Combination of KAT6 inhibitor and ar protac

Abstract

The present disclosure relates to a combination of a KAT6 inhibitor with an androgen receptor-targeting proteolysis targeting chimera (AR PROTAC). Specifically, the present disclosure relates to the use of a KAT6 inhibitor in combination with an AR PROTAC in the preparation of a drug for treating tumors, and in particular, to the use of the two in combination for treating metastatic castration-resistant prostate cancer.

Description

Combination of KAT6 inhibitors and AR PROTAC Technical Field

[0001] This disclosure relates to the use of a KAT6 inhibitor in combination with an androgen receptor-targeting protein degradation chimera (AR PROTAC) in the preparation of a therapeutic tumor drug, and belongs to the pharmaceutical field. Background Technology

[0002] Prostate cancer is one of the most common malignant tumors in men, and its incidence is increasing year by year. According to data collected by the National Cancer Registry Center, prostate cancer ranked first in incidence among urological tumors in China in 2022, with 134,200 new cases. In Europe and America, the vast majority of patients are diagnosed early, with a 5-year survival rate of 90-99%; however, 5% of patients are diagnosed with distant metastases at initial diagnosis, and their 5-year survival rate is only 30-40%. In my country, up to 54% of newly diagnosed prostate cancers are metastatic. Almost all patients will progress to metastatic chronic prostate cancer (mCRPC) after late-stage endocrine therapy, and once this stage is reached, the prognosis is generally poor. Researchers have been working to find new treatment strategies to further improve patient outcomes.

[0003] In recent years, novel endocrine therapies have gradually become the first-line standard treatment for mCRPC. Abiraterone acetate is a CYP17 inhibitor. The COU-AA-302 study showed that abiraterone combined with prednisone significantly prolonged median overall survival (mOS = 34.7 months vs 30.3 months, HR 0.81, p = 0.0033) and nearly doubled median recurrent progression-free survival (rPFS = 16.5 months vs 8.2 months, HR 0.52, p < 0.0001), with PSA50 rates of 68% vs 29%, respectively. Similar conclusions were obtained in the ABI-PRO-3002 study targeting Asian populations, where abiraterone combined with prednisone significantly prolonged the time to PSA progression compared to placebo (NR vs 3.8 months, HR 0.418, p < 0.0001). Enzalutamide is a second-generation AR antagonist. In the PREVAIL study, the 12-month rPFS rate in the enzalutamide group was significantly better than that in the placebo group (65% vs 14%, HR 0.19, p<0.001), and the PSA50 was significantly better in the enzalutamide group (78% vs 3%). After long-term follow-up, the median survival in the enzalutamide group remained better than that in the placebo group (mOS = 36 months vs 31 months, HR 0.83, p<0.001). The Asian PREVAIL study, targeting an Asian population, also confirmed the benefit of enzalutamide treatment. Both drugs are approved for marketing by the FDA and NMPA. Reveludil is another second-generation AR antagonist. Phase I / II study results showed that all dose groups of reveludil had antitumor activity, with PSA50 reaching 68.0% at week 12, and the rate of maximum PSA reduction exceeding 50% was 78.2%; the stabilization rate of bone lesions at week 12 was 88.3%; the response rate of soft tissue lesions at week 12 was 34.4%, and the disease control rate was 86.9%; the median PFS was 14.0 months, and the median OS was 27.5 months.

[0004] Although abiraterone and second-generation AR antagonists have achieved significant clinical efficacy in CRPC, patients develop resistance as the disease progresses. The resistance mechanisms of second-generation AR antagonists (plus abiraterone) mainly include reactivation of the AR pathway [AR amplification, point mutations in the AR ligand-binding domain (AR LBD), AR-V7, etc.], persistent activation of the AR bypass pathway, persistent androgen activation, or AR-independent resistance mechanisms. Currently, there is no standard treatment for mCRPC patients resistant to both novel endocrine therapies and taxanes. Patients resistant to novel endocrine therapies are unlikely to benefit again from treatment with other second-generation AR antagonists, necessitating new treatment options to change the existing treatment pathway. Summary of the Invention

[0005] This disclosure provides the use of a KAT6 inhibitor in combination with an androgen receptor-targeting protein degradation-targeting chimera (AR PROTAC) in the preparation of a therapeutic oncology drug.

