Pharmaceutical composition composed of HID-1121 and PARP inhibitor and application thereof

Abstract

The invention belongs to the field of biological medicine, and particularly relates to a pharmaceutical composition composed of HID-1121 and a PARP inhibitor and application of the pharmaceutical composition. The invention provides a drug combination composition of HID-1121 and a PARP inhibitor, and a better treatment effect is achieved through the synergistic effect of the drugs.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a drug combination consisting of HID-1121 and a PARP inhibitor and its application. Background Technology

[0002] Epigenetics, also known as pseudogenetics, epigenetics, exogenous genetics, or postgenetics, studies, in biology and specific genetic fields, changes in heritable gene expression or cellular phenotypes caused by certain mechanisms without altering the DNA sequence. The main research areas of epigenetics include DNA / RNA methylation, histone modifications, nucleosome localization, and the three-dimensional structure of non-coding RNA and chromatin.

[0003] Histone deacetylases (HDACs) are a class of enzymes that play important biological functions in cells. The mechanism of action of HDAC inhibitors can be explained by their antagonistic properties against histone deacetylases, which are involved in regulating processes related to apoptosis, cell growth, tumor progression, cancer metastasis, and cell adhesion. These properties prevent HDACs from binding to their natural ligands (which can be histones or cytoplasmic proteins such as tubulin) and from their normal catalytic activation, namely the deacetylation of ε-N-acetylsine residues present in these proteins. CN102648177B discloses a novel histone deacetylase inhibitor that can be used to prepare drugs for cancer treatment. HID-1121 is a highly selective and potent HDAC 6 inhibitor. HID-1121 has also shown high efficacy in two different mouse models of multiple sclerosis (see WO2018 / 087082).

[0004] Poly(ADP-ribose) polymerase (PARP) is a ribozyme involved in various DNA repair pathways. PARP inhibitors (PARPi) are a class of drugs that primarily exert their anti-tumor effects by targeting and inhibiting PARP1 / 2 proteins, thereby inducing synthetic lethality in tumor cells with BRCA1 / 2 mutations or HRD positivity.

[0005] Cancer is a disease characterized by the development of abnormal cells. These abnormal cells divide uncontrollably and have the ability to infiltrate and destroy normal human tissues. Cancer often manifests as unexplained lumps, pain, ulcers, bleeding, obstruction, and other abnormalities in the body. The causes of cancer are currently unclear, but it is generally believed to be related to a variety of factors, including genetics, environmental pollution, radiation, and unhealthy habits. Cancer is the second leading cause of death worldwide. Cancer treatment often involves comprehensive approaches, primarily combining surgery, chemotherapy, and radiotherapy. In some cases, targeted therapy and biological therapy may be added to improve prognosis. The post-treatment prognosis depends on factors such as the type and stage of cancer, and the patient's general health condition.

[0006] Chemotherapy, also known as chemotherapy, is a treatment strategy used to kill tumor cells. It works by using chemical drugs systemically or locally to inhibit tumor growth or eliminate the tumor. Because chemotherapy is highly effective against certain types of tumors, such as hematopoietic malignancies and solid tumors, its role in cancer treatment remains irreplaceable. However, chemotherapy targets all cells in the body, including tumor cells and normal cells, meaning the drugs used have a certain degree of toxicity and may damage both normal and tumor cells, potentially causing various side effects. Combination therapy for cancer offers several advantages, primarily in enhancing efficacy, reducing drug resistance, minimizing side effects, and improving patients' quality of life. Summary of the Invention

[0007] This disclosure aims to develop a novel combination therapy regimen that can achieve better therapeutic effects through synergistic effects between the drugs. The combination therapy regimen of this disclosure can address the problems of drug resistance, side effects, and insufficient efficacy faced by conventional chemotherapy regimens.

[0008] On one hand, this disclosure provides a drug combination or pillbox, the drug combination or pillbox comprising a first drug and a second drug.

[0009] The first agent is a histone deacetylase (HDAC) inhibitor, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof;

[0010] The second agent is a PARP inhibitor, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof.

[0011] Preferably, the first agent is a histone deacetylase 6 inhibitor, wherein the histone deacetylase 6 inhibitor is selected from one or more of HID-1121, ACY-1215 (CAS No. 1316214-52-4), ACY241 (CAS No. 1316215-12-9), KA2507 (CAS No. 1636894-46-6), WT161 (CAS No. 1206731-57-8), Tubacin (CAS No. 537049-40-4), and Tubastatin (CAS No. 1252003-15-8).

[0012] Preferably, the first agent is HID-1121, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof, wherein HID-1121 has the structure shown in formula (I):

[0013]

[0014] More specifically, the PARP inhibitors include AZD2461 (CAS No. 1174043-16-3), CEP8983 (CAS No. 374071-46-2), DR2313 (CAS No. 284028-90-6), E7016 (CAS No. 902128-92-1), E7449 (CAS No. 1140965-47-4), NU1025 (CAS No. 90417-38-2), NU1064 (CAS No. 63916-38-1), and IMP4297 ( Senaparib, fluzoparib (SHR3162), niraparib (ZEJULA, MK-4827), olaparib (AZD2281), rucaparib (RUBRACA, AG-014699, PF-01367338), simmiparib, talazoparib (BMN-673), and veliparib (ABT-888).

[0015] Preferably, the second agent is olaparib, its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug.

[0016] In some embodiments, the molar ratio of HID-1121 to olaparib is 1:(0.01-100), based on the content of HID-1121; specifically, it may include: 1:(0.01, 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100), preferably 1:(0.05:50); preferably 1:(0.1-10); preferably 1:(0.2-5).

[0017] In some embodiments, the drug combination or kit contains 1-1000 mg of HID-1121, based on the amount of HID-1121; preferably, 5-500 mg; preferably, 10-300 mg; preferably, 20-200 mg; preferably, 10-100 mg. In clinical practice, those skilled in the art can flexibly adjust the dosage of HID-1121 according to the patient's specific condition, physical status, and other relevant factors.

[0018] In some embodiments, the drug combination or kit contains 1-5000 mg of olaparib, based on the amount of olaparib; preferably, 10-4000 mg; preferably, 50-2000 mg; preferably, 100-1000 mg; preferably, 300-600 mg. In clinical practice, those skilled in the art can flexibly adjust the dosage of olaparib according to the patient's specific condition, physical status, and other relevant factors.

[0019] In some embodiments, the weight ratio of HID-1121 to olaparib is 1:(0.01-100), based on the content of HID-1121; specifically, it may include: 1:(0.01, 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100), preferably 1:(0.5-50), preferably 1:(0.1-10), and preferably 1:(0.25-5).

[0020] In some embodiments, the final concentration of HID-1121 in the drug, drug combination, or kit is 1-20 mg / mL, for example, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, or 20 mg / mL, preferably 5-15 mg / mL, preferably 7-13 mg / mL, preferably 8-12 mg / mL, and more preferably 9-11 mg / mL.

