) for an additional 24 h. The medium was then replaced, and cells were allowed to grow for the indicated times to recover PIM1 levels. All experiments were conducted three independent times.
  • FIG. 211 is an immunoblot in which PC3 cells with VHL knocked down with RNAi (50 nM) were treated 24 h post transfection with dimethylsulfoxide (DMSO), PROTAC SGI-1776-VHL-02 (1.5 [tM), or PROTAC PIM447-VHL-01 (1.5
  • DMSO dimethylsulfoxide
  • PROTAC SGI-1776-VHL-02 1.5 [tM)
  • PROTAC PIM447-VHL-01 1.5
  • FIG. 21J is a graph showing the relative PIM1 mRNA expression exhibited by PC3 cells treated with dimethylsulfoxide (DMSO), PROTAC SGI-1776-VHL-02 (1.5
  • FIGs. 22A-22D are immunoblots showing PIM2 and PIM3 kinase degradation by PIM PROTACs of formula (I) in PC3 cells.
  • PIM2 was induced with doxycycline (1 [tg/ml, 24 h), and SGI-1776-VHL-02 (FIG. 22A) or PIM447-VHL-01 (FIG.
  • FIGs. 22C and 22D PC3 cells were incubated in normoxia for 24 h, followed by incubation with DMSO, the indicated PROTACs (SGI-1776- VHL-02 (FIG. 22C) or PIM447-VHL-01 (FIG. 22D)), or PIM inhibitors (SGI-1776 (FIG. 22C) or PIM447 (FIG. 22D)) at the indicated concentrations for 10 days. Cells were then lysed, and expression of the different PIM kinase isoforms was evaluated by immunoblot.
  • FIG. 22E is an immunoblot showing the c-myc expression levels of PC3 and LNCaP cells treated with dimethylsulfoxide (DMSO), PROTAC SG1-1776-VHL-02 (3.75 ptM), PROTAC PIM447-VHL-01 (3.75 ptM), small-molecule SGI-1776 (3.75 jxM), or smallmolecule PIM447 (3.75
  • DMSO dimethylsulfoxide
  • FIG. 22G is an immunoblot showing the PIM1, PIM2, PIM3 expression levels exhibited by LNCaP cells treated with dimethylsulfoxide (DMSO), PROTAC SGI-1776- VHL-02, or small-molecule SGI-1776 at the indicated concentrations for 10 days with media and inhibitors replaced every 96 h.
  • DMSO dimethylsulfoxide
  • FIG. 22H is an immunoblot showing the PIM1, PIM2, PIM3 expression levels exhibited by LNCaP cells treated with dimethylsulfoxide (DMSO), PROTAC P1M447-VHL- 01, or small-molecule PIM447 at the indicated concentrations for 10 days with media and inhibitors replaced every 96 h.
  • DMSO dimethylsulfoxide
  • PROTAC P1M447-VHL- 01 small-molecule PIM447
  • FIG. 221 is an immunoblot showing the PIM1, PIM2, PIM3 expression levels exhibited by C4-2 cells treated with dimethylsulfoxide (DMSO), PROTAC SGI-1776-VHL- 02, or small-molecule SGI-1776 at the indicated concentrations for 10 days with media and inhibitors replaced every 96 h.
  • DMSO dimethylsulfoxide
  • PROTAC SGI-1776-VHL- 02 PROTAC SGI-1776-VHL- 02
  • small-molecule SGI-1776 at the indicated concentrations for 10 days with media and inhibitors replaced every 96 h.
  • FIG. 22J is an immunoblot showing the PIM1, PIM2, PIM3 expression levels exhibited by C4-2 cells treated with dimethylsulfoxide (DMSO), PROTAC PIM447-VHL-01, or small-molecule PIM447 at the indicated concentrations for 10 days with media and inhibitors replaced every 96 h.
  • DMSO dimethylsulfoxide
  • PROTAC PIM447-VHL-01 small-molecule PIM447
  • FIG. 23A shows a colony formation assay of PC3 cells (14 days) treated with the corresponding PIM PROTACs (SGI-1776-VHL-02 or PIM447-VHL-01) or inhibitors (SGI- 1776 or PIM447) at the indicated concentrations. Media and treatments were replaced every 96 h.
  • FIGs. 23B and 23C are graphs showing percentage of apoptotic cells as a function of DMSO (control), docetaxel, SGI1176 (FIG. 23B) or PIM1447 (FIG. 23C), a compound of formula (I) alone, or a combination of a compound of formula (I) and docetaxel.
  • PC3 cells were pre-treated with DMSO or the corresponding PROTACs or inhibitors at the indicated concentrations for 4 h. Cells were then treated with docetaxel (2 nM) where indicated and allowed to grow for 48 h.
  • Apoptosis was evaluated by flow cytometry via Annexin V- Propidium iodide staining. Percentage of apoptotic cells detected after the corresponding treatments (mean ⁇ SD) is plotted.
  • FIG. 23D are representative dot-plots of experiments conducted as in FIGs. 23B and 23C. * P ⁇ 0.05, *** P ⁇ 0.001 , **** P ⁇ 0.0001 , n.s., not significant; one-way ANOVA, Tukey multiple comparisons posttest.
  • FIG. 23E is a graph showing the relative cell viability of LNCaP cells, seeded (1.25 x 10 5 cells/well, 6-well plate) and pre-treated with docetaxel (2 nM, 4 h) 24 h after seeding where indicated, treated with dimethylsulfoxide (DMSO), PROTAC SGI-1776-VHL- 02, or small-molecule SGI-1776 for 48 h.
  • Data represent mean ⁇ SD of cell viability (cell area) relative to DMSO (control from three independent experiments. * P ⁇ 0.05, *** P ⁇ 0.001, **** P ⁇ 0.0001, n.s., not significant; one-way ANOVA, Tukey multiple comparisons posttest.
  • FIG. 23E is a graph showing the relative cell viability of LNCaP cells, seeded (1.25 x 10 5 cells/well, 6-well plate) and pre-treated with docetaxel (2 nM, 4 h) 24 h after seeding where indicated, treated with dimethylsulfoxide
  • 23F is a graph showing the relative cell viability of LNCaP cells, seeded (1 .25 x 10 5 cells/well, 6-well plate) and pre-treated with docetaxel (2 nM, 4 h) 24 h after seeding where indicated, treated with dimethylsulfoxide (DMSO), PROTAC PIM447-VHL- 01, or small-molecule PIM447 for 48 h.
  • Data represent mean ⁇ SD of cell viability (cell area) relative to DMSO (control from three independent experiments. * P ⁇ 0.05, *** P ⁇ 0.001, **** P ⁇ 0.0001, n.s., not significant; one-way ANOVA, Tukey multiple comparisons posttest.
