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WO2025174721A1 - Inhibiteurs de vps4 - Google Patents

Inhibiteurs de vps4

Info

Publication number
WO2025174721A1
WO2025174721A1 PCT/US2025/015343 US2025015343W WO2025174721A1 WO 2025174721 A1 WO2025174721 A1 WO 2025174721A1 US 2025015343 W US2025015343 W US 2025015343W WO 2025174721 A1 WO2025174721 A1 WO 2025174721A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
compound
compound according
alkyl
halo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/015343
Other languages
English (en)
Inventor
Daniel CIZNADIJA
Daniel Chen
Bikash DEBNATH
Maxwell HILBERT
Sonam MEHROTRA
Abdul MONDAL
Michael Ritchie
Ralph Rivero
Kakajan KOMUROV
Randon V JONES
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Degage Gemechis
Champions Oncology Inc
Original Assignee
Degage Gemechis
Champions Oncology Inc
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Filing date
Publication date
Application filed by Degage Gemechis, Champions Oncology Inc filed Critical Degage Gemechis
Publication of WO2025174721A1 publication Critical patent/WO2025174721A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—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

Definitions

  • This invention relates to novel VPS4 inhibitors and uses thereof for treatment of cancers or solid or hematological tumors, which are characterized by the loss of VPS4A or VPS4B.
  • the vacuolar protein sorting 4 (VPS4) protein is a member of the AAA ATPase protein family associated with a variety of cellular activities. Many important cellular processes including DNA replication, nuclear-cytoplasmic transport, organelle biogenesis, vesicular trafficking, protein degradation, and oncogenic transformation rely on one or more members of the AAA ATPase subfamily.
  • VPS4A and VPS4B are selective genetic vulnerabilities for tumors harboring genomic loss of SMAD4 or CDH1 because of co-deletion of VPS4B or VPS4A, respectively.
  • Targeting VPS4A and/or VPS4B in cancer cells is considered an effective advance in the treatment of cancers.
  • the invention provides a compound represented by formula (I) wherein R 1 is aryl, heteroaryl, or C 3 -C 7 cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of C 1 -C 6 alkyl, halo, C 1 -C 3 haloalkyl, -ORa, - NR m R n , CN, and NO 2 ;
  • R 2 and R 3 are each independently H or C 1 -C 3 alkyl, or together with the carbon atom they are attached to form a C 3 -C 7 cycloalkyl group;
  • Y is 0, S, or NR b ;
  • R 4 is C 1 -C 6 alkyl, halo, C 1 -C 3 haloalkyl, -ORa, -NRcRd, CN, or NO 2 ;
  • Y is 0, S, or NRb; and Zis N.
  • the compound is represented by
  • the present invention provides a compound represented by formula (II) wherein
  • R 2 is substituted aryl or heteroaryl.
  • R1 is aryl, heteroaryl, or C 3 -C 7 cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of C 1 -C 6 alkyl, halo, C 1 -C 3 haloalkyl, -ORa, -NRmRn, CN, and NO 2 ;
  • R 2 is substituted aryl or heteroaryl.
  • the present invention provides a compound represented by formula (III)
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of the invention as described herein.
  • the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor.
  • the compound is a VPS4A inhibitor and/or a VPS4B inhibitor.
  • Figure 1A depicts that CHAMP-003 strongly induced the inflammatory cytokines IFN- ⁇ and CXCL10 in A549 NSCLC cells.
  • Figure IB depicts that CHAMP-002 weakly induced the inflammatory cytokine CXCL10 in A549 NSCLC cells.
  • Figure 2A depicts that CHAMP-003 potently induced the inflammatory cytokines IFN- ⁇ and CXCL10 in A549 NSCLC cells in the presence of pro-inflammatory DNA-damage.
  • Figure 2B depicts that CHAMP-002 had no effect on the secretion of inflammatory cytokines IFN- ⁇ and CXCL10 in A549 NSCLC cells in the presence of pro-inflammatory DNA- damage.
  • FIG. 3A depicts that treatment of A549 NSCLC cells with CHAMP-003 induced a transcriptomic profile associated with genetic knockdown of VPS4.