[0021] In some embodiments, the final concentration of olaparib or its derivative in the drug, drug combination or cassette is 0.1-200 mg / ml, based on the content of olaparib, for example, it can be 0.1, 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 mg / ml, preferably 0.1-100 mg / ml, preferably 0.5-50 mg / ml, preferably 1-20 mg / ml, preferably 2.5-10 mg / ml, preferably 2.5 mg / ml or 10 mg / ml.

[0022] In some embodiments, the drug combination or kit contains 1-1000 mg of HID-1121, based on the amount of HID-1121; preferably, 5-500 mg; preferably, 10-300 mg; preferably, 20-200 mg; preferably, 10-100 mg. In clinical practice, those skilled in the art can flexibly adjust the dosage of HID-1121 according to the patient's specific condition, physical status, and other relevant factors.

[0023] In some embodiments, the drug combination or kit contains 1-5000 mg of olaparib, based on the amount of olaparib; preferably, 10-4000 mg; preferably, 50-2000 mg; preferably, 100-1000 mg; preferably, 300-600 mg. In clinical practice, those skilled in the art can flexibly adjust the dosage of olaparib according to the patient's specific condition, physical status, and other relevant factors.

[0024] In some embodiments, the drug combination or cassette may further include one or more pharmaceutically acceptable carriers.

[0025] In some embodiments, the pharmaceutically acceptable carrier is selected from antioxidants, preservatives, wetting agents, emulsifiers, and dispersants.

[0026] In some embodiments, the pharmaceutical combinations of this disclosure further comprise a buffer (i.e., a buffer salt dissolved therein). Optionally, the buffer may be selected from the group consisting of: MES, Bis-Tris, ADA, ACES, PIPES, MOPSO, BES, MOPS, TES, HEPES, DIPSO, MOBS, TAPSO, Tris-HCl, HEPPSO, POPSO, TEA, EPPS, Tris(hydroxymethyl)glycine (Tricine), Gly-Gly, N,N-dihydroxyethylglycine (Bicine), HEPBS, TAPS, AMPD, TABS, AMPSO, CHES, CAPSO, APS, CHAPS, CABS, phosphates, and histidine, or combinations thereof. Where it is not desired to be bound by theory, the use of a buffer is believed to help stabilize the drug or pharmaceutical combination at physiological pH. The concentration range of buffer salts in aqueous drugs or drug combinations can be 1 mM to 1 M, preferably 1 mM to 100 mM, preferably 5 mM to 50 mM, or preferably 5 mM to 20 mM.

[0027] In some embodiments, the pharmaceutical composition disclosed herein may also contain counterions and salts, such as sodium counterions, chloride ions, or NaCl dissolved in solution.

[0028] In some embodiments, the HID-1121 in the drug combination or kit is contained in one or more of the following formulations: powder, injection, tablet, capsule, pill, suspension, syrup, solution, lozenge, suppository, inhaler, and spray; and the olaparib is contained in one or more of the following formulations: powder, injection, tablet, capsule, pill, suspension, syrup, solution, lozenge, suppository, inhaler, and spray.

[0029] In some embodiments, the HID-1121 in the drug combination or kit is contained in one or more formulations of powder, injection, tablet, capsule, pill, suspension, or syrup, and the olaparib is contained in one or more formulations of powder, injection, tablet, capsule, pill, suspension, or syrup.

[0030] In some embodiments, the HID-1121 in the drug combination or kit is contained in one or more formulations of powder or injection, and the olaparib is contained in one or more formulations of powder or injection.

[0031] In some implementations, HID-1121 and olaparib in the drug combination or kit may be included in the same formulation or in different formulations.

[0032] The "medicine" or "medicine combination" described in this disclosure can be administered to a patient or subject requiring such treatment via any suitable route of administration, such as oral, intravenous, parenteral, rectal, pulmonary, or local administration. When intended for oral administration, the medicine or medicine combination can be formulated as an oral preparation, such as an oral solid preparation, like tablets, capsules, pills, granules, etc.; or an oral liquid preparation, such as an oral solution, oral suspension, syrup, etc. When formulated as an oral preparation, the medicine preparation may also contain suitable fillers, binders, disintegrants, lubricants, etc.

[0033] The drugs or drug combinations disclosed herein can be formulated into any pharmaceutically acceptable dosage form for oral, nasal, topical (including oral cavity and sublingual), rectal, vaginal and / or parenteral administration, for example, they can be formulated into tablets, lozenges, capsules, pills, powders, granules, solutions, suspensions, syrups, injections, suppositories, inhalers or sprays.

[0034] In some embodiments, the pharmaceutical or pharmaceutical combination of this disclosure is a solid dosage form, such as capsules, tablets, granules, powders, or sachets. In some embodiments, the pharmaceutical or pharmaceutical combination of this disclosure is a sterile injectable solution in one or more aqueous or non-aqueous, non-toxic, parenteral-acceptable buffer systems, diluents, solubilizers, cosolvents, or carriers. The sterile injectable formulation may also be a sterile injectable aqueous or oily suspension or a suspension in a non-aqueous diluent, carrier, or cosolvent, which may be formulated according to known procedures using one or more suitable dispersants or wetting agents and suspending agents. The pharmaceutical or pharmaceutical combination may be a solution for intravenous (iv) bolus / infusion, or a lyophilized system (alone or with excipients) reconstituted with a buffer system and / or not with other excipients. The lyophilized material may be prepared from non-aqueous or aqueous solvents. The dosage form may also be a concentrate for further dilution for subsequent infusion.

[0035] In some embodiments, HID-1121 or its derivatives are administered by injection. The administration can be carried out by infusion (continuous) or bolus injection (discontinuous). Methods of administration by injection include, for example, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrasheathic, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intra-articular, subarachnoid, and intrasternal injection. Preferably, administration is carried out by intravenous infusion or intravenous injection (bolus injection). More preferably, administration is carried out by intravenous infusion.

[0036] On the other hand, this disclosure provides the use of the aforementioned first and second pharmaceutical agents, or the aforementioned pharmaceutical combinations or kits, in the preparation of pharmaceutical agents, pharmaceutical combinations, or kits for the prevention and / or treatment of cancer.

[0037] Preferably, the cancers include pancreatic cancer, cervical cancer, seminoma, testicular lymphoma, prostate cancer, ovarian cancer, lung cancer, rectal cancer, breast cancer, colon cancer, liver cancer, esophageal cancer, thyroid cancer, bladder transitional cell carcinoma, leukemia, brain tumor, gastric cancer, peritoneal cancer, head and neck cancer, endometrial cancer, kidney cancer, female reproductive tract cancer, carcinoma in situ, neurofibroma, bone cancer, skin cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, and sarcoma.

[0038] Preferably, the cancer is one or more of prostate cancer, breast cancer, and pancreatic cancer.

[0039] Preferably, the prostate cancer includes adenocarcinoma, ductal adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, and adenosquamous carcinoma.

[0040] Preferably, the types of breast cancer include luminal A, luminal B, HER2 overexpression, and triple-negative breast cancer;

[0041] Preferably, the pancreatic cancer includes drug-resistant pancreatic cancer.