  • FIG. 23G is a graph showing the relative cell viability of C4-2 cells, seeded (1.25 x 10 5 cells/well, 6-well plate) and pre-treated with docetaxel (2 nM, 4 h) 24 h after seeding where indicated, treated with dimethylsulfoxide (DMSO), PROTAC SGI-1776-VHL-02, or small-molecule SGI-1776 for 48 h.
  • Data represent mean ⁇ SD of cell viability (cell area) relative to DMSO (control from three independent experiments.
  • FIG. 23H is a graph showing the relative cell viability of C4-2 cells, seeded (1.25 x 10 5 cells/well, 6-well plate) and pre-treated with docetaxel (2 nM, 4 h) 24 h after seeding where indicated, treated with dimethylsulfoxide (DMSO), PROTAC PIM447-VHL-01, or small-molecule PIM447 for 48 h.
  • Data represent mean ⁇ SD of cell viability (cell area) relative to DMSO (control from three independent experiments.
  • FIGs. 24A and 24B are graphs showing the dose response curves for three prostate cancer cell lines (i.e., PC3, LNCaP, and C4-2) treated with SGI-1776-VHL-02 (FIG. 24A) or PIM447-VHL-01 (FIG. 24B) for 72 h.
  • Cell viability was evaluated in an MTS assay, and the IC50 calculated with GraphPad Prism.
  • the graph represents the fitted curves, where each dot indicates the mean value ⁇ SD of at least three independent experiments, each conducted in triplicate.
  • FIG. 24C shows a colony formation assay for LNCaP cells (top) and C4-2 cells (bottom) treated with dimethylsulfoxide (DMSO), PROTAC SGI-1776-VHL-02, PROTAC PIM447-VHL-01, small-molecule SGI-1776, or small-molecule PIM447 at the indicated concentration for 10 days with media and inhibitors replaced every 96 h.
  • DMSO dimethylsulfoxide
  • FIGs. 24D and 24E are graphs showing the effect on PC3 tumor growth in vivo exhibited by PIM inhibitor, AZD-1208, and PIM kinase PROTAC SGI-1776-VHL-02 (FIG. 24D) and PROTAC PIM447-VHL-01 (FIG. 24E).
  • PIM targeted PROTACs of the present invention are found to be superior to PIM catalytic inhibitors for promoting cancer cell death and chemo-sensitization. It was discovered that inhibition of PIM activity can promote intrinsic resistance to PIM inhibitors through stabilization of the PIM kinases, and the use of PROTACs to target PIM kinases for degradation can target PIM-mediated oncogenic functions.
  • X 1 is a residue with an affinity for a Proviral Integration site for Moloney murine leukemia virus (PIM) kinase;
  • PIM Moloney murine leukemia virus
  • L is a linker
  • X 2 is a residue with an affinity for a ubiquitin ligase
  • X 1 is a monovalent residue of a PIM inhibitor (e.g., a small molecule PIM inhibitor with an open valency for bonding to linker L), such as SGI- 1776, AZD-1208, or PTM-447.
  • a PIM inhibitor e.g., a small molecule PIM inhibitor with an open valency for bonding to linker L
  • SGI- 1776, AZD-1208, or PTM-447 such as SGI- 1776, AZD-1208, or PTM-447.
  • X 1 can be
  • VHL von Hippel-Lindau
  • CRBN Cereblon
  • Cullin 4-Ring ubiquitin ligase or a monovalent residue targeting the
  • X 2 can be [0062]
  • linker L has a structure of formula (II) -x 3 -x 5 -x 4 -
  • X 5 is an alkylenyl, alk lenyloxy, phenyl, pyridinyl, pyrazinyl, heterocycloalkyl, or a combination thereof, each of which is optionally substituted.
  • X 5 can be alkylenyl, alkylenyloxy, phenyl, pyridinyl, pyrazinyl, heterocycloalkyl (e.g., N-containing heterocycloalkyl), a combination of alky lenyl and alkylenyloxy, a combination of alkylenyl and phenyl, a combination of alkylenyloxy and pyridinyl, a combination of alkylenyloxy and pyrazinyl, a combination of alkylenyloxy and phenyl, a combination of alkylenyloxy and pyridinyl, a combination of alkylenyloxy and pyrazinyl, a combination of alkylenyl and heterocycloalkyl (e.g., N-containing heterocycloalkyl), a combination of alkylenyloxy and heterocycloalkyl (e.g., N-
  • the linker L can have a structure of formula (Ila)
  • R 1 , R 2 , R 3 , R 4 , and R 5 are the same or different and each is H, alkyl, or OH; m is 0 or an integer of 1 to 20; n is 0 or 1 ; p is 0 or an integer of 2 to 20; and provided that m and p are not both 0.
  • X 3 and X 4 are each a bond, and m is 0.
  • R 3 and R 4 can each be H, and R 5 can be H when present.
  • R 5 is absent.
  • R 5 is present.
  • R 3 and R 4 are each H, n is 0, and p is 2-8 (i.e., 2, 3, 4,
  • R 1 and R 2 can each be H or alkyl.
  • m is 3-8 (i.e., 3, 4, 5,
  • the linker L has a structure of formula (lib)
  • X 6 and X 7 are the same or different and each is C or N;
  • X 8 is a bond, optionally substituted phenyl, or optionally substituted heterocycloalkyl
  • R 6 is alkyl, OH, alkoxy, amino, alkylamino, halo, cyano, or nitro; and q is 0 or an integer of I to 4.
  • the linker L has a structure of formula (Tib) that is
  • X 6 and X 7 are both C. In other aspects, one of
  • X 6 and X 7 is N and the other is C.
  • An exemplary compound of formula (I) is selected from
  • the compound of formula (I) is SGI-1776-VHL-02 or PIM447-VHL-01, more preferably SGI-1776-VHL-02.
  • alkyl implies a straight-chain or branched alkyl substituent containing, for example, from about 1 to about 8 carbon atoms, e.g., from about 1 to about 6 carbon atoms, or from about 1 to about 4 carbon atoms.
  • alky l groups include methyl, ethyl, w-propyl, isopropyl, «-butyl, sec-butyl, isobutyl, tert-butyl, n- pentyl, isopentyl, w-hexyl, and the like.
  • alkyl occurs as part of a group, such as, e.g., in Cs-Ce cycloalkylalkyl, hydroxyalkyl, haloalkyl (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl), cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, alkylammoalkyl, dialkylaminoalkyl, alkylcarbonyl (-C(O)alkyl), alkylcarboxy (-C(O)Oalkyl), arylalkyl, heteroarylalkyl, etc.