  • Figure 3B depicts that treatment of A549 NSCLC cells with CHAMP-002 weakly induced a transcriptomic profile associated with genetic knockdown of VPS4.
  • Figure 4A depicts that treatment of A549 NSCLC cells with CHAMP-003 induced a transcriptomic profile associated with chemical inhibition of VPS4.
  • Figure 4B depicts that treatment of A549 NSCLC cells with CHAMP-002 induced a transcriptomic profile associated with the chemical inhibition of VPS4.
  • Figure 5A depicts that treatment of A549 NSCLC cells with CHAMP-003 weakly induced a transcriptomic profile associated with activation of the pro-inflammatory interferon pathway.
  • Figure 5B depicts that treatment of A549 NSCLC cells with CHAMP-002 induced a transcriptomic profile associated with activation of the pro-inflammatory interferon pathway.
  • FIG. 6A depicts that CHAMP-003 potently induced interferon regulatory factor (IRF) activity in A549 NSCLC cells in the presence and absence of pro-inflammatory DNA- damage.
  • IRF interferon regulatory factor
  • FIG. 6B depicts that CHAMP-002 induced interferon regulatory factor (IRF) activity in A549 NSCLC cells in the presence and absence of pro-inflammatory DNA-damage.
  • Figure 7A depicts that CHAMP-003 had minimal effect on the short-term viability of A549 NSCLC cells in the presence or absence of pro-inflammatory DNA-damage.
  • FIG. 7B depicts that CHAMP-002 had minimal effect on the short-term viability of A549 NSCLC cells in the presence or absence of pro-inflammatory DNA-damage.
  • Figure 8B depicts that prolonged treatment of A549 NSCLC cells with CHAMP-002 strongly reduced cell viability.
  • Figure 9A depicts that prolonged treatment of A549 NSCLC cells with CHAMP-003 strongly reduced cell viability with low micromolar potency.
  • Figure 9B depicts that prolonged treatment of A549 NSCLC cells with CHAMP-002 strongly reduced cell viability with potentially moderate micromolar potency.
  • Figure 10A depicts that prolonged treatment of A549 NSCLC cells with CHAMP-003 strongly induced interferon regulatory factor (IRF) activity.
  • IRF interferon regulatory factor
  • Figure 10B depicts that prolonged treatment of A549 NSCLC cells with CHAMP-002 strongly induced interferon regulatoiy factor (IRF) activity.
  • IRF interferon regulatoiy factor
  • Figure 11A depicts that prolonged treatment of A549 NSCLC cells with CHAMP-003 strongly induced interferon regulatoiy factor (IRF) activity with potentially moderate micromolar potency.
  • Figure 11B depicts that prolonged treatment of A549 NSCLC cells with CHAMP-002 strongly induced interferon regulatory factor (IRF) activity with potentially high micromolar potency.
  • Figure 12B depicts that CHAMP-002 bound to and stabilized VPS4B protein, causing a large shift in its melting curve profile.
  • FIG. 13A depicts that CHAMP-003 bound to and stabilized VPS4B protein, causing a small increase in melting temperature (Tm).
  • FIG. 13B depicts that CHAMP-002 bound to and stabilized VPS4B protein, causing a large increase in melting temperature (T m ).
  • Figure 14 depicts that CHAMP-002 directly prevented the ATPase activity of VPS4B from being stimulated.
  • R 2 and R 3 are each independently H or C 1 -C 3 alkyl, or together with the carbon atom they are attached to form a C 3 -C 7 cycloalkyl group;
  • Ra, Rm, and Rn are each independently H or C 1 -C 3 alkyl
  • C 1 -C 3 alkyl, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl are each optionally substituted with one or more substituents selected from the group consisting of halo, NRmRn, CN, -ORa, -COORa, and -CONRmRn, or a pharmaceutically acceptable salt thereof.
  • R 1 is aryl. In some embodiments, R 1 is phenyl.
  • R 2 is H and R 3 is C 1 -C 3 alkyl. In some embodiments, R 2 is H and R 3 is methyl. In certain embodiments, R 2 is H and R 3 is ethyl, isopropyl, or n-propyl.