[0006] In some embodiments, the KAT6 inhibitor described herein is selected from at least one of PF-07248144, PF-9363, OP-3136, MEN-2312, ISM-5043, and the compound shown in formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the KAT6 inhibitor described herein is the compound shown in formula (I) or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the dosage of the KAT6 inhibitor described herein is selected from 0.1 mg to 100 mg, for example, 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, or any value between two values. In some embodiments, the dosage of the KAT6 inhibitor described herein is selected from 0.1 to 50 mg. In some embodiments, the dosage of the KAT6 inhibitor described herein is selected from 1 to 50 mg. In some embodiments, the dosage of the KAT6 inhibitor described in this disclosure is selected from 1-20 mg. In some embodiments, the dosage of the KAT6 inhibitor described in this disclosure is selected from 2.5-10 mg. In some embodiments, the dosage of the KAT6 inhibitor described in this disclosure is selected from 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, and 50 mg. In some embodiments, the dosage of the KAT6 inhibitor described herein is selected from 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, and 20 mg. In some embodiments, the dosage of the KAT6 inhibitor described herein is selected from 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, and 20 mg.In some embodiments, the dosage of the KAT6 inhibitor described herein is selected from 2.5 mg, 5 mg, 7.5 mg, and 10 mg. The dosage of the KAT6 inhibitor described herein is selected from 5 mg and 10 mg. The dosage of the KAT6 inhibitor described herein is 5 mg.

[0008] In some embodiments, the KAT6 inhibitor described in this disclosure is administered once daily, twice daily, three times daily, once every two days, once every three days, or once a week. In some embodiments, the KAT6 inhibitor described in this disclosure is administered once daily or twice daily. In some embodiments, the KAT6 inhibitor described in this disclosure is administered once daily.

[0009] In some embodiments, the dosage of the KAT6 inhibitor described herein is selected from 0.1-50 mg, and the frequency of administration is selected from once or twice a day.

[0010] In some embodiments, the dosage of the KAT6 inhibitor described herein is selected from 1-50 mg, and the frequency of administration is once or twice a day.

[0011] In some embodiments, the dosage of the KAT6 inhibitor described herein is selected from 1-20 mg, and the frequency of administration is once daily.

[0012] In some embodiments, the dosage of the KAT6 inhibitor described herein is selected from 2.5-10 mg, and the frequency of administration is once daily.

[0013] In some embodiments, the dosage of the KAT6 inhibitor described herein is selected from 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg and 20 mg, and the dosing frequency is once daily.

[0014] In some embodiments, the dosage of the KAT6 inhibitor described herein is selected from 2.5 mg, 5 mg, 7.5 mg and 10 mg, and the frequency of administration is once daily.

[0015] In some embodiments, the dosage of the KAT6 inhibitor described herein is 5 mg or 10 mg, administered once daily.

[0016] In some embodiments, the dosage of the KAT6 inhibitor described herein is 5 mg, administered once daily.

[0017] In some embodiments, the dosage and frequency of administration of the KAT6 inhibitor described herein are selected from the following:

[0018] (a-1) The dosage is 2.5 mg, and the frequency of administration is once a day;

[0019] (a-2) The dosage is 5 mg, and the frequency of administration is once a day;

[0020] (a-3) The dosage is 7.5 mg, and the frequency of administration is once a day;

[0021] (a-4) The dosage is 10 mg, and the frequency of administration is once a day.

[0022] In some embodiments, the androgen receptor-targeting protein degradation chimera (AR PROTAC) described herein is selected from at least one of ARV-110, ARV-766, GT-20029, BMS-986365, HP-518, RG-6537, AC-0176, HSK-38008, HC-X029, and compounds of formula (II) or pharmaceutically acceptable salts thereof. In some embodiments, the androgen receptor-targeting protein degradation chimera (AR PROTAC) described herein is a compound of formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the androgen receptor-targeting protein degradation-targeting chimera (AR PROTAC) described in this disclosure is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, or a compound of formula (II-2) or a pharmaceutically acceptable salt thereof. In some embodiments, the protein degradation targeting chimera (AR PROTAC) targeting androgen receptors described in this disclosure is a compound of formula (II-1) or a pharmaceutically acceptable thereof.

[0023] In some embodiments, the protein degradation targeting chimera (AR PROTAC) targeting androgen receptors described herein is selected from at least one of ARV-110 and ARV-766.

[0024] In some embodiments, the dosage of the androgen receptor-targeting protein degradation-targeting chimeric (AR PROTAC) described in this disclosure is selected from 1-1500 mg (calculated as free base), for example 60 mg, 90 mg, 120 mg, 150 mg, 180 mg, 210 mg, 240 mg, 270 mg, 300 mg, 330 mg, 360 mg, 390 mg, 420 mg, 450 mg, 480 mg, 510 mg, 540 mg, 570 mg, 600 mg, 630 mg, 660 mg, 690 mg, 720 mg, 750 mg, 7 The dosage of the AR PROTAC described herein is selected from 1 mg to 800 mg. In some embodiments, the dosage of the AR PROTAC described herein is selected from 200 mg to 700 mg. In some embodiments, the dosage of the AR PROTAC described herein is selected from 300 mg to 600 mg. In some embodiments, the dosage of the AR PROTAC described in this disclosure is selected from 90 mg, 120 mg, 150 mg, 180 mg, 210 mg, 240 mg, 270 mg, 300 mg, 330 mg, 360 mg, 390 mg, 420 mg, 450 mg, 480 mg, 510 mg, 540 mg, 570 mg, 600 mg, and 630 mg. In some embodiments, the dosage of the AR PROTAC described in this disclosure is selected from 90 mg, 180 mg, 240 mg, 270 mg, 360 mg, 450 mg, 540 mg, and 630 mg. In some embodiments, the dosage of the AR PROTAC described in this disclosure is selected from 90 mg, 180 mg, 270 mg, 360 mg, 450 mg, 540 mg, and 630 mg. In some embodiments, the dosage of the AR PROTAC described in this disclosure is selected from 240 mg, 270 mg, 360 mg, 450 mg, and 540 mg. In some embodiments, the dosage of the AR PROTAC described in this disclosure is 240 mg or 360 mg.In some embodiments, the dosage of AR PROTAC described in this disclosure is 240 mg. In some embodiments, the dosage of AR PROTAC described in this disclosure is 360 mg.

[0025] In some embodiments, the AR PROTAC described in this disclosure is administered once daily, twice daily, three times daily, once every two days, once every three days, or once a week. In some embodiments, the AR PROTAC described in this disclosure is administered once daily or twice daily. In some embodiments, the AR PROTAC described in this disclosure is administered twice daily. In some embodiments, the AR PROTAC described in this disclosure is administered once daily.

[0026] In some embodiments, the dosage of AR PROTAC described in this disclosure is selected from 1 mg to 800 mg, and the frequency of administration is once or twice a day.

[0027] In some embodiments, the dosage of AR PROTAC described in this disclosure is selected from 200 mg to 700 mg, and the frequency of administration is once or twice a day.

[0028] In some embodiments, the dosage of AR PROTAC described in this disclosure is selected from 300 mg to 600 mg, and the frequency of administration is once or twice a day.

[0029] In some embodiments, the dosage of the AR PROTAC inhibitors described herein is selected from 90 mg, 180 mg, 240 mg, 270 mg, 360 mg, 450 mg, 540 mg and 630 mg, and the dosing frequency is once or twice a day.

[0030] In some embodiments, the dosage of the AR PROTAC inhibitor described herein is selected from 90 mg, 180 mg, 270 mg, 360 mg, 450 mg, 540 mg and 630 mg, and the dosing frequency is once or twice a day.

[0031] In some embodiments, the dosage of AR PROTAC described in this disclosure is selected from 90 mg, 180 mg, 270 mg, 360 mg, 450 mg, 540 mg and 630 mg, and the frequency of administration is once daily.

[0032] In some embodiments, the dosage of AR PROTAC described in this disclosure is 240 mg or 360 mg, and the frequency of administration is once or twice a day.

[0033] In some embodiments, the dosage of AR PROTAC described in this disclosure is 360 mg, administered once or twice daily.

[0034] In some embodiments, the dosage of AR PROTAC described in this disclosure is selected from 360 mg, administered once daily.

[0035] In some embodiments, the dosage of AR PROTAC described in this disclosure is selected from 240 mg, administered twice daily.