  • haloalkyl e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl
  • cyanoalkyl aminoalkyl, alkylamino, dialkylamino, alkylammoalkyl, dialkylaminoalkyl, alkylcarbonyl (-C
  • alkyl can be substituted or unsubstituted, as described herein.
  • An alky lenyl is a divalent alkyl (e.g., -(CH2)m-), in which the alkyl group can be substituted or unsubstituted as described herein.
  • heterocycloalkyl means a stable, saturated, or partially unsaturated monocyclic, bicyclic, or spiro ring system containing 3 to 7 ring members of carbon atoms and other atoms selected from nitrogen, sulfur, and/or oxygen.
  • a heterocycloalkyl is a 5, 6, or 7-membered monocyclic ring and contains one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the heterocycloalkyl is a 5- or 6-membered monocyclic ring that contains one or two nitrogen atoms.
  • the heterocycloalkyl may be attached to the parent structure through a carbon atom or through any heteroatom (e g., N) of the heterocycloalkyl that results in a stable structure.
  • heterocycloalkyl rings are isoxazolyl, thiazolinyl, imidazolidinyl, piperazinyl, homopiperazinyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyranyl, piperidinyl, oxazolyl, and morpholinyl.
  • the heterocycloalkyl is an N-containing heterocycloalkyl, such as piperidinyl, piperazinyl, pyrollyl, pyrrolinyl, pyrzaolyl, pyranyl, or morpholinyl.
  • the heterocycloalkyl can be substituted or unsubstituted, as described herein.
  • the term “hydroxy” refers to the group -OH.
  • cyano refers to the group -CN
  • thiocyano refers to -SCN
  • nitro refers to the group -NO2.
  • alkoxy and alkylenyloxy refer to linear or branched alkyl and alkylenyl groups, respectively, that are attached to a divalent oxygen.
  • the alkyl and alkylenyl groups are the same as described herein.
  • halo refers to a halogen selected from fluorine, chlorine, bromine, and iodine.
  • amino refers to the group -NH2.
  • alkylamino refers to an amino with one or two alkyl substituents -NHR, in which alkyl groups in the ammo are the same or different and each is a substituted or unsubstituted alkyl group, as described herein.
  • carboxylato refers to the group -C(O)OH.
  • the term “amido” refers to the group -C(O)NRR', in which R and R’ are the same or different and each is hydrogen or a substituted or unsubstituted alkyl group, as described herein.
  • heteroaryl refers to aromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, or 11 to 14 membered tricyclic groups which have at least one heteroatom (O, S, or N) in at least one of the rings.
  • Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom.
  • the fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated.
  • the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quatemized.
  • Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic.
  • the heteroaryl group may be attached at any available nitrogen or carbon atom of any ring.
  • heteroaryl groups are pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl, triazinyl, imidazolyl, (1,2,3)- and (l,2,4)-triazolyl, pyrazinyl, tetrazolyl, furyl, pyrrolyl, thienyl, isothiazolyl, thiazolyl, isoxazolyl, and oxadiazolyl.
  • the heteroaryl can be substituted or unsubstituted, as described herein.
  • any substituent that is not hydrogen can be an optionally substituted moiety.
  • the substituted moiety typically comprises at least one substituent (e.g., 1, 2, 3, 4, 5, 6, etc.) in any suitable position (e g , 1-, 2-, 3-, 4-, 5-, or 6-position, etc ).
  • the substituent is at least one (e.g., 1 or 2) alkyl, hydroxy, halo, and/or haloalkyl.
  • a range of 1-8 carbon atoms e.g., Ci-Cs
  • 1- 6 carbon atoms e.g., Ci-Ce
  • 1-4 carbon atoms e.g., C1-C4
  • 1-3 carbon atoms e.g., C1-C3
  • 2-8 carbon atoms e.g., C2-C8
  • any chemical group e.g., alkyl, heterocycloalkyl, etc.
  • any sub-range thereof e.g., 1 -2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms
  • the subscript “m” represents the number of alklylenyl repeat units in formula (Ila).
  • the subscript m is 0 (i.e., absent from formula (Ila)) or an integer of 1-20 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • m is 2-8 or 3-7, or 4- 6, or 5.
  • the subscript “n” represents the number of methylenyl repeat units in formula (ITa).
  • the subscript n is 0 (i.e., absent from formula (TTa)) or an integer of 1 (forming a propylenyloxy moiety).
  • n is 0 to form an ethylenyloxy (polyethylene glycol) moiety.
  • the subscript “p” represents the number of alkylenyloxy repeat units in formula (Ila).
  • the subscript p is 0 (i.e., absent from formula (Ila)) or an integer of 2-20 (i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • p is 2-10 or 3-9, or 4-8.
  • the subscript “q” represents the number of substituents on the phenyl, pyridinyl, or pyrazinyl ring in formula (lib).
  • q is 0 (i.e., the phenyl, pyridinyl, or pyrazinyl nng is unsubstituted) or an integer of 1-4 (i.e., I, 2, 3, or 4). In some preferred aspects, q is 0.
  • some aspects of the compound of formula (I) can be in the form of a pharmaceutically acceptable salt.
  • the phrase “salt” or “pharmaceutically acceptable salt” is intended to include nontoxic salts synthesized by conventional chemical methods from the parent compound, and which contain a basic or acidic moiety. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • an inorganic acid e.g., hydrochlonc acid, sulfuric acid, phosphoric acid, or hydrobromic acid
  • an organic acid e.g., oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, or benzylsulfonic acid
  • an inorganic base e g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or ammonium hydroxide
  • an organic base e.g., methylamine, diethylamine, tri ethyl amine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, guanidine, choline, or cinchonine
  • an amino acid e.g., lysine, arginine, or alanine
  • nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical.
  • suitable salts are found in Remington: The Science and Practice of Pharmacy , 21st Edition, Lippincott Williams & Wilkins, Philadelphia, PA (2001), and Berge et al., Journal of Pharmaceutical Science, 66(1): 1-19 (1977).
  • they can be a salt of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or an ammonium salt.
  • Components of the compounds described herein can be purchased commercially or synthetically prepared. General methods for preparing a PROTAC compound formula (T) of the invention are described herein.
  • a pharmaceutical composition comprises at least one compound of formula (I) and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable excipients described herein for example, vehicles, adjuvants, carriers or diluents, are well- known to those who are skilled in the art and are readily available.
  • the pharmaceutically acceptable carrier is one that is chemically inert to the active compounds and one that has no detrimental side effects or toxicity under the conditions of use.
  • the pharmaceutical compositions can be administered as oral, sublingual, transdermal, subcutaneous, topical, absorption through epithelial or mucocutaneous linings, intravenous, intranasal, intraarterial, intraperitoneal, intramuscular, intratumoral, peritumoral, intraperitoneal, intrathecal, rectal, vaginal, or aerosol formulations.
  • the pharmaceutical composition is administered orally or intravenously.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice and include an additive, such as cyclodextrin (e.g., a-, P-, or y-cyclodextrin, hydroxypropyl cyclodextrin) or polyethylene glycol (e.g., PEG400); (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions and gels.
  • diluents such as water, saline, or orange juice
  • an additive such as cyclodextrin (e.g., a-, P-, or y-cyclodextrin, hydroxypropyl cyclodextr
  • Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, com starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound of formula (I) or a salt thereof can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose,
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, com, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatly amine oxides, fatty acid alkanolamides, and poly oxy ethylene-polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and mixtures thereof.
  • the parenteral formulations will typically contain from about 0.5 to about 25% by weight of the inhibitors in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-lipophile balance
  • parenteral formulations can be presented in unit-dose or multidose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • a compound of formula (I) can be made into injectable formulations.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Banker, Gilbert S., and Robert K. Chalmers.
  • Topically applied compositions are generally in the form of liquids (e.g., mouthwash), creams, pastes, lotions and gels.
  • Topical administration includes application to the oral mucosa, which includes the oral cavity, oral epithelium, palate, gingival, and the nasal mucosa.
  • the composition contains at least one active component and a suitable vehicle or carrier. It may also contain other components, such as an anti-irritant.
  • the carrier can be a liquid, solid or semi-solid.
  • the composition is an aqueous solution, such as a mouthwash.
  • the composition can be a dispersion, emulsion, gel, lotion or cream vehicle for the various components.
  • the primary vehicle is water or a biocompatible solvent that is substantially neutral or that has been rendered substantially neutral.
  • the liquid vehicle can include other materials, such as buffers, alcohols, glycerin, and mineral oils with various emulsifiers or dispersing agents as known in the art to obtain the desired pH, consistency and viscosity. It is possible that the compositions can be produced as solids, such as powders or granules. The solids can be applied directly or dissolved in water or a biocompatible solvent prior to use to form a solution that is substantially neutral or that has been rendered substantially neutral and that can then be applied to the target site.
  • the vehicle for topical application to the skin can include water, buffered solutions, various alcohols, glycols such as glycerin, lipid materials such as fatty acids, mineral oils, phosphoglycerides, collagen, gelatin and silicone based materials.
  • the compound of formula (I), alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
  • the dose administered to the subject, particularly human and other mammals, in accordance with the present invention should be sufficient to affect the desired response.
  • dosage will depend upon a variety of factors, including the age, condition or disease state, predisposition to disease, genetic defect or defects, and body weight of the mammal.
  • the size of the dose will also be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular inhibitor and the desired effect. It will be appreciated by one of skill in the art that various conditions or disease states may require prolonged treatment involving multiple administrations.
  • the inventive methods comprise administering an effective amount of a compound of formula (I) (i.e., a compound of formula (I) for use in treating cancer in a mammal).
  • An “effective amount” means an amount sufficient to show a meaningful benefit in an individual, e.g., promoting at least one aspect of tumor cell cytotoxicity (e.g., inducing apoptosis, inhibition of growth, inhibiting survival of a cancer cell, reducing proliferation, reducing size and/or mass of a tumor (e.g., solid tumor)), or treatment, healing, prevention, delay of onset, halting, or amelioration of other relevant medical condition(s) associated with a particular cancer.
  • tumor cell cytotoxicity e.g., inducing apoptosis, inhibition of growth, inhibiting survival of a cancer cell, reducing proliferation, reducing size and/or mass of a tumor (e.g., solid tumor)
  • the meaningful benefit observed in the subject can be to any suitable degree (10, 20, 30, 40, 50, 60, 70, 80, 90% or more) relative to the state of the subject/tissue/cell prior to the inventive method or use.
  • one or more symptoms of the cancer are prevented, reduced, halted, or eliminated subsequent to administration of a compound of formula (I), thereby effectively treating the cancer to at least some degree.
  • Effective amounts may vary depending upon the biological effect desired in the individual, condition to be treated, and/or the specific characteristics of the compound of formula (I), and the individual.
  • any suitable dose of the compound of formula (I) can be administered to the subject (e.g., human), according to the type of cancer to be treated.
  • the dose of the compound of formula (I) desirably comprises about 0.01 mg per kilogram (kg) of the body weight of the subject (mg/kg) or more (e.g., about 0.05 mg/kg or more, about 0.1 mg/kg or more, about 0.5 mg/kg or more, about 1 mg/kg or more, about 2 mg/kg or more, about 5 mg/kg or more, about 10 mg/kg or more, about 15 mg/kg or more, about 20 mg/kg or more, about 30 mg/kg or more, about 40 mg/kg or more, about 50 mg/kg or more, about 75 mg/kg or more, about 100 mg/kg or more, about 125 mg/kg or more, about 150 mg/kg or more, about 175 mg/kg or more, about 200 mg/kg or more, about 225 mg/kg or more, about 250 mg/kg or more, about 275 mg/kg or more, about 300 mg/kg or more, about 325 mg/kg or more, about 350 mg/kg or more, about 375 mg/kg or more,
  • the dose will be about 500 mg/kg or less (e.g., about 475 mg/kg or less, about 450 mg/kg or less, about 425 mg/kg or less, about 400 mg/kg or less, about 375 mg/kg or less, about 350 mg/kg or less, about 325 mg/kg or less, about 300 mg/kg or less, about 275 mg/kg or less, about 250 mg/kg or less, about 225 mg/kg or less, about 200 mg/kg or less, about 175 mg/kg or less, about 150 mg/kg or less, about 125 mg/kg or less, about 100 mg/kg or less, about 75 mg/kg or less, about 50 mg/kg or less, about 40 mg/kg or less, about 30 mg/kg or less, about 20 mg/kg or less, about 15 mg/kg or less, about 10 mg/kg or less, about 5 mg/kg or less, about 2 mg/kg or less, about 1 mg/kg or less, about 0.5 mg/kg or less, or about 0.1 mg/kg or less, about
  • the PIM kinases are serine/threonine kinases that include three different isoforms, PIM1, PIM2, and PIM3.
  • the PIM kinases phosphorylate a wide range of substrates that control tumorigenic phenotypes, including proliferation and cell survival. Activation of the PIM kinases can promote cancer progression and resistance to chemotherapy.
  • preclinical studies indicate that pharmacological inhibition of PIM has the potential to improve the efficacy of both chemotherapies and precision medicines.
  • the compound of formula (I) degrades one or more PIM kinases (e.g., PIM1, PIM2, and/or PIM3). In an aspect, the compound of formula (I) degrades at least PIM1.
  • the compound of formula (I) selectively degrades PIM1 relative to PIM2 and/or PIM3.
  • the compound of formula (I) can be at least 2 times (e g , at least 4 times, at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, or at least 100 times) more selective for PIM1 compared to one or more other PIM kinases.
  • PIM PROTAC of formula (I) effectively down- modulates PIM levels through the ubiquitin-proteasome pathway. Degradation of PIM kinases is more potent than inhibition of catalytic activity in inducing cell apoptosis in a prostate cancer cell line model.
  • the present invention is directed to a method of treating cancer in a mammal comprising administering to the mammal an effective amount of a compound of formula (I) (i.e., a compound of formula (I) for use in treating cancer in a mammal), wherein the cancer comprises cancer cells that overexpress Proviral Integration for the Moloney murine leukemia virus (PIM) kinase relative to non-cancerous cells of the same tissue type.
  • PIM Moloney murine leukemia virus
  • Anti-cancer activity can be measured by any suitable method, including the assays described herein.
  • the cancer comprises cancer cells that overexpress PIM1, and the compound of formula (I) selectively degrades PIM1.
  • targeting PIM kinases for degradation offers superior efficacy over inhibition, since the degradation of PIM kinases down-regulates both activity-dependent and -independent mechanisms of tumorigenesis.
  • cancers including cancerous cells and tissue, of the head and neck, eye, skin, mouth, throat, esophagus, chest, bone (e.g., bone marrow), blood, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart, or adrenals.
  • bone e.g., bone marrow
  • cancers include solid tumor, sarcoma, carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelio sarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,
  • the cancer is prostate cancer, breast cancer, colon cancer, endometrial cancer, gastric cancer, acute myeloid leukemia, or pancreatic cancer.
  • the cancer is prostate cancer.
  • the cancer is acute myeloid leukemia.
  • the compound of formula (I) is co-administered with an anti-cancer agent (e.g., a chemotherapeutic agent) and/or radiation therapy.
  • the method or use comprises administering an amount of a compound of formula (I) that is effective to sensitize the cancer cells to one or more therapeutic regimens (e.g., chemotherapy or radiation therapy).
  • the co-administration of an anti-cancer agent and a compound of formula (I) provides a synergistic effect with respect to the apoptotic capacity of the anti-cancer agent on its own.
  • co-administered” or “co-administration” used herein refer to simultaneous or sequential administration.
  • a compound of formula (I) can be administered before. concurrently with, or after administration of another anti-cancer agent (e.g., a chemotherapeutic agent).
  • One or more than one, e.g., two, three, or more anti-cancer agents can be administered.
  • the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a combination of the compound of formula (I) and at least one (e.g., 1, 2, or 3, etc.) anti-cancer agent (e.g., chemotherapeutic agent).
  • anti-cancer agents include platinum compounds (e.g., cisplatin, carboplatin, and oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, and bendamustine), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mitomycin C, plicamycin, and dactinomycin), taxanes (e.g., paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, pemetrexed, thioguanine, floxuridine, capecita
  • the term “subject” preferably is directed to a mammal.
  • Mammals include, but are not limited to, the order Rodentia, such as mice, and the order Lagomorpha, such as rabbits. It is preferred that the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals are from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perissodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Cebids, or Simioids (monkeys) or of the order Anthropoids (humans and apes). An especially preferred mammal is a human.
  • Flash chromatography was performed by using a REDISEPTM Rf NP-silica (40-63 pm 60 A) or a REDISEPTM Rf Gold RP-C18 column (20-40 pm 100 A) in a COMBIFLASHTM Rf 200 purification system unless otherwise specified (Teledyne ISCO, Thousand Oaks, CA).
  • X H NMR spectra were recorded on an Agilent 400 MHz spectrometer and are reported in parts per million (ppm) on the 8 scale relative to CDCh (8 7.26) and deurated dimethylsulfoxide (DMSO-tL) (8 2.50) as internal standards (Agilent, Santa Clara, CA).
  • AZD1208 (cat HY-15604), PIM447 (cat. HY-19322), SGI-1776 (cat. HY-13287), and MG-132 (cat. HY-13259) were obtained from MedChemExpress (Monmouth Junction, NJ). Cycloheximide (cat. C7698) and doxycycline (cat. D3072) were obtained from Millipore-Sigma. Docetaxel (Hikma Pharmaceuticals USA Inc.; NDC: 00143-9204-01) was obtained from the National Institutes of Health Division of Veterinary Resources Pharmacy.
  • HA-PIM1 and HA-PIM1-K67M were gifts from Dr. Andrew S Kraft (University of Arizona). Cells were transfected with JETPRIMETM (Polyplus Transfections, France) according to the manufacturer’s protocol.
  • HATU [bis(di methyl ami no)metbylene]-l H-l ,2,3-triazo1o[4,5-b]pyridimum 3-oxide hexafluorophosphate
  • DIPEA ALV-diisopropylethylamine
  • This example demonstrates a synthesis of an SGI- 1776-based PROTAC of formula (I) in an aspect of the invention.
  • This example demonstrates a synthesis of an SGI- 1776-based PROTAC of formula (I) in an aspect of the invention.
  • the crude SGI-1776-IAP-Boc amine was subjected to 1 mL CH2CI2/TFA (1: 1) and stirred for 1 hour (monitored by LC-MS).
  • the solvent and TFA were removed under reduced pressure and the crude material was purified by a preparatory HPLC with an XBridge BEH C18 OBD Prep Column, 130 , 5 pm, 30 mm X 150 mm reversed-phase column as the stationary phase (Waters, Milford, MA).
  • This example demonstrates a synthesis of an SGI- 1776-based PROTAC of formula (I) in an aspect of the invention.
  • SGI-1776-VHL-02-epimer was synthesized using the same reaction procedure as SGI-1776-VHL-02 (Example 4).
  • Starting materials S7 (30 mg, 0.06 mmol), E3 ligase ligand 1 -epimer (34 mg, 0.06 mmol) and DIPEA (35 pL, 0. 18 mmol) were used.
  • the reaction mixture was then stirred for 2 hours (monitored by LC-MS), and the crude material was purified by a preparatory HPLC with an XBridge BEH C18 OBD Prep Column, 130A, 5 pm, 30 mm X 150 mm reversed-phase column as the stationary phase (Waters, Milford, MA).
  • This example demonstrates a synthesis of an AZD-1208-based PROTACs of formula (I) in an aspect of the invention.
  • E3 ligase Ligand 1 (3 g, 6.24 mmol) and di-A-succinimidyl suberate S8 (2.8 g, 7.5 mmol) in CH2CI2 (30 mL) were added to Et>N (2 mL, 13.72 mmol). The suspension was stirred overnight, then concentrated under reduced pressure. The residue was subjected to flash chromatography (CH2Ch/MeOH) to yield 2.3 g (53% yield) of the desired product S9 as a colorless glassy residue. See FIG. 8.
  • A-hydroxysuccinimide (NHS) ester S9 (66 mg, 0.09 mmol) and AZD1208 (36 mg, 0.09 mmol) in CH2CI2 (2 mL) were added to ELN (16 pL, 13.72 mmol) at room temperature under argon atmosphere. The reaction mixture was then stirred overnight, quenched with aqueous NaHCOs solution, extracted with CH2CI2 and dried (N ⁇ SCE). After concentration, the crude product was purified by a COMBIFLASHTM (Teledyne ISCO, Thousand Oaks, CA) silica gel column (CEhCh/MeOH) to provide AZD1208-VHL-01 (46 mg, 52% yield). See FIG. 9.
  • PIM447-VHL-01 PROTAC was synthesized using the same method as SGI-1776-
  • VHL-01 (Example 1). Starting materials S9 (41 mg, 0.06 mmol), PIM447 (30 mg, 0.06 mmol) and EhN (35 pL, 0.24 mmol) were used to provide PIM447-VHL-01 (37 mg, 61%). See FIG. 10.
  • NHS ester S9-epimer was synthesized using the same reaction procedure as S9 (Example 6). Starting materials E3 ligase Ligand 1 -epimer (200 mg, 0.52 mmol), S8 (574 mg, 1.56 mmol) and EtsN (150 pL, 1.06 mmol) were used to provide S9-epimer (235 mg, 65%). See FIG. 11.
  • PIM447-VHL-01 (Example 7). Starting materials S9-epimer (41 mg, 0.06 mmol), PIM447 (30 mg, 0.06 mmol) and EhN (35 pL, 0.24 mmol) were used. See FIG. 12.
  • PC3, LNCaP, or C4-2 cells were treated with DMSO, 3
  • whole-cell extracts were prepared by lysing the cells on ice using radioimmunoprecipitation assay (RIP A) lysis buffer (Sigma- Aldrich, cat. R0278, St. Louis, MO) with the addition of ethylenediaminetetraacetic acid (EDTA) free protease inhibitors (Roche, cat. 05 056 489 001, Switzerland) and phosphatase inhibitor cocktail 2 and 3 (Sigma-Aldrich, cat. P2850 and P5726, St. Louis, MO). Lysates were cleared (12,500 x .
  • RIP A radioimmunoprecipitation assay
  • lysis buffer Sigma- Aldrich, cat. R0278, St. Louis, MO
  • EDTA ethylenediaminetetraacetic acid
  • phosphatase inhibitor cocktail 2 and 3 Sigma-Aldrich, cat. P2850 and P5726, St. Louis, MO
  • RRID:AB_2299591 PIM2 (D1D2) (#4730, 1 : 1000; RRID:AB_2163921), PIM3 (D17C9) (#4165, 1 :1000), p-IRSl SI 101 (#2385, 1:500; RRID:AB_330363), ubiquitin (#3933, 1 :2000; RRID:AB_2180538), HA (C29F4) (#3724, 1 :2000; RRID:AB_1549585), and p-actin (8H10D10) (#3700, 1 :5000; RRID:AB_2242334) were purchased from Cell Signaling Technology (Danvers, MA).
  • HRP Horseradish peroxidate
  • PIM kinase inhibitors increased the levels of all three PIM isoforms (FIGs. 13B and 13C). Despite increased PIM kinase expression, signaling downstream of PIM kinases remained reduced after inhibition, as assessed by phosphorylation of the PIM substrates IRS-1 and BAD.
  • ubiquitination assays were conducted, based on the following procedure.
  • HA-PIM1 -transfected PC3 cells were incubated with DMSO or the PIM-inhibitor PIM447 (3 pM) 30 min prior to treatment with MG-132 (10 pM) for 0.5h, Ih, 2h, or 4h, and PIM1 immunoprecipitated (FIG. 14A).
  • PIM1 ubiquitination was evaluated by immunoblot on the immunoprecipitation fractions.
  • PIM1 ubiquitination was significantly reduced by approximately 3 -fold in the presence of the ATP-competitive inhibitor, indicating PIM catalytic activity is critical for promoting PIM ubiquitination (FIG. 14B).
  • PC3 cells were transfected with HA-tagged PIM1. Cells were then treated with PIM447 or DMSO prior to MG-132 addition for the indicated times. Cells were harvested in IP lysis buffer (20 mM Tris HC1 pH 8, 137 mM NaCl, 10% glycerol, 1% Nonidet P-40, and 2 mM EDTA) with protease inhibitors. Lysates were incubated overnight at 4 °C with HA magnetic beads (Pierce Biotechnology. Waltham, MA, USA, cat. 88836; RRID:AB_2749815) and subjected to immunoblotting.
  • IP lysis buffer (20 mM Tris HC1 pH 8, 137 mM NaCl, 10% glycerol, 1% Nonidet P-40, and 2 mM EDTA
  • Lysates were incubated overnight at 4 °C with HA magnetic beads (Pierce Biotechnology. Waltham, MA, USA, cat. 88836; RRID:AB_
  • PIM1 degradation kinetics were evaluated by conducting cycloheximide (CHX) chase experiments to prevent PIM1 translation.
  • PC3 cells transfected with wild-type (WT) or kinase-dead (K67M) HA-PIM were treated with cycloheximide (CHX, 10 pM) with or without AZD1208 (3 pM) for Oh, 0.5h, Ih, 2h, 3h, or 4h, and cells collected to evaluate PIM1 degradation by immunoblot according to the following procedure (FIG. 15 A). Where indicated, cells were pre-treated with AZDI 208 (concentration, time) before incubating with CHX. A half-life for wild-type PIM1 in PC3 cells of approximately 1.1 hours was determined, whereas the half-life of a kinase-dead mutant (PIM1 K67M) increased to more than 4 hours (FIG. 15B).
  • PC3 cells were transfected with HA- PIM1 or HA PIM1 (K67M) or a control vector. The following day, cells were treated with 10 pM cycloheximide with or without PIM447 and lysates were harvested at the stated timepoints. Immunoblotting was performed as described above.
  • PIM1 degradation kinetics were evaluated by conducting cycloheximide (CHX) chase experiments to prevent PIM1 translation.
  • PC3 were pre-incubated with dimethylsulfoxide (DMSO) or PIM447 (3 pM) 30 min prior to treatment with cycloheximide (CHX, 10 pM) for Oh, Ih, 2h, or 4h. Lysates were collected to evaluate P1M1 degradation and PIM1 inhibition was assessed as reduced IRS-Serl 101 phosphorylation.