  • * represents S configuration
  • the compound of formula (I) is represented by formula (IA) wherein
  • R 1 is aryl or heteroaiyl, optionally substituted by one or more substituents selected from the group consisting of C 1 -C 6 alkyl, halo, C 1 -C 3 haloalkyl, -0R a , -NRmRn, CN, and NO 2 ;
  • Y is 0, S, or NRb
  • R 5 is C 1 -C 6 alkyl, halo, C 1 -C 3 haloalkyl, -0R a , -NRmRn, CN, and NO 2 ; and p is 0, 1, 2, 3, or 4.
  • R 5 is halo. In some embodiments, R 5 is F or Cl. In some embodiments, p is 0. In other embodiments, p is 1.
  • the compound of the invention is represented by
  • the present invention provides a compound represented by formula (II) wherein
  • R 1 is aryl, heteroaiyl, or C 3 -C 7 cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of C 1 -C 6 alkyl, halo, C 1 -C 3 haloalkyl, -ORa, -NRmRn, CN, and NO 2 ;
  • R 2 is substituted aryl or heteroaryl.
  • Examples of compounds with formula II include, but are not limited to:
  • R C 1 -C 6 alkyl, halo, C 1 -C 3 haloalkyl, -ORa, -NRmRn, CN, or NO 2 ; and substitution can be anywhere on the ring;
  • R 2 is substituted aryl or heteroaryl.
  • Example of compounds with formula IIA includes, but is not limited to:
  • the present invention provides a compound represented by formula (IIB) wherein R1 is aryl, heteroaryl, or C 3 -C 7 cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of C 1 -C 6 alkyl, halo, C 1 -C 3 haloalkyl, -ORa, -NRmRn, CN, and NO 2 ;
  • R 2 is substituted aryl or heteroaryl.
  • Example of compounds with formula IIB includes, but is not limited to:
  • the present invention provides a compound represented by formula (III)
  • the compound of the invention is a VPS4A inhibitor and/or a VPS4B inhibitor.
  • the compounds of the invention can be prepared based on the methods known in the art and the examples as described herein.
  • alkyl refers to a saturated hydrocarbon group which is straight-chained or branched.
  • Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g, n-propyl and isopropyl), butyl e.g, n-butyl, isobutyl, t- butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
  • An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, "heteroaryl" may be optionally substituted at any one or more positions capable of bearing a hydrogen atom.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF3, C2F5, CHF2, CCI3, CHCI2, C2CI5, and the like.
  • each of alkyl, aryl, and heteroaryl may be optionally substituted with independently selected groups such as alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxylic acid and derivatives thereof, including esters, amides, and nitrites, hydroxy, alkyloxy, acyloxy, amino, alky and dialkylamino, acylamino, thio, and the like, and combinations thereof.
  • substituents may be the same or different
  • Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, CN, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like.
  • any of amino, hydroxyl, CH, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.
  • the functional groups are the substituents described herein for any one of variables.
  • the groups in question may be the same or different Certain of the herein defined terms may occur more than once in the structure, and upon such occurrence each term shall be defined independently of the other.
  • the formulas also include any and all hydrates and/or solvates of the compound formulas. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and/or coordination compounds with water and/or various solvents, in the various physical forms of the compounds. Accordingly, the above formulas are to be understood to include and represent those various hydrates and/or solvates.
  • the phrase "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/ risk ratio.
  • the present invention also includes "pharmaceutically acceptable salts" of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the compound of the invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • Other pharmaceutically acceptable salts can include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and quaternary ammonium salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • the invention further includes derivatives of the compound of the invention.
  • derivatives includes but is not limited to ether derivatives, acid derivatives, amide derivatives, ester derivatives and the like.
  • the invention further includes metabolites of the compound of the invention.
  • metabolite means any substance produced from another substance by metabolism or a metabolic process.
  • the invention further includes prodrugs of the compound of the invention.
  • prodrug means a substance which can be converted in vivointo a biologically active agent by such reactions as hydrolysis, esterification, de-esterification, activation, salt formation and the like.
  • This invention further includes crystals of the compound of the invention. Further, this invention provides polymorphs of the compound of the invention.