[0036] In some embodiments, the dosage of the KAT6 inhibitor described herein is 5 mg, administered once daily; the dosage of the AR PROTAC described herein is 360 mg, administered once daily; or the dosage of the AR PROTAC described herein is 240 mg, administered twice daily.

[0037] In some embodiments, the dosage of the KAT6 inhibitor described herein is 5 mg, administered once daily; the dosage of the AR PROTAC described herein is 360 mg, administered once daily.

[0038] In some embodiments, the dosage of the KAT6 inhibitor described herein is 5 mg, administered once daily; the dosage of the AR PROTAC described herein is 240 mg, administered twice daily.

[0039] In some implementations, the dosage described in this disclosure is a unit dose.

[0040] In some embodiments, the unit dose of the KAT6 inhibitor described herein is selected from 0.5 mg, 2.5 mg, 5 mg, and 10 mg. In some embodiments, the unit dose of the KAT6 inhibitor described herein is 0.5 mg or 2.5 mg. In some embodiments, the unit dose of the KAT6 inhibitor described herein is 2.5 mg.

[0041] In some embodiments, the unit dose of the AR PROTAC described in this disclosure is selected from 10-100 mg. In some embodiments, the unit dose of the AR PROTAC described in this disclosure is selected from 10 mg, 15 mg, 25 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, and 100 mg. In some embodiments, the unit dose of the AR PROTAC described in this disclosure is 15 mg or 60 mg. In some embodiments, the unit dose of the AR PROTAC described in this disclosure is 60 mg.

[0042] In some embodiments, the KAT6 inhibitor of this disclosure is administered for a period of 4 weeks. In some embodiments, the compound of formula (I) of this disclosure or a pharmaceutically acceptable salt thereof is administered for a period of 4 weeks.

[0043] In some embodiments, the AR PROTAC of this disclosure is administered for a period of 4 weeks. In some embodiments, the compound of formula (II), (II-1), or (II-2) of this disclosure, or a pharmaceutically acceptable salt thereof, is administered for a period of 4 weeks. In some embodiments, the compound of formula (II-1) of this disclosure, or a pharmaceutically acceptable salt thereof, is administered for a period of 4 weeks.

[0044] In some embodiments, the KAT6 inhibitor of this disclosure is administered for a period of 4 weeks, and the AR PROTAC is administered for a period of 4 weeks. In some embodiments, the compound of formula (I) of this disclosure or a pharmaceutically acceptable salt thereof is administered for a period of 4 weeks, and the compound of formula (II-1) or a pharmaceutically acceptable salt thereof is administered for a period of 4 weeks.

[0045] In some embodiments, the KAT6 inhibitors of this disclosure are administered orally. In some embodiments, the compounds of formula (I) of this disclosure or their pharmaceutically acceptable salts are administered orally.

[0046] In some embodiments, the AR PROTAC of this disclosure is administered orally. In some embodiments, the compound of formula (II), (II-1) or (II-2) of this disclosure, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, the compound of formula (II-1) of this disclosure, or a pharmaceutically acceptable salt thereof, is administered orally.

[0047] In some embodiments, the KAT6 inhibitors, compounds of formula (I) or pharmaceutically acceptable salts thereof, AR PROTAC, compounds of formula (II) or pharmaceutically acceptable salts thereof, compounds of formula (II-1) or pharmaceutically acceptable salts thereof, and compounds of formula (II-2) or pharmaceutically acceptable salts thereof may be present in any pharmaceutically acceptable formulation. For example, they may be tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection, and concentrated solutions for injection), suppositories, inhalers, or sprays.

[0048] In some embodiments, the KAT6 inhibitors of this disclosure are present in tablet form. In some embodiments, the compound of formula (I) of this disclosure, or a pharmaceutically acceptable salt thereof, is present in tablet form. In some embodiments, the AR PROTAC of this disclosure is present in tablet form. In some embodiments, the compound of formula (II), formula (II-1), or formula (II-2) of this disclosure, or a pharmaceutically acceptable salt thereof, is present in tablet form. In some embodiments, the compound of formula (II-1) of this disclosure, or a pharmaceutically acceptable salt thereof, is present in tablet form.

[0049] In some implementations, the tumor described in this disclosure is prostate cancer.

[0050] In some embodiments, the tumor described in this disclosure is castration-resistant prostate cancer.

[0051] In some embodiments, the tumor described in this disclosure is metastatic castration-resistant prostate cancer.

[0052] In some embodiments, the tumor described in this disclosure is prostate cancer that has received first-line systemic standard therapy (e.g., novel endocrine therapy, surgery, medication, radiotherapy, chemotherapy). In some embodiments, the tumor described in this disclosure is castration-resistant prostate cancer that has received first-line systemic standard therapy (e.g., novel endocrine therapy, surgery, medication, radiotherapy, chemotherapy). In some embodiments, the tumor described in this disclosure is metastatic castration-resistant prostate cancer that has received first-line systemic standard therapy (e.g., novel endocrine therapy, surgery, medication, radiotherapy, chemotherapy).

[0053] In some embodiments, the tumor described in this disclosure is prostate cancer that has failed treatment with at least one novel endocrine therapy (such as abiraterone or enzalutamide). In some embodiments, the tumor described in this disclosure is castration-resistant prostate cancer that has failed treatment with at least one novel endocrine therapy (such as abiraterone or enzalutamide). In some embodiments, the tumor described in this disclosure is metastatic castration-resistant prostate cancer that has failed treatment with at least one novel endocrine therapy (such as abiraterone or enzalutamide). In some embodiments, the tumor described in this disclosure is histologically confirmed prostate adenocarcinoma (mCRPC) that has undergone medical or surgical castration, has castration-level testosterone during the screening period, and is at the castration level.

[0054] In some embodiments, the castration described in this disclosure is medical castration or surgical castration. In some embodiments, medical castration is continuous luteinizing hormone-releasing hormone analog (LHRHA) treatment. In some embodiments, surgical castration is a bilateral orchiectomy.

[0055] This disclosure provides the use of a KAT6 inhibitor in the preparation of an AR PROTAC therapy for cancer treatment.

[0056] In some embodiments, the tumor, KAT6 inhibitor, and AR PROTAC are defined as defined in the foregoing uses. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II), (II-1), or (II-2) or a pharmaceutically acceptable salt thereof. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof.

[0057] This disclosure provides the use of AR PROTAC in the preparation of a drug for the treatment of tumors in combination with a KAT6 inhibitor.

[0058] In some embodiments, the tumor, KAT6 inhibitor, and AR PROTAC are defined as defined in the foregoing uses. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II), (II-1), or (II-2) or a pharmaceutically acceptable salt thereof. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof.

[0059] This disclosure provides a method for treating tumors, comprising administering a therapeutically effective amount of a KAT6 inhibitor and AR PROTAC to a patient.

[0060] In some embodiments, the tumor, KAT6 inhibitor, and AR PROTAC are defined as defined in the foregoing uses. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II), (II-1), or (II-2) or a pharmaceutically acceptable salt thereof. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof.

[0061] In some implementations, the method for treating tumors provided in this disclosure uses a dosing cycle of 4 weeks.

[0062] This disclosure provides a KAT6 inhibitor for the treatment of tumors, wherein the KAT6 inhibitor is administered in combination with AR PROTAC.

[0063] In some embodiments, the tumor, KAT6 inhibitor, and AR PROTAC are defined as defined in the foregoing uses. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II), (II-1), or (II-2) or a pharmaceutically acceptable salt thereof. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof.

[0064] This disclosure provides an AR PROTAC for the treatment of tumors, wherein the AR PROTAC is administered in combination with a KAT6 inhibitor.

[0065] In some embodiments, the tumor, KAT6 inhibitor, and AR PROTAC are defined as defined in the foregoing uses. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II), (II-1), or (II-2) or a pharmaceutically acceptable salt thereof. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof.

[0066] This disclosure also provides a composition comprising a KAT6 inhibitor and AR PROTAC.

[0067] In some embodiments, the KAT6 inhibitor and AR PROTAC are defined as defined in the foregoing uses. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II), (II-1), or (II-2) or a pharmaceutically acceptable salt thereof. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof.

[0068] This disclosure also provides a pharmaceutical composition comprising a KAT6 inhibitor, AR PROTAC, and one or more pharmaceutically acceptable carriers.

[0069] In some embodiments, the KAT6 inhibitor and AR PROTAC are defined as defined in the foregoing uses. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II), (II-1), or (II-2) or a pharmaceutically acceptable salt thereof. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the pharmaceutical composition can be formulated into any pharmaceutically acceptable dosage form. For example, it can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection, and concentrated solutions for injection), suppositories, inhalers, or sprays.

[0071] The pharmaceutical composition containing a KAT6 inhibitor and AR PROTAC described in this disclosure can be administered alone or in combination with one or more therapeutic agents.

[0072] The combined administration methods described in this disclosure are selected from simultaneous administration, independently prepared and co-administered, or independently prepared and sequentially administered.

[0073] The combined routes of administration described in this disclosure are selected from oral administration, parenteral administration, and transdermal administration, wherein parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.

[0074] In the scheme described in this disclosure, the combination may optionally include other components, including but not limited to other anti-tumor drugs.

[0075] In this disclosure, the components to be combined (e.g., KAT6 inhibitors and AR PROTAC, and optionally any other component drugs) may be administered simultaneously or sequentially. Furthermore, the components to be combined may also be administered in combination in the same formulation or in separate formulations.

[0076] In some embodiments, the pharmaceutically acceptable salts of the compounds represented by formula (I), formula (II), formula (II-1) or formula (II-2) of this disclosure may be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, hydroxyethylsulfonate, maleate, malate, tartrate, benzoate, bis(hydroxynaphthyl)ate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate, or lauryl sulfonate, etc.

[0077] In some embodiments, the compound represented by formula (I) of this disclosure is a pharmaceutically acceptable salt, specifically the compound represented by formula (I).

[0078] In some embodiments, the compound represented by formula (II) of this disclosure is a pharmaceutically acceptable salt, specifically the compound represented by formula (II).

[0079] In some embodiments, the compound of formula (II-1) described in this disclosure is a pharmaceutically acceptable salt, specifically the compound of formula (II-1).

[0080] In some embodiments, the compound of formula (II-2) described in this disclosure is a pharmaceutically acceptable salt, specifically the compound of formula (II-2).

[0081] In an optional implementation, the patients in this disclosure have received first-line systemic standard treatment (e.g., endocrine therapy, surgery, radiotherapy, chemotherapy).

[0082] This disclosure also provides a pharmaceutical kit containing the aforementioned KAT6 inhibitor and AR PROTAC.

[0083] In some embodiments, the KAT6 inhibitor and AR PROTAC are defined as defined in the foregoing uses. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II), (II-1), or (II-2) or a pharmaceutically acceptable salt thereof. In some embodiments, the KAT6 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; the AR PROTAC is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof.

[0084] In some implementations, the subjects described in this disclosure are humans or non-human mammals.

[0085] In some implementations, the subjects described in this disclosure are humans.

[0086] In some embodiments, the subjects described in this disclosure are patients with prostate cancer. In some embodiments, the subjects described in this disclosure are patients with castration-resistant prostate cancer. In some embodiments, the subjects described in this disclosure are patients with metastatic castration-resistant prostate cancer.

[0087] Terminology Definition

[0088] The term "combination" as used in this disclosure refers to a route of administration that administers at least one dose of a KAT6 inhibitor and at least one dose of an AR PROTAC within a specified time period, wherein both drugs exhibit pharmacological effects. The time period can be within a dosing cycle, preferably within 4 weeks, 3 weeks, 2 weeks, 1 week, or within 24 hours, more preferably within 12 hours. The KAT6 inhibitor and AR PROTAC can be administered simultaneously or sequentially. This period includes treatments in which the KAT6 inhibitor and AR PROTAC are administered via the same or different routes of administration. The route of administration for the combination described in this disclosure is selected from simultaneous administration, independently formulated and co-administered administration, or independently formulated and sequentially administered administration.

[0089] "Optional" or "optionally" means that the event or situation described below may, but does not have to, occur, and the description includes the circumstances under which the event or situation may or may not occur.

[0090] The term "effective amount" or "effective therapeutic amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0091] "Pharmaceutical-acceptable salts" refer to salts of the compounds disclosed herein, which may be selected from inorganic or organic salts. These salts are safe and effective when used in mammals and possess the expected biological activity. Salts can be prepared separately during the final isolation and purification of the compound, or by reacting suitable groups with suitable bases or acids. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0092] The term "pharmaceutically acceptable carrier" as used in this disclosure means any type of non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation excipient.

[0093] The term “pharmaceutically acceptable carrier” as used in this disclosure includes, but is not limited to, any adjuvant, flow aid, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration (FDA) for use in humans or livestock.

[0094] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as a physiologically pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0095] The values ​​in this disclosure are instrument measurements and are subject to a certain degree of error. Generally, ±10% is within the reasonable error range. Of course, the context in which the value is used must be considered. For example, in the case of particle size of the active ingredient, where the measurement error variation does not exceed ±10%, the value can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0096] PSA50: The percentage of individuals in the efficacy analysis dataset whose PSA levels decreased by ≥50% from baseline.

[0097] PSA30: The percentage of individuals in the efficacy analysis set whose PSA levels decreased by ≥30% from baseline.

[0098] PSA progression time: refers to the time from the first dose of medication until the first occurrence of PSA progression or death from any cause (whichever comes first).

[0099] Objective response rate (ORR): defined as the percentage of subjects who achieved a CR or PR at baseline from the first dose of the study to the subject's discharge from the study, out of the total number of subjects with measurable target lesions at baseline in the efficacy analysis set.

[0100] Disease control rate (DCR): The percentage of subjects who achieved CR, PR, or SD out of the total number of subjects with measurable target lesions at baseline in the efficacy analysis set.

[0101] Duration of Response (DoR): The time period from the first evaluation of CR / PR (whichever comes first) to relapse or PD.

[0102] Radiographic progression-free survival (rPFS): The time from first administration of the drug until the first radiographic progression of disease (PD) or death from any cause (whichever occurs first). Time to next bone-related event: The time from first administration of the drug until the next bone-related event. Bone-related events include radiation or surgery targeting the bone, pathological fractures, spinal cord compression, or changes in antitumor therapy to relieve bone pain.

[0103] Overall survival (OS): refers to the time from the first administration of the drug until death from any cause. If a subject is lost to follow-up during the survival period, the time cutoff point is the last time the subject's survival status was determined.

[0104] Median survival (mOS): also known as "half-survival", it is the survival time corresponding to a 50% survival rate on the survival curve, that is, the time when 50% of the individuals participating in the experiment survive.

[0105] Progression-free survival (PFS): defined as the date from the first dose to the first recorded PD or death from any cause, whichever comes first.

[0106] Baseline tumor status was assessed in enrolled subjects using imaging techniques (PET-CT or CT), with subsequent tumor evaluations performed every 12 weeks. Efficacy was determined according to the 2014 revised Lugano criteria for evaluating the efficacy of treatment for malignant lymphoma. PET-CT was recommended for subjects suspected of having disease progression (PD) to obtain histopathological results to confirm or rule out PD status.

[0107] CR = Complete remission; PR = Partial remission; SD = Stable disease; PD = Disease progression. Detailed Implementation

[0108] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0109] Example 1: Evaluation of the efficacy and safety of combination therapy in metastatic castration-resistant prostate cancer.

[0110] 1. Research drugs

[0111] Drug A is manufactured by Shandong Shengdi Pharmaceutical Co., Ltd., in tablet form, 2.5 mg / tablet, for oral administration.

[0112] The active ingredient of drug A is the compound shown in formula (I), which can be prepared by referring to the method provided in WO2023016484A.

[0113] Drug B is manufactured by Jiangsu Hengrui Medicine Co., Ltd., in tablet form, 60mg / tablet, for oral administration.

[0114] The active ingredient of drug B is the compound shown in formula (II-1), which can be prepared by referring to the method provided in WO2023093845A.

[0115] 2. Dosing regimen

[0116] As of September 29, 2025, a total of 12 subjects had been enrolled.

[0117] In 6 cases, the administration method was oral administration of drug A, 5 mg once a day, and oral administration of drug B, 360 mg once a day;

[0118] In 6 cases, drug A was administered orally at a dose of 5 mg once daily, and drug B was administered orally at a dose of 240 mg twice daily.

[0119] 3. Study subjects: Metastatic castration-resistant prostate cancer patients who had previously undergone novel endocrine therapy.

[0120] 4. Inclusion criteria

[0121] 1) Prostate adenocarcinoma confirmed by histological or cytological examination;

[0122] 2) Medical castration or surgical castration, with testosterone levels at castration levels (≤50 ng / dL or 1.73 nmol / L) during screening;

[0123] 3) Failure to respond to at least one prior treatment with a novel endocrine therapy (such as abiraterone or enzalutamide);

[0124] 4) It has metastatic lesions.

[0125] 5. Clinical Outcomes

[0126] Regarding efficacy, nine subjects underwent at least one post-baseline PSA test in the study. Four of these subjects received drug A 5mg combined with drug B 360mg, and five received drug A 5mg combined with drug B 240mg. Of the nine subjects with evaluable PSA response rates, five experienced a decrease in PSA. In the drug A 5mg combined with drug B 360mg group, two of the four subjects experienced a decrease in PSA, both reaching PSA30 (a ≥30% reduction in serum PSA level from baseline during treatment), with one (25%) achieving PSA50 (a ≥50% reduction in serum PSA level from baseline during treatment). In the combination of drug A 5mg and drug B 240mg, among 5 subjects, 3 subjects experienced a decrease in PSA. One subject's PSA level decreased by 21.8% from baseline before rising to more than 50% above the lowest PSA level (defined as PSA progression); one subject's PSA level did not reach the PSA 30 standard from baseline; and one subject (20%) reached a PSA 50. Overall, this combination regimen demonstrated antitumor activity in terms of PSA levels.

[0127] In terms of safety, all 12 subjects completed dose-limiting toxicity (DLT) observation, and the safety was manageable.

Claims

1. The use of a KAT6 inhibitor in combination with AR PROTAC in the preparation of a therapeutic tumor drug.

2. The use according to claim 1, wherein the KAT6 inhibitor is selected from at least one of PF-07248144, PF-9363, OP-3136, MEN-2312, ISM-5043 and the compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably the compound of formula (I) or a pharmaceutically acceptable salt thereof.

3. The use according to claim 1 or 2, wherein the dosage of the KAT6 inhibitor is selected from 0.1 mg to 100 mg (calculated as free base), preferably selected from 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg and 20 mg, more preferably 5 mg.

4. The use according to any one of claims 1-3, wherein the KAT6 inhibitor is administered once a day, twice a day, three times a day, once every two days, once every three days, or once a week, preferably once a day or twice a day, more preferably once a day.

5. The use according to any one of claims 1-4, wherein the AR PROTAC is selected from at least one of ARV-110, ARV-766, GT-20029, BMS-986365, HP-518, RG-6537, AC-0176, HSK-38008, HC-X029 and the compound of formula (II) or a pharmaceutically acceptable salt thereof, preferably the compound of formula (II) or a pharmaceutically acceptable salt thereof. More preferably, the compound of formula (II-1) or its pharmaceutically acceptable salt, or the compound of formula (II-2) or its pharmaceutically acceptable salt. 、 Further preferred are the compounds shown in formula (II-1) or their pharmaceutically acceptable salts.

6. The use according to any one of claims 1-5, wherein the dosage of said AR PROTAC is selected from 1-1500 mg (calculated as free base), preferably 90 mg, 180 mg, 240 mg, 270 mg, 360 mg, 450 mg, 540 mg and 630 mg, and more preferably 240 mg or 360 mg.

7. The use according to any one of claims 1-6, wherein the AR PROTAC is administered once a day, twice a day, three times a day, once every two days, once every three days, or once a week, preferably once a day or twice a day, more preferably twice a day.

8. The use according to any one of claims 1-7, wherein the dosing cycle of the KAT6 inhibitor is 4 weeks and / or the dosing cycle of the AR PROTAC is 4 weeks.

9. The use according to any one of claims 1-8, wherein the KAT6 inhibitor is administered orally.

10. The use according to any one of claims 1-9, wherein the AR PROTAC is administered orally.

11. The use according to any one of claims 1-10, wherein the tumor is prostate cancer, preferably castration-resistant prostate cancer, more preferably metastatic castration-resistant prostate cancer.

12. A composition comprising the KAT6 inhibitor of any one of claims 1-10 and the AR PROTAC of any one of claims 1-10.

13. A pharmaceutical composition comprising the KAT6 inhibitor of any one of claims 1-10, the AR PROTAC of any one of claims 1-10, and one or more pharmaceutically acceptable carriers.

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