[0042] Preferably, the pancreatic cancer includes pancreatic head cancer, pancreatic neck cancer, pancreatic body cancer, and pancreatic tail cancer.

[0043] Preferably, the pancreatic cancer includes ductal cell carcinoma, acinar cell carcinoma, islet cell carcinoma, and rare types of carcinoma.

[0044] In some implementations, the first and second agents are administered simultaneously, sequentially, or alternately.

[0045] In some implementations, the drug, drug combination, or cassette as described above has at least one effect selected from the following: significant reduction in tumor volume; significant reduction in relative tumor volume.

[0046] In a third aspect, this disclosure provides a combined treatment method comprising the aforementioned first and second agents, wherein the first and second agents are administered to the subject simultaneously, sequentially, or separately.

[0047] In another aspect, this disclosure provides a method for treating cancer, comprising administering a PARP inhibitor at any time before, during, or after administration of the HDAC6 inhibitor or a derivative thereof disclosed herein.

[0048] In another aspect, this disclosure provides a method for improving the efficacy of an HDAC6 inhibitor or a derivative thereof, comprising administering a PARP inhibitor at any time before, during, or after administration of the HDAC6 inhibitor or a derivative thereof disclosed herein.

[0049] In this disclosure, unlike other histone deacetylase inhibitors, HID-1121 advantageously does not exhibit signs of genotoxicity, particularly clastogenicity or aneugenicity. Similarly, it has been unexpectedly observed that HID-1121 possesses better biological activity, improved pharmacokinetic properties, particularly a longer half-life and a larger volume of distribution, and better safety compared to other histone deacetylase inhibitors.

[0050] Generally, the effective dose of compound HID-1121 to be administered will depend on a range of factors, such as the severity of the disease being treated and the subject's weight. Compound HID-1121 is usually administered once or more daily, such as 1, 2, 3 or 4 times daily, with a typical total daily dose ranging from 0.01 to 1000 mg / kg / day.

[0051] In some embodiments, the HDAC6 inhibitor or its derivative is administered at the same or different cycles as a chemotherapy drug such as olaparib. In some preferred embodiments, the HDAC6 inhibitor or its derivative is administered at different cycles than a chemotherapy drug such as olaparib.

[0052] In some embodiments, the single-dose dose of HID-1121 or its derivatives, based on the content of HID-1121, is 1-100 mg / kg, for example, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, or 100 mg / kg, preferably 10-80 mg / kg, more preferably 40-80 mg / kg, and even more preferably 50-70 mg / kg. For human patients, it is preferred to administer a dose of 1 to 20 mg / kg, more preferably 4 to 10 mg / kg. Preferably, HID-1121 is administered to human patients at a dose of 25 mg to 4500 mg daily, preferably 50 mg to 3000 mg, and more preferably 250 mg to 1500 mg. In some preferred embodiments, HID-1121 is administered once daily for the first week of continuous administration. The single dose for mice, based on the HID-1121 content, is 100 mg / kg, equivalent to approximately 4.8 mg / kg for human patients. In clinical practice, those skilled in the art can flexibly adjust the dosage according to the patient's specific condition, physical status, and other relevant factors; for example, the dosage may be increased or decreased according to the patient's weight.

[0053] In some embodiments, the single-dose dose of olaparib, based on its content, is 1-5000 mg; preferably, 10-4000 mg; preferably, 50-2000 mg; preferably, 100-1000 mg; preferably, 300-600 mg. In clinical practice, those skilled in the art can flexibly adjust the dosage according to the patient's specific condition, physical status, and other relevant factors, for example, increasing or decreasing the dosage according to the patient's weight.

[0054] In some embodiments, compound HID-1121 or a pharmaceutical composition containing compound HID-1121 is administered by injection. The administration can be carried out by infusion (continuous) or bolus injection (discontinuous). Injection methods can include, for example, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal injection. Preferably, administration is carried out by intravenous infusion or intravenous injection (bolus injection). More preferably, administration is carried out by intravenous infusion.

[0055] In some embodiments, this disclosure provides a method for treating cancer in a mammalian subject, the method being to administer a first agent and a second agent of either of the foregoing aspects simultaneously, sequentially, or separately to the subject.

[0056] In some embodiments, according to the application of this disclosure, the cancers include pancreatic cancer, cervical cancer, seminoma, testicular lymphoma, prostate cancer, ovarian cancer, lung cancer, rectal cancer, breast cancer, colon cancer, liver cancer, esophageal cancer, thyroid cancer, transitional cell carcinoma of the bladder, leukemia, brain tumor, gastric cancer, peritoneal cancer, head and neck cancer, endometrial cancer, kidney cancer, female reproductive tract cancer, carcinoma in situ, neurofibroma, bone cancer, skin cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, and sarcoma.

[0057] Preferably, the cancer is one or more of prostate cancer, breast cancer, and pancreatic cancer.

[0058] Preferably, the prostate cancer includes adenocarcinoma, ductal adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, and adenosquamous carcinoma.

[0059] Preferably, the types of breast cancer include luminal A, luminal B, HER2 overexpression, and triple-negative breast cancer;

[0060] Preferably, the pancreatic cancer includes drug-resistant pancreatic cancer.

[0061] Preferably, the pancreatic cancer includes pancreatic head cancer, pancreatic neck cancer, pancreatic body cancer, and pancreatic tail cancer.

[0062] Preferably, the pancreatic cancer includes ductal cell carcinoma, acinar cell carcinoma, islet cell carcinoma, and rare types of carcinoma.

[0063] In some implementations, the combination therapy of this disclosure includes combining the first agent of this disclosure with olaparib.

[0064] In some embodiments, the combined treatment method of this disclosure administers the first and second agents at the dosage of either of the foregoing aspects.

[0065] The drug combination of the present invention can be administered orally, parenterally, systemically, or locally. For example, it can be administered via intravenous injection (e.g., drip infusion), intramuscular injection, intraperitoneal injection, subcutaneous injection, suppository, colonic injection, or oral administration. The method of administration can be appropriately selected based on the patient's age and condition. The upper and lower limits of the actual dose are affected by the dosing frequency; for example, the dose per dose increases when the dosing interval is long, and decreases when the dosing interval is short. In some embodiments, those skilled in the art can flexibly adjust the dosage according to the patient's specific condition, physical status, and other relevant factors; for example, the dosage can be increased or decreased according to the patient's weight.

[0066] In some implementation schemes, the first dose is administered continuously for one week, followed by a one-week break, and then another one-week continuous administration.

[0067] In some implementations, the first dose is administered only for the first week of a course of treatment.

[0068] In some implementation schemes, the first dose is administered daily.

[0069] In some implementations, the second dose is administered according to the standard clinical protocol for olaparib. Attached Figure Description

[0070] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with this specification and, together with the description, serve to explain the principles of this specification.

[0071] Figure 1 The figure shows the weight change curves of animals in each group at each time point in a prostate cancer animal model; the figure shows the mean weight ± standard error of each group.

[0072] Figure 2 The figure shows the tumor volume of each group at each time point in an animal model of prostate cancer; the figure shows the mean ± standard error of the tumor volume of each group.

[0073] Figure 3 The figure shows the relative tumor volume of animals in each group at each time point in an animal model of prostate cancer; the figure shows the mean ± standard error of the relative tumor volume of each group.

[0074] Figure 4 The figure shows the weight change curves of animals in each group at each time point in a breast cancer animal model; the figure shows the average weight ± standard error of each group.

[0075] Figure 5 The figure shows the tumor volume of each group at each time point in the animal model of breast cancer; the figure shows the mean ± standard error of the tumor volume of each group.

[0076] Figure 6 The figure shows the relative tumor volume of animals in each group at each time point in a breast cancer animal model; the figure shows the mean ± standard error of the relative tumor volume of each group.

[0077] Figure 7 The figure shows the weight change curves of animals in each group at each time point in an animal model of pancreatic cancer; the figure shows the mean ± standard error of the weight of animals in each group.

[0078] Figure 8The figure shows the tumor volume of each group at each time point in an animal model of pancreatic cancer; the figure shows the mean ± standard error of the tumor volume of each group.

[0079] Figure 9 The figure shows the relative tumor volume of animals in each group at each time point in an animal model of pancreatic cancer; the figure shows the mean ± standard error of the relative tumor volume of each group.

[0080] Figure 10 The figure shows the weight change curves of animals in each group at each time point in an animal model of drug-resistant pancreatic cancer; the figure shows the mean ± standard error of the weight of animals in each group.

[0081] Figure 11 The figure shows the tumor volume of each group at each time point in an animal model of drug-resistant pancreatic cancer; the figure shows the mean ± standard error of the tumor volume of each group.

[0082] Figure 12 The figure shows the relative tumor volume of animals in each group at each time point in an animal model of drug-resistant pancreatic cancer; the figure shows the mean ± standard error of the relative tumor volume of each group. Detailed Implementation

[0083] To make the objectives, technical solutions, and advantages of this disclosure clearer, the following detailed description is provided through specific embodiments. Obviously, the described embodiments are merely some, not all, of the embodiments of this disclosure. All other implementations obtained by those skilled in the art based on the embodiments of this disclosure without inventive effort are within the scope of protection of this disclosure.

[0084] This disclosure may be implemented in other specific forms without departing from its essential attributes. It should be understood that, without conflict, any and all embodiments of this disclosure may be combined with technical features of any or more other embodiments to obtain further embodiments. This disclosure includes such further embodiments obtained through combination.

[0085] Definitions and Explanations

[0086] To facilitate understanding of this disclosure, certain technical and scientific terms are specifically defined below. In this disclosure, unless otherwise stated, the scientific and technical terms used herein have meanings commonly understood by those skilled in the art. Furthermore, the cell and tissue culture, microbiology-related terms, and laboratory procedures used herein are all widely used terms and routine procedures in their respective fields. Meanwhile, to better understand this disclosure, definitions and explanations of relevant terms are provided below. It should be understood that this disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems, and variations thereof are certainly possible. It should also be understood that the terminology used in this application is for describing specific embodiments only and is not intended to be limiting.

[0087] All publications and patents mentioned in this disclosure are incorporated herein by reference in their entirety. In the event of any conflict between the use or terminology used in any publications and patents incorporated by reference and the use or terminology used in this disclosure, the use and terminology of this disclosure shall prevail. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter.

[0088] Unless otherwise expressly stated, the terms “a,” “an,” and “the” as used in this specification and the appended claims cover one or more types.

[0089] As used in this article, the conjunction term “and / or” between multiple elements means to include both “and” and “or” meanings. For example, the phrase “A, B and / or C” is intended to cover each of the following: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0090] As used herein, the terms “comprising,” “including,” “having,” and “containing,” and any variations thereof, are intended to cover non-exclusive inclusion. The term is intended to be open-ended to specify the presence of any of the stated features, elements, integers, steps, or components, but does not exclude the presence or addition of one or more other features, elements, integers, steps, components, or groups thereof. Therefore, the term “comprising” includes the more restrictive terms “consisting of” and “substantially consisting of”.

[0091] The numerical ranges used in this article should be understood as including all numbers within that range. For example, the range 1 to 20 should be understood to include any number, combination of numbers, or subrange from the following group: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0092] As used herein, the term "about" indicates a range of ±20% of the following value. In some embodiments, the term "about" indicates a range of ±10% of the following value. In some embodiments, the term "about" indicates a range of ±5% of the following value.

[0093] In the description herein, references to “some embodiments,” “some implementations,” or “some implementation schemes” describe a subset of all possible embodiments. However, it is understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0094] As used herein, the terms “histone deacetylase,” “histone deacetylase,” “histone deacetylase,” “histone deacetylase,” and “HDAC” are used interchangeably to refer to any of the enzyme families that remove an acetyl group from the ε-amino group of a lysine residue at the N-terminus of histone or tubulin. HDAC6 is the largest protein in the HDAC family and functions in cells by regulating non-histone substrates and signaling pathways.

[0095] As used herein, the term "pharmacy box" refers to one or more components packaged separately or placed in a container, such as a tube, bottle, vial, bag, blister pack, syringe, or other suitable container device. The pharmaceutical boxes described herein may also include instructions for using the components of the pharmaceutical box to carry out the subject method (e.g., instructions for preparing and / or using the drug combination described herein). Instructions for carrying out the subject method are typically recorded on a suitable recording medium. For example, instructions may be printed on a substrate such as paper or plastic. Thus, instructions may exist in the form of a package insert within the pharmaceutical box, or on a label of the container of the pharmaceutical box or its components (i.e., components associated with the packaging or sub-package). In some embodiments, instructions exist as an electronic storage data document stored on a suitable computer-readable storage medium (e.g., CD-ROM, disk, etc.). In other embodiments, the actual instructions are not present in the pharmaceutical box, but means are provided for obtaining the instructions from a remote source, such as via the Internet. An example of this embodiment is a pharmaceutical box that includes a URL where the instructions are located and / or from which the instructions can be downloaded.

[0096] As used herein, the terms “cancer,” “carcinoma,” “tumor,” and “tumor” are used interchangeably to refer to a disease characterized by the uncontrolled growth of abnormal cells, including precancerous lesions as well as malignant cancers and tumors. Tumor cells can spread locally or through the bloodstream and lymphatic system to other parts of the body, and said cancers include solid tumors and hematologic malignancies. Examples of various cancers are described herein, including but not limited to pancreatic cancer, cervical cancer, seminoma, testicular lymphoma, prostate cancer, ovarian cancer, lung cancer, rectal cancer, breast cancer, colon cancer, liver cancer, esophageal cancer, thyroid cancer, transitional cell carcinoma of the bladder, leukemia, brain tumor, gastric cancer, peritoneal cancer, head and neck cancer, endometrial cancer, kidney cancer, female reproductive tract cancer, carcinoma in situ, neurofibroma, bone cancer, skin cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, and sarcoma. Preferably, said cancer is one or more of prostate cancer, breast cancer, and pancreatic cancer. The prostate cancer includes adenocarcinoma, ductal adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, and adenosquamous carcinoma; the breast cancer types include luminal A, luminal B, HER2-overexpressing, and triple-negative breast cancer; the pancreatic cancer includes drug-resistant pancreatic cancer; the pancreatic cancer includes pancreatic head cancer, pancreatic neck cancer, pancreatic body cancer, and pancreatic tail cancer; the pancreatic cancer includes ductal cell carcinoma, acinar cell carcinoma, islet cell carcinoma, and rare types of cancer.

[0097] As used herein, the term “treatment” is intended to include prevention and treatment, methods by which beneficial or desired outcomes, including clinical outcomes, can be obtained. For the purposes of this application, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: relief of one or more symptoms caused by the disease; reduction of the severity of the disease; stabilization of the disease (e.g., prevention or delay of disease progression); prevention or delay of disease spread (e.g., metastasis); prevention or delay of disease recurrence; delay or slowing of disease progression; improvement of disease status; provision of disease remission (partial or complete); reduction of the dosage of one or more other medications required to treat the disease; delay of disease progression; improvement or enhancement of quality of life; increased weight gain and / or prolonged survival. “Treatment” also includes a reduction in the pathological outcome of cancer (e.g., tumor volume). In the context of cancer, “treatment” includes any or all of the following: inhibition of cancer cell growth; inhibition of cancer cell replication and metastasis; reduction of overall tumor burden; and improvement of one or more symptoms associated with the disease.

[0098] As used herein, the term "effective dose" or "therapeutic effective dose" includes an amount sufficient to improve or prevent the symptoms or condition of a medical condition. An effective dose also means an amount sufficient to allow or facilitate diagnosis. The effective dose for a particular patient or veterinary subject can 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 dose can be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0099] As used herein, the terms “subject,” “individual,” or “patient” are used interchangeably and refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, mice, apes, humans, farm animals, sports animals, and pets.

[0100] The amount of medication administered can depend on the subject being treated, the subject's age, health status, sex, and weight, the type of concurrent treatment (if any), the severity of the condition, the nature of the desired effect, the manner and frequency of treatment, and the prescribing physician's judgment. The frequency of administration can also depend on the pharmacodynamic effect on arterial oxygen partial pressure. However, the optimal dose can be adjusted for individual subjects, as understood by those skilled in the art and determined without tolerance testing. This typically involves adjusting the standard dose (e.g., reducing the dose if the patient is underweight).

[0101] As used herein, the term "administration" refers to a method of giving a subject (e.g., a patient) a dose of a pharmaceutical composition (e.g., a combination of the first and second pharmaceutical agents of this disclosure or a cassette). Administration can be made by any suitable route, such as by injection, like intravenous, intramuscular, or subcutaneous injection, depending in part on whether the administration is short-term or long-term.

[0102] In some implementations, drug combinations or kits are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Various dosing regimens are considered herein, including but not limited to single or multiple administrations at different time points.

[0103] As used herein, the term "injection" means any form of injection known to a person skilled in the art, such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrasheath, intraspinal, intrabursal, subbursal, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal injection. Injection can refer to an infusion process (e.g., continuous administration) as well as a bolus injection (discontinuous administration).

[0104] As used herein, the terms "combined administration," "combination," or "co-administration" are a method of administration that includes various situations in which two, three, or more different drugs are administered simultaneously, separately, or sequentially. The term "simultaneous" administration includes administration within the same dosing cycle, such as within two days or one day, of two, three, or more different drugs. The term "sequential" administration means that two, three, or more different drugs are therapeutically effective within the same time frame. "Sequential" administration allows for administration of another drug 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, or several hours after administering one drug, provided that the circulating half-life of the first administered drug allows for the simultaneous presence of therapeutically effective amounts of both. The time delay between administrations of the components will vary depending on the exact nature of the components, their interactions, and their respective half-lives. The term "separate" means that the interval between administration of one drug and another is significant, i.e., when the second drug is administered, the first administered drug may no longer be present in the bloodstream at a therapeutically effective amount. All of the above administration methods fall under the category of combined administration as described in this disclosure. This administration includes co-administering the therapeutic agents in a substantially simultaneous manner, such as in a single capsule containing the active ingredients in a fixed proportion. Alternatively, this administration includes co-administering the individual active ingredients in multiple or separate containers (e.g., tablets, capsules, powders, and liquids). Powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. Furthermore, this administration includes using each type of therapeutic agent sequentially at substantially the same time or at different times. In either case, the treatment regimen will provide the beneficial effect of the pharmaceutical composition in treating the condition or symptom described herein.

[0105] As used herein, the term "histone deacetylase 6 inhibitor" or "HDAC6 inhibitor" refers to compounds that can interact with and inhibit the activity of histone deacetylase 6, more specifically, inhibit its enzymatic activity. Inhibition of the enzymatic activity of histone deacetylase 6 means reducing the ability of histone deacetylase 6 to remove acetyl groups from histones or tubulin. Preferably, this inhibition is specific, i.e., the histone deacetylase 6 inhibitor reduces the ability of histone deacetylase 6 to remove acetyl groups from histones or tubulin at concentrations below the inhibitory concentrations required to produce some other unrelated biological effects. The term "HDAC6 inhibitor" is intended to include all known or future discovered compounds and their derivatives capable of inhibiting the enzymatic activity of HDAC6.

[0106] As used herein, the term "HID-1121" includes those with The compound with the structure shown or its derivatives are compounds that specifically inhibit HDAC6. References to the term "HID-1121" herein are intended to include the crystalline form of HID-1121 and its adducts, as well as pharmaceutically acceptable salts of HID-1121 (e.g., its trifluoroacetate), stereoisomers of HID-1121, solvates of HID-1121, or prodrugs of HID-1121. Methods for preparing HID-1121 and indications of its biological activity in various medical treatments are described, for example, in WO2011 / 039353 and WO2018 / 087082, the contents of which are incorporated herein by reference. Advantageous pharmaceutical formulations containing HID-1121 are further described in CN202210325433.9 (CN114652715B), the contents of which are incorporated herein by reference.

[0107] As used herein, compounds including one or more asymmetric centers, such as HID-1121, can exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, compounds disclosed herein, such as HID-1121, can be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or can be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis.

[0108] As used herein, HID-1121 can be in an amorphous or crystalline form (crystalline or polymorphic), and HID-1121 can exist in one or more crystalline forms. Therefore, this disclosure includes all amorphous or crystalline forms of HID-1121. The term "polymorph" refers to a crystalline form (or its salt, hydrate, or solvate) with a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to become dominant.

[0109] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that, when administered to a recipient, can (directly or indirectly) provide HID-1121 as described in this invention. "Pharmaceutically acceptable" preferably refers to compositions and molecular entities that are physiologically tolerable and generally do not produce allergic reactions or similar adverse reactions, such as gastritis, dizziness, etc., when administered to humans or animals. In this disclosure, the salt can be prepared by methods known in the art. For example, pharmaceutically acceptable salts can be synthesized from a primary compound containing basic residues using conventional chemical methods. Generally, the salt is prepared, for example, by reacting the free basic form of the compound with a suitable base or acid in water, or in an organic solvent, or in a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Examples of acid addition salts include inorganic acid addition salts, such as hydrochlorides, hydrobroms, hydroiodates, sulfates, nitrates, and phosphates; and organic acid addition salts, such as acetates, maleates, fumarates, citrates, oxalates, succinates, tartrates, malates, mandelates, methanesulfonates, and p-toluenesulfonates. Examples of base addition salts include inorganic salts, such as sodium, potassium, calcium, ammonium, magnesium, aluminum, and lithium salts; and organic salts, such as basic salts of ethylenediamine, ethanolamine, N,N-dialkylethanolamine, triethanolamine, glucosamine, and amino acids.

[0110] As used herein, the term "solvent" refers to a form of compound bound to a solvent, typically formed by the decomposition of a solvent. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. "Solvent" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates. When the solvent is water, the complex is called a "hydrate." This disclosure covers all solvates of HID-1121.

[0111] As used herein, the HID-1121 also includes isotopically labeled HID-1121, which are equivalent to HID-1121 but with one or more atoms replaced by atoms of different atomic masses or mass numbers than those commonly found in nature. Examples of isotopes that may be introduced into the HID-1121 of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. Other isotopes of the HID-1121 of this disclosure containing the above-mentioned isotopes and / or other atoms, as well as their prodrugs and pharmaceutically acceptable salts, are within the scope of this disclosure. Certain isotopically labeled HID-1121 of this disclosure, for example, incorporating radioactive isotopes (e.g., 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e.14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H may be preferred in some cases because its higher metabolic stability can provide therapeutic benefits, such as prolonged half-life or reduced dosage requirements.

[0112] As used herein, the term "pharmaceutically acceptable carrier" refers to non-toxic solid, semi-solid, or liquid fillers, diluents, encapsulating materials, formulation adjuvants or carriers, excipients, adjuvants, buffers, pH adjusters, preservatives, antioxidants, antibacterial agents, stabilizers, suspending agents, solubilizers, surfactants (e.g., wetting agents), colorants, and isotonic solutes (i.e., those that make the formulation isotonic with the blood or other relevant bodily fluids of the intended recipient), which together constitute a drug or combination of drugs for individual administration. Suitable carriers, diluents, excipients, etc., can be found in standard pharmaceutical literature. Pharmaceutically acceptable carriers are non-toxic to the recipient at the doses and concentrations used and are compatible with other components of the formulation. Pharmaceutically acceptable carriers are suitable for the formulation used. Suitable carriers are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, liposomes, polymer micelles, or inorganic nanocarriers, etc.

[0113] As used in this article, HID-1121 can specifically inhibit HDAC6 to a large extent. In order to enhance the anti-tumor activity of HID-1121, the inventors unexpectedly discovered that when it is used in combination with olaparib to treat cancer, it has a significant synergistic effect, which significantly enhances the tumor inhibition effect. The inhibition rate can reach 82.43% for prostate cancer, 88.36% for breast cancer, 61.98% for pancreatic cancer, and 14.03% for drug-resistant pancreatic cancer. At the same time, it can improve the dosage and duration of treatment, which is beneficial to overcome the development of side effects that are usually associated with the use of higher doses of single chemotherapy agents, thereby improving patient adherence to the drug.

[0114] As used herein, the term "PARP inhibitors" refers to a class of targeted drugs that exert their anti-tumor effects by inhibiting the activity of poly(ADP-ribose) polymerase (PARP). Specifically, these PARP inhibitors include AZD2461 (CAS No. 1174043-16-3), CEP8983 (CAS No. 374071-46-2), DR2313 (CAS No. 284028-90-6), E7016 (CAS No. 902128-92-1), E7449 (CAS No. 1140965-47-4), NU1025 (CAS No. 90417-38-2), NU1064 (CAS No. 63916-38-1), and IMP4297 (…). The PARP inhibitors are sennaparib, fluzoparib (SHR3162), niraparib (ZEJULA, MK-4827), olaparib (AZD2281), rucaparib (RUBRACA, AG-014699, PF-01367338), simmiparib, talazoparib (BMN-673), and veliparib (ABT-888). Most preferably, the PARP inhibitor is olaparib. The term "olaparib" is also known as Olaparib, Lynparza, Olanib, Olaparix, and Lynib, with the molecular formula C. 24 H 23 FN4O3 has a molecular weight of 434.46. It belongs to the PARP (polymerase-associated adenosine diphosphate ribose polymerase) inhibitor class, which can block the single-strand DNA repair pathway in cells, thereby leading to DNA damage and cancer cell death.

[0115] As used herein, the term "drug combination" refers to a combination of one or more components suitable for administration of different drug components, which may be administered simultaneously, separately, or sequentially. Different drug components may be used together to form a composition (e.g., a pharmaceutical composition) or may exist independently, for example, in separate formulations and / or packages.

[0116] For the purpose of clarity and concise description, the features are described herein as part of some identical or separate embodiments; however, it will be understood that the scope of this disclosure may include some embodiments having a combination of all or some of the features described.

[0117] Example

[0118] To make the objectives, technical solutions, and advantages of the embodiments of this disclosure clearer, the technical solutions of the embodiments of this disclosure will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this disclosure, and not all embodiments. The following is merely a further description of this disclosure, and the protection scope of this disclosure is not limited thereto.

[0119] The raw materials and equipment used in the specific embodiments of this disclosure are all known products, obtained by purchasing commercially available products or by using disclosed methods. For example, compound HID-1121 in the following examples can be obtained by referring to the preparation method of CN102648177B, or it can be directly purchased as a commercial product.

[0120] Commonly used abbreviations are listed in the table below:

[0121] Table 1. Commonly Used Abbreviations

[0122] abbreviation definition D sky Qd Once a day iv Intravenous injection po oral TV Tumor volume RTV relative tumor volume TGI Tumor growth inhibition rate

[0123] Example 1: The efficacy of HID-1121 and olaparib in the treatment of prostate cancer

[0124] 1. Experimental Materials

[0125] HID-1121 (purchased from QUIMATRYX, SL, batch number CC-5570.0-02, purity 99.3%), and related experimental reagents and equipment were all commercially available products. Weigh 13.90g of β-cyclodextrin powder, add 30.00mL of sterile water for injection, stir until completely dissolved, continue stirring and add 5.0mL of 1N NaOH dropwise, then add sterile water for injection to bring the volume to 100mL for later use.

[0126] A total of 45 NCG mice (13 spares) were purchased from the supplier to select animals with suitable weight range and tumor size for enrollment. The mice were used to study the effects of HID-1121 and olaparib on the growth of subcutaneous ectopic xenografts of the human prostate cancer LNCap clone FGC cell line in NCG mice.

[0127] 2. Experimental Methods

[0128] 2.1 Cell Culture and Drug Administration

[0129] The human prostate cancer LNcap Clone FGC cell line used in this experiment was cultured in RPMI-1640 medium supplemented with 15% FBS at 37°C in an incubator containing 5% CO2. Before ten consecutive passages of cell culture, approximately 1×10⁻⁶ cells were added to the medium. 7LNcap CloneFGC cells were mixed with 100 μL of PBS and an equal volume of Matrigel, and then subcutaneously injected into the right back of each mouse near the axilla, with an injection volume of approximately 200 μL. Mice were anesthetized with 3-4% isoflurane prior to injection.

[0130] When the tumor grew to an average size of approximately 116 mm 3 At approximately [time missing], 32 tumor-bearing mice were randomly divided into 4 groups of 8 mice each using E-WorkBook software based on tumor volume and body weight. The day of grouping and drug administration was defined as day 0. Grouping and administration regimens are shown in Table 2.

[0131] Table 2. Grouping and Dosing Regimens

[0132]

[0133]

[0134] 2.2 Evaluation Indicators and Statistical Analysis

[0135] Animal weight: Mouse weight was measured and recorded three times a week during the administration period, grouped (before the first dose) and during the administration period.

[0136] Tumor volume (TV): For the subcutaneous xenograft model, tumor volume was measured three times a week after grouping. Tumor volume (V) was calculated as follows: V = (length × width) 2 ) / 2.

[0137] The relative tumor volume (RTV) is calculated as follows: RTV = Vt / V0, where Vt is the volume measured each time and V0 is the volume at the start of treatment.

[0138] Relative tumor inhibition rate (TGI): TGI% = (1-T / C) × 100%. Where T and C are the relative tumor volumes (RTV) of the experimental group and the negative control group at a specific time point, respectively.

[0139] 3. Results

[0140] 3.1 Weight

[0141] During the experiment, the weight of the animals in each group remained relatively stable. During the drug administration period, all animals were in normal physical condition, moved freely, and no adverse reactions or deaths occurred. The weight changes of the animals in each group at each time point are as follows: Figure 1 .

[0142] 3.2 Tumor volume and relative tumor volume

[0143] During the experiment, the tumor volume in the G1 control group mice continued to increase (see...). Figure 2The average tumor volume on day 0 was 116.06 ± 2.47 mm. 3 On day 28, the average tumor volume reached 1352.99 ± 102.23 mm. 3 The relative mean tumor volume increased to 11.67 ± 0.84 (see...) Figure 3 This indicates that the human prostate cancer LNcap Clone FGC cell line was successfully established in the BALB / c nude mouse subcutaneous ectopic xenograft model in this experiment.

[0144] The mean tumor volume on day 0 in group G2 was 116.60 ± 2.85 mm. 3 On day 28, the average tumor volume reached 924.24 ± 154.36 mm. 3 The relative tumor volume was 7.90±1.29. Compared with the G1 control group at the same time point, the tumor volume was significantly reduced during days 4 and 14–21, and the relative tumor volume was significantly reduced during days 4 and 14–25 (p<0.05 or p<0.01).

[0145] The mean tumor volume on day 0 in group G3 was 115.75 ± 2.94 mm. 3 On day 28, the average tumor volume reached 640.55 ± 140.24 mm. 3 The relative tumor volume was 5.43 ± 1.10. Compared with the G1 control group at the same period, the tumor volume was significantly reduced from day 7 to day 28, and the relative tumor volume was significantly reduced from day 4 to day 28 (p < 0.05 or p < 0.01).

[0146] The mean tumor volume on day 0 in group G4 was 117.48 ± 2.28 mm. 3 On day 28, the average tumor volume reached 239.21 ± 22.44 mm. 3 The relative tumor volume was 2.05 ± 0.21. Compared with the G1 control group at the same time point, the tumor volume and relative tumor volume were significantly reduced during the period from day 4 to day 28 (p < 0.05 or p < 0.01).

[0147] 3.3 Relative tumor inhibition rate (%)

[0148] The relative tumor inhibition rates of each group at each time point are shown in Table 3. After administration, the relative tumor inhibition rates of groups G2-G4 on day 28 were 32.34%, 53.45%, and 82.43%, respectively.

[0149] Table 3. Relative Tumor Inhibition Rate (TGI) (%)

[0150] Grouping Day 4 Day 7 Day 11 Day 14 Day 18 Day 21 Day 25 Day 28 G2 14.45 10.01 15.10 28.28 30.84 33.01 32.60 32.34 G3 9.66 18.20 21.07 44.58 49.75 53.56 55.47 53.45 G4 12.40 24.84 36.19 58.41 69.43 81.42 82.85 82.43

[0151] 4. Experimental Conclusions

[0152] This experiment successfully established a subcutaneous ectopic xenograft model of human prostate cancer LNcap Clone FGC cell line in BALB / c nude mice. The tumor volume in the G1 control group mice steadily increased, with a mean tumor volume of 116.06 mm² on day 0. 3 At the end of the experiment (day 28), the average tumor volume reached 1352.99 mm. 3 The relative tumor volume reached 11.67.

[0153] Compared with the G1 blank group, the G2 to G4 groups all showed a significant reduction in tumor volume (TV) and relative tumor volume (RTV) during the administration period (p<0.05 or p<0.01).

[0154] In summary, all treatment groups showed significant tumor-inhibiting effects. Among them, the HID-1121 (100 mg / kg) + olaparib (25 mg / kg) combination group had smaller tumor volume and higher TGI% than other treatment groups, showing greater advantages and better tumor growth inhibition.

[0155] Example 2: The efficacy of HID-1121 and olaparib in the treatment of breast cancer

[0156] 1. Experimental Materials

[0157] HID-1121 (purchased from QUIMATRYX, SL, batch number CC-5570.0-02, purity 99.3%), and related experimental reagents and equipment were all commercially available products. Weigh 13.90g of β-cyclodextrin powder, add 30.00mL of sterile water for injection, stir until completely dissolved, continue stirring and add 5.0mL of 1N NaOH dropwise, then add sterile water for injection to bring the volume to 100mL for later use.

[0158] A total of 45 BALB / c nude mice (13 spares) were purchased from the supplier to study the effect of the test substance on the growth of subcutaneous ectopic xenografts in BALB / c nude mice from the human breast cancer MDA-MB-436 cell line.

[0159] 2. Experimental Methods

[0160] 2.1 Cell Culture and Drug Administration

[0161] The human breast cancer MDA-MB-436 cell line used in this experiment was cultured in L15 medium supplemented with 20% FBS and 10 μg / mL human recombinant insulin in a CO2-free incubator at 37°C. Before ten passages of continuous cell culture, approximately 1×10⁻⁶ cells were added to the medium.7 MDA-MB-436 cells were mixed with 100 μL of PBS and an equal volume of Matrigel, and then subcutaneously injected into the right back of each mouse near the armpit, with an injection volume of approximately 200 μL. Mice were anesthetized with 3-4% isoflurane prior to injection.

[0162] When the tumor grows to an average size of approximately 139 mm 3 At approximately [time missing], 32 tumor-bearing mice were randomly divided into 4 groups of 8 mice each using E-WorkBook software based on tumor volume and body weight. The day of grouping and drug administration was defined as day 0. Grouping and administration regimens are shown in Table 4.

[0163] Table 4. Grouping and Dosing Regimens

[0164] Group test drug Number dose Dosing regimen G1 Vehicle (Blank Group) 8 N / A N / A G2 HID-1121 8 100mg / kg IV, QD*7 days G3 Olapalli 8 25mg / kg po, QD*28 days G4 HID-1121 + Olaparib 8 100mg / kg + 25mg / kg IV, QD*7+PO, QD*28 days

[0165] 2.2 Evaluation Indicators and Statistical Analysis

[0166] Animal weight: Mouse weight was measured and recorded three times a week during the administration period, grouped (before the first dose) and during the administration period.

[0167] Tumor volume (TV): For the subcutaneous xenograft model, tumor volume was measured three times a week after grouping. Tumor volume (V) was calculated as follows: V = (length × width) 2 ) / 2.

[0168] The relative tumor volume (RTV) is calculated as follows: RTV = Vt / V0, where Vt is the volume measured each time and V0 is the volume at the start of treatment.

[0169] Relative tumor inhibition rate (TGI): TGI% = (1-T / C) × 100%. Where T and C are the relative tumor volumes (RTV) of the experimental group and the negative control group at a specific time point, respectively.

[0170] 3. Results

[0171] 3.1 Weight

[0172] During the experiment, the weight of the animals in each group remained relatively stable. During the drug administration period, all animals were in normal physical condition, moved freely, and no adverse reactions or deaths occurred. The weight changes of the animals in each group at each time point are as follows: Figure 4 .

[0173] 3.2 Tumor volume and relative tumor volume

[0174] During the experiment, the tumor volume in the G1 control group mice continued to increase (see...). Figure 5 On day 0, the average tumor volume was 139.90 ± 2.22 mm. 3On day 28, the average tumor volume reached 376.47 ± 12.62 mm. 3 The relative mean tumor volume increased to 2.70 ± 0.11 (see...) Figure 6 This indicates that the human breast cancer MDA-MB-436 cell line was successfully established in the BALB / c nude mouse subcutaneous ectopic xenograft model in this experiment.

[0175] The mean tumor volume on day 0 in group G2 was 138.61 ± 2.54 mm. 3 On day 28, the average tumor volume reached 267.64 ± 9.32 mm. 3 The relative tumor volume was 1.94 ± 0.09. Compared with the G1 control group at the same time point, the tumor volume and relative tumor volume were significantly reduced during the period from day 7 to day 28 (p < 0.05).

[0176] The mean tumor volume on day 0 in group G3 was 138.00 ± 2.62 mm. 3 On day 28, the average tumor volume reached 73.37 ± 11.52 mm. 3 The relative tumor volume was 0.53 ± 0.08. Compared with the G1 control group at the same time point, the tumor volume was significantly reduced from day 7 to day 28; the relative tumor volume was significantly reduced from day 11 to day 28 (p < 0.05 or p < 0.01).

[0177] The mean tumor volume on day 0 in group G4 was 139.63 ± 2.65 mm. 3 On day 28, the average tumor volume reached 43.98 ± 3.90 mm. 3 The relative tumor volume was 0.31 ± 0.03. Compared with the G1 control group at the same time point, the tumor volume and relative tumor volume were significantly reduced during the period from day 7 to day 28 (p < 0.01).

[0178] 3.3 Relative tumor inhibition rate (%)

[0179] The relative tumor inhibition rates of each group at each time point are shown in Table 5. After administration, the relative tumor inhibition rates of groups G2-G4 on day 28 were 28.17%, 80.44%, and 88.36%, respectively.

[0180] Table 5. Relative Tumor Inhibition Rate (TGI) (%)

[0181] Grouping Day 4 Day 7 Day 11 Day 14 Day 18 Day 21 Day 25 Day 28 G2 0.85 10.42 14.51 18.71 21.70 23.93 26.58 28.17 G3 2.48 9.99 14.54 41.76 57.91 69.55 75.32 80.44 G4 2.67 14.51 18.91 45.16 65.61 74.76 82.75 88.36

[0182] 4. Experimental Conclusions

[0183] This experiment successfully established a subcutaneous ectopic tumor model of human breast cancer MDA-MB-436 cell line in BALB / c Nude mice. The tumor volume in the G1 control group mice steadily increased, with a mean tumor volume of 139.90 mm² on day 0. 3 At the end of the experiment (day 28), the average tumor volume reached 376.47 mm. 3 The relative tumor volume reached 12.62.

[0184] Compared with the G1 blank group, the G2 to G4 groups of the test substance all reduced tumor volume (TV) and relative tumor volume (RTV) during the administration period, with significant differences (p<0.05 or p<0.01).

[0185] In summary, all treatment groups showed significant tumor-inhibiting effects. Among them, the HID-1121 (100 mg / kg) + olaparib (25 mg / kg) combination group had smaller tumor volume and higher TGI% than other treatment groups, showing greater advantages and better tumor growth inhibition.

[0186] Example 3: The efficacy of HID-1121 and olaparib in the treatment of pancreatic cancer

[0187] 1. Experimental Materials

[0188] HID-1121 (purchased from QUIMATRYX, SL, batch number CC-5570.0-02, purity 99.3%), and related experimental reagents and equipment were all commercially available products. Weigh 13.90g of β-cyclodextrin powder, add 30.00mL of sterile water for injection, stir until completely dissolved, continue stirring and add 5.0mL of 1N NaOH dropwise, then add sterile water for injection to bring the volume to 100mL for later use.

[0189] A total of 45 BALB / c nude mice (13 spares) were purchased from the supplier to study the effect of the test substance on the growth of subcutaneous ectopic xenografts in the human pancreatic cancer Capan-1 cell line BALB / c nude mice.

[0190] 2. Experimental Methods

[0191] 2.1 Cell Culture and Drug Administration

[0192] The Capan-1 human pancreatic cancer cell line used in this experiment was cultured in IMDM medium supplemented with 20% FBS at 37°C in an incubator containing 5% CO2. Before ten consecutive passages of cell culture, approximately 1×10⁻⁶ cells were added to the medium. 6After mixing 100 μL of PBS with an equal volume of Matrigel, Capan-1 cells were subcutaneously injected into the right back of each mouse near the axilla, with an injection volume of approximately 200 μL. Mice were anesthetized with 3-4% isoflurane prior to injection.

[0193] When the tumor grows to an average size of approximately 115 mm 3 At approximately [time missing], 32 tumor-bearing mice were randomly divided into 4 groups of 8 mice each using E-WorkBook software based on tumor volume and body weight. The day of grouping and drug administration was defined as day 0. Grouping and administration regimens are shown in Table 6.

[0194] Table 6. Grouping and Dosing Regimens

[0195] Group test drug Number Dosage (mg / kg) