WO2026020038A1 - N-desméthyl ruboxistaurine en tant qu'inhibiteur de cdk4/6 pour une utilisation thérapeutique lors d'un cancer - Google Patents

N-desméthyl ruboxistaurine en tant qu'inhibiteur de cdk4/6 pour une utilisation thérapeutique lors d'un cancer

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Publication number
WO2026020038A1
WO2026020038A1 PCT/US2025/038123 US2025038123W WO2026020038A1 WO 2026020038 A1 WO2026020038 A1 WO 2026020038A1 US 2025038123 W US2025038123 W US 2025038123W WO 2026020038 A1 WO2026020038 A1 WO 2026020038A1
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WO
WIPO (PCT)
Prior art keywords
cancer
ruboxistaurin
desmethyl
pharmaceutically acceptable
acceptable salt
Prior art date
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Pending
Application number
PCT/US2025/038123
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English (en)
Inventor
Pablo LAPUERTA
Daniel E. Levy
Sarina MOHANTY
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.)
4m Therapeutics Inc
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4m Therapeutics Inc
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Publication of WO2026020038A1 publication Critical patent/WO2026020038A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • aspects of this invention are related to methods for treating cancers, including breast cancer, liposarcoma, lung cancer, glioblastoma, melanoma, germ cell tumors, advanced solid tumors, and hematologic malignancies, where N-desmethyl ruboxistaurin is clinically useful.
  • N-desmethyl ruboxistaurin as a CDK4/6 inhibitor for the treatment of cancer.
  • Ruboxistaurin which has been shown to modulate GSK3 signaling and inhibit protein kinase C, has been investigated in several clinical trials for the treatment of diabetes mellitus and its complications. See A. Girach, US Patent Publication No. 2008/0096923, incorporated herein by reference in its entirety. While ruboxistaurin has not been studied in clinical trials for the treatment of cancer, inhibition of GSK3 signaling and inhibition of protein kinase C signaling have each been proposed as beneficial for certain cancer types that have aberrant signaling of GSK3 and protein kinase C pathways.
  • CDK4/6 inhibition is known to disrupt the cell cycle in cancer cells and presents an opportune target in breast cancer therapy with potential applications across diverse cancer pathologies, including liposarcoma, lung cancer, glioblastoma, melanoma, germ cell tumors and other advanced solid tumors, and hematologic malignancies including lymphoma and leukemia.
  • CDK4/6 modulation has been a subject of interest in cancer research due to its impact on tumor progression and development.
  • CDK4/6 pathway plays a central role in activating the Gl-S cell cycle transition, and CDK4/6 inhibition provides a selective means of targeting this important cascade.
  • Tumor types characterized by activation of this pathway have aberrant Cyclin D-CDK4/6 signaling.
  • Three CDK4/6 inhibitors (palbociclib, abemaciclib, and ribociclib) have been approved as combination treatments for hormone receptorpositive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer.
  • CDK4/6 inhibitors have been proposed for use in combination with aromatase inhibitors, endocrine therapy, anti-PDl immune therapy, or other therapies in cancer patients.
  • CDK 4/6 inhibitor has been approved as a therapeutic for supportive care during chemotherapy to reduce chemotherapy-induced bone marrow suppression in patients with extensive-stage small cell lung cancer (SCLC) and is proposed to reduce chemotherapy-induced bone marrow suppression in patients with other cancer types, including non-small cell lung cancer (NSCLC), colorectal cancer (particularly metastatic colorectal cancer), breast cancer (particularly metastatic triple-negative breast cancer), and bladder cancer (particularly advanced/metastatic bladder cancer).
  • NSCLC non-small cell lung cancer
  • CDK 4/6 inhibition has been associated with neutropenia and interstitial lung disease/pneumonitis. Severe and fatal cases of interstitial lung disease/pneumonitis have been reported, indicating a need to improve the safety of CDK 4/6 inhibition.
  • Other CDK 4/6 inhibitors are in various stages of development for different types of cancer, highlighting the importance of this target in developing new cancer therapeutics.
  • aspects of this invention are related to the use of N-desmethyl ruboxistaurin as a CDK4/6 inhibitor for the treatment of cancer.
  • One aspect of the invention is directed to a method of treating a disease/disorder comprising aberrant signaling of CDK4/6 by administering to a subject in need thereof a therapeutically effective dose of N-desmethyl ruboxistaurin or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
  • the invention provides N-desmethyl ruboxistaurin or a pharmaceutically acceptable salt thereof, for use in treating a disease/disorder characterized by aberrant signaling of CDK4/6, by administering to a subject in need thereof a therapeutically effective dose of the N-desmethyl ruboxistaurin or a pharmaceutically acceptable salt thereof.
  • the subject has cancer or a history of cancer.
  • the disease/disorder is selected from breast cancer, liposarcoma, lung cancer, glioblastoma, melanoma, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, colorectal cancer, bladder cancer, hepatocellular carcinoma, osteosarcoma, germ cell tumors, and advanced solid tumors, lymphoma, leukemia and other hematologic malignancies.
  • N-desmethyl ruboxistaurin, or a pharmaceutically acceptable salt thereof is administered to reduce chemotherapy-induced bone marrow suppression in cancer patients receiving cytotoxic therapy.
  • N-desmethyl ruboxistaurin, or a pharmaceutically acceptable salt thereof is administered in an amount of about 32 to about 320 mg once daily, or about 16 to about 160 mg twice daily.
  • the N-desmethyl ruboxistaurin or pharmaceutically acceptable salt thereof is administered in combination with aromatase inhibitors, endocrine therapy, anti-PDl immune therapy, or other cancer therapies.
  • the subject has been previously treated with a CDK4/6 inhibitor and experienced neutropenia and/or interstitial lung disease/pneumonitis.
  • the invention extends to providing supportive care during radiation or chemotherapy (to reduce chemotherapy-induced bone marrow suppression) and preventing cancer relapse.
  • FIG. 1 displays the chemical structure of Ruboxistaurin.
  • FIG. 2 displays the chemical structure of N-desmethyl ruboxistaurin.
  • FIG. 3 shows a graph of the mean plasma concentration versus time profile following single-dose administration of 32 mg Ruboxistaurin in healthy subjects. Results in the insert are in the fed state.
  • FIG. 4 shows a synthetic scheme for N-desmethyl ruboxistaurin.
  • FIG. 5 displays the N-desmethyl ruboxistaurin inhibition of CDK4/6.
  • the IC S o for CDK4 was derived by assessing enzymatic inhibition (relative to DMSO controls) at 10 different concentrations of N- desmethyl ruboxistaurin with a 3-fold serial dilution starting at 100 pM. Reactions were carried out at 10 pM ATP. The curve fit was performed where the CDK4 activity at the highest concentration of N-desmethyl ruboxistaurin was less than 65%.
  • Table 1 shows the percentage of enzymatic activity remaining (relative to DMSO controls) for both CDK4 and CDK6 when the respective enzymes were exposed to a 1 pM concentration of N-desmethyl ruboxistaurin. Only 19% of activity remained of CDK4, and only 11.2% remained of CDK6, indicating potent inhibition.
  • the term “about” generally includes up to plus or minus 10% of the indicated number.
  • “about 10%” can indicate a range of 9% to 11%, and “about 20” can mean from 18 to 22.
  • Preferably “about” includes up to plus or minus 6% of the indicated value.
  • “about” includes up to plus or minus 5% of the indicated value.
  • Other meanings of “about” may be apparent from the context, such as rounding off, so, for example "about 1" can also mean from 0.5 to 1.4.
  • salts include acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethanedisulfonic acid,
  • the term "therapeutically effective amount” means an amount of compound of the present invention which is capable of alleviating the symptoms of the various pathological conditions herein described.
  • the specific dose of a compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the case including, for example, the compound(s) administered, the route of administration, the state of being of the patient, and the pathological condition being treated. Dosing can be once per day, or administered in multiple sub-doses per day, e.g., two, three, or more doses per day.
  • Reference to tumors characterized by 'aberrant signaling' of CDK4/6 means that the tumor type is one where a high proportion of cancers is known to have activation of CDK1 or the Cyclin D-CDK4/6 pathway, or where the tumor is associated with a biomarker (such as a blood test, tumor biopsy result, or PET imaging study) indicating increased activity of CDK4/6, the Cyclin D-CDK4/6 pathway, or its associated signaling networks.
  • the effective dose of N-desmethyl ruboxistaurin, or pharmaceutically acceptable salt thereof is about 32 to about 320 mg once daily, or about 16 to about 160 mg twice daily.
  • a pharmaceutical composition of N-desmethyl ruboxistaurin, or pharmaceutically acceptable salt thereof further comprises at least one pharmaceutically acceptable adjuvant or excipient.
  • Ruboxistaurin has been investigated in several clinical trials for the treatment of diabetes mellitus and its complications, including diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. See A. Girach, US Patent Publication No. 2008/0096923, incorporated herein by reference in its entirety. Its reported safety profile includes no increase in serious adverse events, deaths, or discontinuation due to adverse events compared to placebo. Further development of ruboxistaurin has been encouraged because of its clinical safety profile, and because of growing interest in the use of treatments that can inhibit GSK3.
  • CDK4/6 are important mediators of cellular transition and are critical for the initiation, growth, and survival of various cancers.
  • CDK4/6 inhibitors have become the standard of care for patients with advanced hormone receptor-positive breast cancer.
  • Three CDK4/6 inhibitors have been approved to treat this condition: palbociclib, abemaciclib, and ribocicl ib.
  • An additional CDK4/6 inhibitor, trilaciclib has been approved for supportive care during chemotherapy, to reduce chemotherapy-induced bone marrow suppression in patients with extensive-stage small cell lung cancer.
  • CDK4/6 inhibition has been associated with neutropenia and interstitial lung disease/pneumonitis.
  • N-desmethyl ruboxistaurin (Compound-1) generally follows the methods illustrated in Fig. 4. As shown, starting material 1 is reacted with vinyl Grignard in the presence of copper iodide giving alcohol intermediate 2.
  • vinyl Grignard is useful in effecting the same transformation. Such alternatives include, but are not limited to, vinyl zinc reagents, vinyl cuprate reagents and vinyl lithium reagents.
  • alternatives to copper iodide are useful in facilitating conversion of intermediate 1 to intermediate 2. Such alternatives include, but are not limited to, alternate Lewis acid reagents and chelating agents such as crown ethers.
  • Fig. 4 illustrates conversion to intermediate 3 on reaction with allyl bromide.
  • alternate a llylating agents are useful in the allylation of intermediate 2 to intermediate 3.
  • Such allylating agents generally employ alternates to the bromide leaving group and include, but are not limited to, allyl chloride, allyl iodide and allyl mesylate.
  • alternates to the illustrated potassium tert-butoxide base are useful in effecting the reaction of intermediate 2 with an allylating agent.
  • bases include, but are not limited to, hydride reagents, carbonate reagents, bicarbonate reagents, lithium diisopropylamide, sodium hexamethyl disilazide and the like.
  • Fig. 4 further illustrates the 2-step conversion of intermediate 3 to intermediate 4.
  • the first step is an ozonolysis reaction leading to the cleavage of a bis-olefin to a bis-aldehyde and the second step is a sodium borohydride reduction of a bis-aldehyde to a bis-alcohol.
  • ozonolysis is only one of many reactions or reaction combinations suitable for cleavage of an olefin to an aldehyde. Such conversions include, but are not limited to, dihydroxylation of an olefin followed by cleavage of the resulting diol to an aldehyde.
  • Suitable reagents for the dihydyroxylation of an olefin include, but are not limited to, osmium tetroxide and the like.
  • Suitable reagents for the cleavage of a diol to an aldehyde include, but are not limited to, sodium periodate, lead tetraacetate and the like.
  • sodium borohydride reducing agents are suitable for the reduction of aldehydes to alcohols.
  • Such reagents include, but are not limited to, lithium aluminum hydride, diisopropyl aluminum hydride, lithium borohydride, borane and the like.
  • the process of converting the methyl maleimide to its demethylated version involves initial hydrolysis of intermediate 7 to the maleic anhydride intermediate 8. As illustrated in Fig. 4, this transformation is effected using potassium hydroxide in ethanol.
  • conversion of intermediate 7 to intermediate 8 can employ alternates to potassium hydroxide include, but are not limited to, sodium hydroxide and lithium hydroxide.
  • ethanol can be exchanged for any protic solvent including, but not limited to, methanol and water.
  • maleic anhydride intermediate 8 is to the corresponding maleimide intermediate 9 is accomplished on reaction of intermediate 8 with hexamethyldisilazane.
  • maleic anhydrides can be converted to maleimides using alternate reagents including, but not limited to, ammonia, sodamide and the like.
  • Fig. 4 illustrates cleavage of the trityl protecting group from intermediate 9 to alcohol intermediate 10. While Fig. 4 highlights hydrochloric acid as the reagent effecting trityl cleavage, one of ordinary skill in the art will recognize that alternate acids can be used. Said alternates include, but are not limited to, hydrobromic acid, trifluoroacetic acid, acetic acid and the like.
  • the alcohol of intermediate 10 is converted to the mesylate intermediate 11 on reaction with methanesulfonyl chloride and pyridine.
  • mesylates as leaving groups, are generally useful as are common alternative leaving groups including, but not limited to, chlorides, bromides, iodides, tosylates and the like.
  • alternatives to triethylamine are useful in the conversion of alcohols to mesylates with such alternatives including, but not being limited to, diisopropyl ethylamine, pyridine, carbonate reagents, bicarbonate reagents and the like.
  • Fig. 4 illustrates conversion of intermediate 11 to Compound-1 on reaction with methylamine. While not illustrated in Fig. 4, the methylamine is further converted to its corresponding hydrochloride salt.
  • One of ordinary skill in the art will understand that alternate strategies for conversion of compounds such as intermediate 11 to structures such Compound-1 exist. Such strategies are generally recognizable by one skilled in the art and said strategies are generally supported by resources such as Comprehensive Organic Transformations (Larock, Wiley).
  • composition and treatment methods are relevant to cancers where CDK4/6 inhibition has been proposed, including breast cancer, liposarcoma, lung cancer, glioblastoma, melanoma, germ cell tumors, advanced solid tumors, lymphoma, leukemia and other hematologic malignancies.
  • the presently disclosed compositions and treatment methods also have use in preventing relapse of a disclosed malignancy and ameliorating toxicity caused by other cancer treatments, including the neutropenia and interstitial lung disease/pneumonitis associated with other CDK4/6 inhibitors.
  • compositions and treatment methods also have use in veterinary applications for improving the health and well-being of livestock and companion animals by treating any of the foregoing indications that occur in animals.
  • Step-1 Synthesis of (S)-l-(trityloxy) pent-4-en-2-ol (2):
  • Step-2 Synthesis of (S)-(((2-(allyloxy) pent-4-en-l-yl) oxy) methane trityl) tribenzene (3):
  • Step-3 Synthesis of (S)-3-(2-hydroxyethoxy)-4-(trityloxy) butan-l-ol (4):
  • Step-8 Synthesis of (12E,32E,7S)-7-(hydroxymethyl)-22,25-dihydro-llH,21H,31H-6-oxa-l, 3(3,1)- diindola-2(3,4)-pyrrofacyclononaphane-22, 25-dione (10):
  • Step-10 Synthesis of (12E, 32E,7S)-7-((methylamino)methyl)-22,25-dihydro-llH,21H, 31H-6-oxa-l, 3(3,1)- diindola-2(3,4)-pyrrolacyclononaphane-22, 25-dione hydrochloride (Compound-1): [0096] To a stirred solution of compound-11 (10.0 g, 0.019 mol) in THF (400 mL) was added 2M Methyl amine in THF (400 mL) at -40°C, in an auto-clave. Gradually heated the reaction to 70°C and stirred for 24 h.
  • Substrate was prepared in reaction buffer, cofactors were added, and CDK4 was introduced into the substrate solution. Reactions were carried out at 10 pM ATP. The compound was then added in 100% DMSO, followed by a 20-minute incubation at room temperature.
  • the reaction was initiated by adding 33P-ATP (specific activity 10 pCi/pL), and incubation continued for 2 hours at room temperature. Radioactivity was detected via the filter-binding method. Recorded data included raw readings, percent enzyme activity relative to DMSO controls, and curve fits, with the latter performed when enzyme activities at the highest compound concentrations were less than 65% (Fig. 5). The assay was validated with staurosporine as a control compound.
  • Table 1 activities for CDK4 and CDK6 were evaluated in the same manner as described above, at a 1 pM concentration of N-desmethyl ruboxistaurin. Only 19% of activity remained of CDK4 at 1 p.M, and even less activity remained for CDK6, indicating potent inhibition.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des aspects de la présente invention se rapportent à l'utilisation de N-déméthyl ruboxistaurine et à des formulations pharmaceutiquement acceptables de cette dernière permettant de moduler la signalisation CDK4/6. L'invention concerne des procédés d'administration de N-desméthyl ruboxistaurine à des sujets en ayant besoin, en particulier ceux ayant un historique du cancer ou subissant actuellement un cancer du sein, un liposarcome, un cancer du poumon, un glioblastome, un mélanome, un cancer du pancréas, un cancer de la prostate, un cancer du côlon, un cancer de l'ovaire, un cancer colorectal, un cancer de la vessie, un carcinome hépatocellulaire, un ostéosarcome, des tumeurs germinales, des tumeurs solides avancées, un lymphome, une leucémie et d'autres malignités hématologiques. Les procédés divulgués vont au-delà du traitement de la maladie et incluent les soins de soutien pendant la radiochimiothérapie et la prévention des rechutes de cancer. L'administration de N-desméthyl ruboxistaurine, seule ou en combinaison avec d'autres thérapies anticancéreuses, est efficace pour moduler la signalisation CDK4/6 tout en atténuant la toxicité associée à d'autres traitements.
PCT/US2025/038123 2024-07-17 2025-07-17 N-desméthyl ruboxistaurine en tant qu'inhibiteur de cdk4/6 pour une utilisation thérapeutique lors d'un cancer Pending WO2026020038A1 (fr)

Applications Claiming Priority (2)

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US202463672463P 2024-07-17 2024-07-17
US63/672,463 2024-07-17

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110009353A1 (en) * 2007-11-07 2011-01-13 Cornell Research Foundation, Inc Targeting cdk4 and cdk6 in cancer therapy
US20220062314A1 (en) * 2018-12-17 2022-03-03 MitoPower, LLC Nicotinyl riboside compounds and their uses
WO2023192984A1 (fr) * 2022-03-31 2023-10-05 4M Therapeutics Inc. N-déméthyl ruboxistaurine en tant qu'inhibiteur de kinase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110009353A1 (en) * 2007-11-07 2011-01-13 Cornell Research Foundation, Inc Targeting cdk4 and cdk6 in cancer therapy
US20220062314A1 (en) * 2018-12-17 2022-03-03 MitoPower, LLC Nicotinyl riboside compounds and their uses
WO2023192984A1 (fr) * 2022-03-31 2023-10-05 4M Therapeutics Inc. N-déméthyl ruboxistaurine en tant qu'inhibiteur de kinase

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