  • crystal means a substance in a crystalline state.
  • polymorph refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point, and the like.
  • the compounds of the invention are used for treatment of cancer.
  • the cancer depends on VPS4A and/or VPS4B for survival.
  • the cancer is characterized by the loss of VPS4A or by the loss of VPS4B.
  • the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor.
  • the cancer is lung cancer.
  • the cancer is liver cancer.
  • the cancer is bladder cancer.
  • the cancer is breast cancer.
  • the compounds of the invention are used for treatment of a cancer that depends on VPS4A and/or VPS4B for survival.
  • the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor.
  • the cancer is lung cancer.
  • the cancer is liver cancer.
  • the cancer is bladder cancer.
  • the cancer is breast cancer.
  • the cancer is colorectal cancer.
  • the cancer is esophageal cancer.
  • the cancer is gastric cancer.
  • the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological tumor. In some embodiments, the cancer is bile duct cancer. In other embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is pediatric rhabdomyosarcoma. In some embodiments, the cancer is non-small cell lung cancer.
  • the present invention further provides a method for treating a cancer, which depends on VPS4A for survival, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention as described herein, or a pharmaceutically acceptable salt thereof.
  • the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor.
  • the cancer is lung cancer.
  • the cancer is liver cancer.
  • the cancer is bladder cancer.
  • the cancer is breast cancer.
  • the cancer is colorectal cancer.
  • the cancer is esophageal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological tumor. In some embodiments, the cancer is bile duct cancer. In other embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is pediatric rhabdomyosarcoma. In some embodiments, the cancer is non-small cell lung cancer.
  • the cancer is esophageal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological tumor. In some embodiments, the cancer is bile duct cancer. In other embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is pediatric rhabdomyosarcoma. In some embodiments, the cancer is non-small cell lung cancer.
  • the present invention further provides a method for treating a cancer, which depends on both VPS4A and VPS4B for survival, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention as described herein, or a pharmaceutically acceptable salt thereof.
  • the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor.
  • the cancer is lung cancer.
  • the cancer is liver cancer.
  • the cancer is bladder cancer.
  • the cancer is breast cancer.
  • the cancer is colorectal cancer.
  • the cancer that can be treated by the compound of the invention includes but is not limited to cancerous and precancerous conditions, including, for example, premalignant and malignant hyperproliferative diseases.
  • the compounds of the invention are used to prevent and/or treat premalignant conditions and to prevent progression to a neoplastic or malignant state, including but not limited to those disorders described above. Such uses are indicated in conditions known to precede or suspected of preceding progression to neoplasia or cancer.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a "therapeutically effective amount" as used herein refers to that amount which provides a therapeutic effect for a given indication and administration regimen.
  • the invention further provides a pharmaceutical composition comprising a compound of the invention as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for use in treating a cancer in a subject in need thereof.
  • the cancer depends on VPS4A and/or VPS4B for survival.
  • the cancer is characterized by the loss of VPS4A or by the loss of VPS4B.
  • the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor.
  • the cancer is bile duct cancer.
  • the cancer is rhabdomyosarcoma.
  • the cancer is pediatric rhabdomyosarcoma.
  • Methods of treatment using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient
  • a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught
  • a syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s).
  • a sugar for example sucrose
  • Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.
  • Parenteral administration may comprise any suitable form of systemic delivery.
  • Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal), etc., and may be carried out by infusion pumps (external or implantable) or any other suitable means appropriate to the desired administration modality.
  • a dosage unit can be prepared for oral dosage forms, such as tablets, capsules, pills, powders, liquid suspensions, and granules.
  • a compound of the invention is administered at a dosage of 1-3000 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 1-1000 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 1-500 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 10-500 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 25-500 mg per day.
  • the compound may be administered at a dosage between 0.2 to 30 mg/kg/day, or 0.2 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, 50 mg/kg/day or 100 mg/kg/day.
  • compositions and methods which are described herein in the context of separate aspects may also be provided in combination in a single aspect Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.