  • the immunoblot results are set forth in FIG. 16A. Using the results set forth in FIG. 16A, PIM1 levels were calculated using the PIM1 /Actin ratio for each condition, and the results are set forth in FIG. 16B.
  • PC3 cells transfected with wild-type (WT) or kinase-dead (K67M) HA- PIM1 were pretreated with PIM447 (3 pM) 30 min prior to treatment with cycloheximide (CHX, 10 pM) for Oh, Ih, 2h, or 4h. Lysates were collected to evaluate PIM1 degradation.
  • the immunoblot results are set forth in FIG. 16C.
  • PIM1 levels were calculated using the HA/ Actin ratio for each condition, and the results are set forth in FIG. 16D.
  • PC3-LN4 cells with PIM1 knocked out (KO) were reconstituted with wild-type (WT) or kinase-dead (K67M) PIM1. Twenty -four hours posttransfection, cells were reseeded and treated with increasing concentrations of docetaxel for 72 hours. Cell viability was evaluated by staining the cells with cry stal violet and quantified by measuring absorbance at 595 nm according to the following procedure.
  • PIM1 expression of transfected cells was evaluated by immunoblot (FIG. 17A). Overexpression of either wild-type or kinase-dead PIM1 reduced the sensitivity of PC3 cells to treatment with docetaxel, indicating that PIM1 has oncogenic functions that do not rely upon catalytic activity of the kinase (FIG. 17B). Overall, the results indicate that PIM1 promotes its auto-degradation, and that small-molecule mediated inhibition of its catalytic activity leads to PIM kinase stabilization. EXAMPLE 14
  • PC3 cells were transfected with either wild-type (WT) or kinase-dead (K67M) HA-PIM. Twenty -four hours post-transfection, cells were reseeded and treated with increasing concentrations of docetaxel for 72 hours. Cell viability was evaluated by staining the cells with crystal violet and quantified by measuring absorbance at 595 nm according to the following procedure.
  • WT wild-type
  • K67M kinase-dead
  • PIM1 expression of transfected cells was evaluated by immunoblot (FIG. ISA). Overexpression of either wild-type or kinase-dead PIM1 reduced the sensitivity of PC3 cells to treatment with docetaxel, indicating that PIM1 has oncogenic functions that do not rely upon catalytic activity of the kinase.
  • SCID mice severe combined immunodeficiency disease (SCID) mice were subcutaneously inoculated with the PC3 cells transfected with either wild-type (WT) or kinase-dead (K67M) HA-PIM, described above, and the tumor growth volume was monitored. The results are set forth in FIG. 18B.
  • WT wild-type
  • K67M kinase-dead
  • This example demonstrates the ability of a compound of formula (I) to degrade PIM1 in an aspect of the invention.
  • the efficacy of PROTACs of formula (I) to degrade PIM1 in PC3 cells expressing doxycycline-inducible PIM1 (PC3-dox-PIMl cells) was studied.
  • SGI-1776-VHL-01 (FIG. 19A) and SGI-1776-IAP-01 (FIG. 19B) caused PIM1 degradation in a dose-dependent manner, with maximal PIM1 degradation achieved at 0.75 M and 1.5 pM, respectively, with PIM1 degradation being reduced at PROTAC concentrations above 3.75 pM (FIGs. 19A- 19C).
  • SGI-1776-VHL-02 was prepared by replacing the 2- PEG linker with a suberoyl linker.
  • SGI-1776-VHL-02 efficiently triggered PIM1 degradation at concentrations of 0.75 pM, with no “hook-effect” observed up to concentrations of 10 pM (FIG. 20A).
  • the suberoyl linker was used to generate two additional PROTACs from the AZDI 208 and PIM447 inhibitors and couple them to the VHL ligand, yielding AZDI 208- VHL-01 and PIM447-VHL-01, respectively.
  • Treatment of PC3-dox-PIMl cells with AZD1208-VHL-01 triggered a dose-dependent reduction of PIM1 levels, with maximal degradation at 6.25 pM, while PIM447-VHL-01 effectively degraded PIM1 at all concentrations tested (0.75 - 10 pM), without the hook effect being observed (FIG. 20B). Therefore, SGI-1776-VHL-02 and PIM447-VHL-01 in this study were the most potent PROTACs generated in targeting PIM1 for degradation.
  • PIM1 degradation with SGI-1776-VHL-02 started after 1 h of treatment, was maximal at 4h post-treatment, and sustained up to 72 h after the addition of the PROTAC (FIG. 20G).
  • PIM447-VHL-01 displayed a similar PIM1 degradation kinetic, with maximal degradation at 2 h after addition of the compound and sustained for 48 h after addition of the PROTAC (FIG. 20H).
  • PIM1 expression began to recover at 72 h after the addition of PIM447-VHL-01.
  • SGI-1776-VHL-02 and PIM447-VHL-01 displayed similar behavior in degrading endogenous PIM1, with both PROTACs achieving maximal PIM1 degradation at 0.75 pM and no “hook effect” detected at the concentrations tested (0.75 - 10 pM) (FIGs. 21A and 21B).
  • VHL levels for downmodulated.
  • PC3 cells with VHL knocked down with RNAi 50 nM were treated 24 h post transfection with dimethylsulfoxide (DMSO), PROTAC SGI-1776-VHL-02 (1.5 pM), or PROTAC PIM447-VHL-01 (1.5 pM). After 24 h the cells were collected and PIM1 and VHL levels were evaluated and the results are set forth in FIG. 211.
  • DMSO dimethylsulfoxide
  • PROTAC SGI-1776-VHL-02 1.5 pM
  • PROTAC PIM447-VHL-01 1.5 pM
  • RNAi-mediated VHL knockdown in PC3 cells did not affect PIM1 levels, but it did prevent the degradation of PIM1 after treatment with both SGI-1776-VHL-02 and PIM447-VHL-01 .
  • SGI-1776 and PIM447 can target all three of the PIM kinase isoforms, although
  • SGI-1776 is more selective towards PIM1 (ICso is 50- and 10-fold higher for PIM2 and PIM3, respectively, versus PIM1) (Burger et al., J Med Chem, 58: 8373-8386 (2015); and Chen et al., Blood, 114: 4150-5157 (2009)).
  • SGI-1776-VHL-02 and PIM447-VHL-01 PROTACs of formula (I) were evaluated to determine if they will degrade PIM2 and PIM3. Following treatment of PC3 cells with doxycycline to induce PIM2 expression, no effect on PIM2 protein levels with any PROTAC was observed at the concentrations tested (0.75 - 10 pM) (FIGs. 22A and 22B).
  • SGI-1776-VHL-02 When evaluating long-term endogenous PIM2 and PIM3 degradation, SGI-1776-VHL-02 triggered PIM2 and PIM3 degradation at 3.75 pM (a 5-fold increased concentration in compared to PIM1) (FIG. 22C). PIM447-VHL-01 partially degraded PIM2 at 3.75 pM, although PIM2 degradation was prevented at higher concentrations (FIG. 22C). Treatment with PIM447-VHL-01 did not affect PIM3 levels (FIG. 22D). Combined, the results indicate that SGI-1776-VHL-02 has the potential to degrade the three PIM kinase isoforms, while PIM447-VHL-01 is a PIMl-specific PROTAC.
  • SGI-1776-VHL-02 and PIM447-VHL-01 PROTACs of formula (I) were evaluated to determine the effects on c-myc as a downstream target of PIM kinases.
  • PC3 and LNCaP cells were treated with dimethylsulfoxide (DMSO), PROTAC SGI-1776-VHL-02 (3.75 pM), PROTAC PIM447-VHL-01 (3.75 pM), small-molecule SGI- 1776 (3.75 pM), or small-molecule PIM447 (3.75 pM) for 24 h and the c-myc expression levels were measured.
  • DMSO dimethylsulfoxide
  • PROTAC SGI-1776-VHL-02 (3.75 pM
  • PROTAC PIM447-VHL-01 3.75 pM
  • small-molecule SGI- 1776 3.75 pM
  • small-molecule PIM447 3.75 pM
  • This example demonstrates the ability of a compound of formula (I) to inhibit the growth of PC3 cells and increase the apoptotic effect of docetaxel in an aspect of the invention.
  • PC3 cells were pre-treated with PROTAC compounds or inhibitors in equivalent doses for 4 hours, and then incubated with DMSO or docetaxel for additional 48 hours. After the treatment, cells were harvested and stained using the Annexin V-FITC apoptosis detection kit (cat. BMS500FI-100, Invitrogen; RRID:AB_2575598, Waltham, MA), according to the manufacturer’s instructions.
  • PC3 cells were seeded into 6-well plates (2000 cells/well) and treated with increasing concentrations of PROTAC compounds (SGI-1776- VHL-02 or PIM447-VHL-01) or inhibitors. Media containing fresh PROTAC compounds or inhibitors were replaced every 96 hours for a total of 14 days. Following the treatment, plates were washed with phosphate-buffered saline (PBS), fixed with 4% paraformaldehyde solution, and stained with crystal violet. Next, wells were thoroughly washed with water and air-dried. Pictures of the plates were taken with a Chemidoc (BioRad; RRID:SCR 019037, Hercules, CA).
  • PBS phosphate-buffered saline
  • PIM kinases One function of PIM kinases is to promote resistance to chemotherapy.
  • PROTACs directed against protein kinases downmodulate both catalytic-dependent and -independent mechanisms of action, as PROTACs trigger the degradation of their intended target.
  • the effect of inhibiting or degrading PIM kinases was tested in combination with sub-lethal doses of docetaxel to evaluate if degrading PIM kinases would have an increased synergistic effect compared to inhibition of catalytic activity to induce apoptotic cell death.
  • LNCaP and C4-2 prostate cancer cell lines Similar results were obtained for LNCaP and C4-2 prostate cancer cell lines.
  • LNCaP or C4-2 cells seeded (1.25 x 10 5 cells/well, 6-well plate) and pre-treated with docetaxel (2 nM, 4 h) 24 h after seeding where indicated, were treated with dimethylsulfoxide (DMSO), PROTAC SGI-1776-VHL-02, PROTAC PIM447-VHL-01, small-molecule SGI-1776, or small-molecule PIM447 for 48 hours and the relative cell viability results are set forth in FIGs. 23E-23H.
  • DMSO dimethylsulfoxide
  • This example demonstrates the impact of degrading PIM kinases on prostate cancer cell lines PC3, LNCaP, and C4-2, exhibited by treatment with PROTAC SGI-1776- VHL-02 or PROTAC PIM447-VHL-01 using an MTS assay.
  • FIG. 24A Three prostate cancer cell lines (i.e., PC3, LNCaP, and C4-2) treated with PROTAC SGI-1776-VHL-02 or PROTAC PIM447-VHL-01 for 72 h. Cell viability was evaluated in an MTS assay, and the IC50 calculated with GraphPad Prism. The results for SGL1776-VHL-02 and PTM447-VHL-01 are set forth in FTGs. 24A and 24B, respectively. [0207] As is apparent from the results set forth in FIG. 24A, SGI-1776-VHL-02 reduced cell viability in the three cell lines tested, with IC50s ranging from 1.0 to 1.6 pM, whereas FIG. 24B shows that PIM447-VHL-01 did not affect prostate cancer cell lines PC3, LNCaP, and C4-2.
  • LNCaP and C4-2 cells were seeded into 6-well plates (2000 cells/well) and treated with increasing concentrations of PROTAC compounds (SGI- 1776-VHL-02 or PIM447-VHL-01) or inhibitors. Media containing fresh PROTAC compounds or inhibitors were replaced every 96 hours for a total of 14 days. Following the treatment, plates were washed with phosphate-buffered saline (PBS), fixed with 4% paraformaldehyde solution, and stained with cry stal violet. Next, wells were thoroughly washed with water and air-dried.
  • PBS phosphate-buffered saline
  • NQO2 N-ribosyldihydronicotinamide:quinone reductase 2

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Abstract

L'invention concerne un composé de formule (I) X1-L-X2 (I), dans laquelle X1 est un résidu ayant une affinité pour un site d'intégration provirale pour la kinase du virus de la leucémie murine de Moloney (PIM) ; L est un lieur ; et X2 est un résidu ayant une affinité pour une ubiquitine ligase. L'invention concerne en outre une méthode de traitement du cancer chez un mammifère comprenant l'administration au mammifère d'une quantité efficace d'un composé de formule (I), le cancer comprenant des cellules cancéreuses surexprimant une kinase PIM par rapport à des cellules non cancéreuses du même type de tissu, comme le cancer de la prostate. [formule II]
PCT/US2023/022017 2022-05-13 2023-05-12 Protac ciblant pim ayant des fractions de liaison pim sgi-1776, azd-1208 ou pim-447 et une fraction de liaison à l'ubiquitine ligase e3 pour traiter le cancer Ceased WO2023220355A1 (fr)

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US20220096642A1 (en) * 2020-09-28 2022-03-31 Creighton University Compositions, use, and method for cdk2-protacs for cancer therapy and hearing loss
WO2022093809A1 (fr) * 2020-10-26 2022-05-05 Trustees Of Tufts College Amélioration de dégradation de protéines induite par hyt à l'aide de l'administration de nanoparticules lipidiques

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