  • Substituted tetrahydro-lH-pyrazolo[3,4-b]quinoline-3,5(2H,6H)-dione analogs of structure III can be prepared by a 3-component condensation of an aldehyde, a 3-amino-l- substituted-lH-pyrazol-5-ol and a 1,3-dicarbonyl compound to form the tetrahydro-lH- pyrazolo[3,4-b]quinoline-3,5(2H,6H)-dione ring as illustrated below:
  • 5-Substituted-N-[lH-pyrazol-3-yl] carboxamide analogs of structure II can be prepared by condensation of a substituted lH-pyrazol-3-amine with an aryl carboxylic acid or carboxylic acid chloride, or with a suitable coupling agent to form the desired carboxamide compounds as illustrated below:
  • 3-substituted-N-(l,2-oxazol-5-yl) carboxamide analogs of structure lib can be prepared by condensation of a 3-substituted-l,2-oxazol-5-amines with an aryl carboxylic acid or carboxylic acid chloride, or with a suitable coupling agent to form the desired carboxamide compounds as illustrated below:
  • Substituted-3-amino indazole carboxamide analogs of structure lie can be prepared by condensation of a substituted-3-amino indazole with an aryl carboxylic acid or carboxylic acid chloride, or with a suitable coupling agent to form the desired carboxamide compounds as illustrated below:
  • Example 1A Effects on inflammatory cytokine CXCL10
  • A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 pM.
  • Double-stranded poly(deoxyadenylic-deoxythymidylic) (polydAdT) (polydAdT), a known stimulant triggering inflammation and the secretion of cytokines, was added at 100 ng/ml as an assay positive control. After treatment, cytokine levels were evaluated using a Luminex assay. The results depict fold changes in the levels of IFN- ⁇ and CXCL10 detected in the media relative to cells treated with the vehicle control, DMSO.
  • CHAMP-003 strongly induced the inflammatory cytokines IFN- ⁇ and CXCL10 in A549 NSCLC cells.
  • A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 pM.
  • Double-stranded poly(deoxyadenylic-deoxythymidylic) (polydAdT) (polydAdT), a known stimulant triggering inflammation and the secretion of cytokines, was added at 100 ng/ml as an assay positive control (not shown, off axes scale). After treatment, cytokine levels were evaluated using a Luminex assay. The results depict fold changes in the levels of IFN- ⁇ and CXCL10 detected in the media relative to cells treated with the vehicle control, DMSO. Results and Discussion
  • Example 2A Effects on the secretion of inflammatory cytokines IFN- ⁇ and CXCL10
  • A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10
  • Double-stranded poly(deoxyadenylic- deoxythymidylic) (polydAdT) was added at 100 ng/ml as an assay positive control.
  • cytokine levels were evaluated using a Luminex® assay. The results depict fold changes in the levels of IFN- ⁇ and CXCL10 detected in the media relative to cells treated with the vehicle control, DMSO.
  • CHAMP-003 potently induced the inflammatory cytokines IFN- ⁇ and CXCL10 in A549 NSCLC cells in the presence of pro-inflammatory DNA-damage (Figure 2A).
  • Example 2B Effects on the secretion of inflammatory cytokines IFN- ⁇ and CXCL10
  • A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 pM and the DNA-damaging chemotherapeutic doxorubicin at 0.5 pM.
  • Double-stranded poly(deoxyadenylic- deoxythymidylic) (polydAdT) was added at 100 ng/ml as an assay positive control (not shown, off axis scale).
  • polydAdT double-stranded poly(deoxyadenylic- deoxythymidylic)
  • cytokine levels were evaluated using a Luminex® assay. The results depict fold changes in the levels of IFN- ⁇ and CXCL10 detected in the media relative to cells treated with the vehicle control, DMSO.
  • Example 3B Treatment of A549 NSCLC cells with Compounds of Invention
  • A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 jiM.
  • the archetypal VPS4 inhibitor MSC 1094308 (Pohler, 2018) was added as a positive control, also at 10 iM.
  • cells were harvested, and poly-A RNA prepared.
  • Gene expression patterns were evaluated using RNASeq and correlated to the transcriptomic pattern in A549 cells in which both VPS4A and VPS4B had been knocked down using siRNA technology. The results depict rank- ordered Pearson's correlation coefficients for all test agents with the position of CHAMP- 002 shown.
  • A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 iM. After treatment, cells were harvested, and poly-A RNA prepared. Gene expression patterns were evaluated using RNASeq and correlated to the transcriptomic pattern in A549 cells treated with 10 pM of the published VPS4B inhibitor, MSC1094308 (Pbhler, 2018). The results depict rank- ordered Pearson's correlation coefficients for all test agents with the position of CHAMP- 003 shown.
  • A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 p.M.
  • the archetypal VPS4 inhibitor MSC 1094308 (Pohler, 2018) was added as a positive control, also at 10 pM.
  • cells were harvested, and poly-A RNA prepared.
  • Gene expression patterns were evaluated using RNASeq and correlated to the known transcriptomic profile for activation of the interferon pathway. The results depict rank-ordered Pearson’s correlation coefficients for all test agents with the position of CHAMP-002 shown.
  • Example 6A Compounds of Invention induced interferon regulatory factor activity
  • A549 NSCLC cells stably transfected with a reporter construct responsive to IRF activity were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 pM, in the presence or absence of the DNA- damaging chemotherapeutic doxorubicin at 0.5 pM.
  • Double-stranded poly(deoxyadenylic- deoxythymidylic) (polydAdT) was added at 100 ng/ml as an assay positive control. After treatment, IRF activity was evaluated using a luminometer.
  • results depict fold changes in IRF activity relative to cells treated with the vehicle control, DMSO, and normalized for cell viability (as measured using the Cell Titer Gio® luminescent assay).
  • the level of IRF activity induced by CHAMP- 003 is shown.
  • CHAMP-003 potently induced interferon regulatory factor (IRF) activity in A549 NSCLC cells in the presence and absence of pro-inflammatoiy DNA-damage ( Figure 6A).
  • Example 6B Compounds of Invention induced interferon regulatory factor activity
  • results depict fold changes in IRF activity relative to cells treated with the vehicle control, DMSO, and normalized for cell viability (as measured using the Cell Titer Gio® luminescent assay).
  • the level of IRF activity induced by CHAMP- 002 is shown.
  • Example 7A Effects on the short-term viability of A549 NSCLC cells
  • Example 9B treatment of A549 NSCLC cells with Compounds of Invention
  • Example 10B treatment of A549 NSCLC cells with Compounds of Invention
  • Example 11A treatment of A549 NSCLC cells with Compounds of Invention
  • A549 NSCLC cells stably transfected with a reporter construct responsive to IRF activity were seeded, allowed to attach overnight, and then treated for 72 hours with CHAMP-003 at concentrations ranging from 0.10 to 20
  • 1M. After treatment, cell viability was evaluated using the Cell Titer Gio® luminescent assay. The results depict changes in cell viability relative to cells treated with the vehicle control, DMSO. Circles show mean ⁇ SD for n 3 wells from a single experiment For the purposes of calculating an ICso value, the DMSO control was assigned a “concentration" of 0.0 lpM. An ECso value for CHAMP-003 could not be accurately estimated because of the non-sigmoidal nature of the dose-response curve.
  • Example 11B treatment of A549 NSCLC cells with Compounds of Invention
  • Example 12A Compounds of Invention bound to and stabilized VPS4B protein
  • Example 12B Compounds of Invention bound to and stabilized VPS4B protein
  • Example 13A Compounds of Invention bound to and stabilized VPS4B protein
  • Example 13B Compounds of Invention bound to and stabilized VPS4B protein

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux inhibiteurs de VPS4 et leurs utilisations pour le traitement de cancers ou de tumeurs solides ou hématologiques, qui sont caractérisés par la perte de VPS4A ou VPS4B.
PCT/US2025/015343 2024-02-12 2025-02-11 Inhibiteurs de vps4 Pending WO2025174721A1 (fr)

Applications Claiming Priority (2)

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US202463552404P 2024-02-12 2024-02-12
US63/552,404 2024-02-12

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WO2025174721A1 true WO2025174721A1 (fr) 2025-08-21

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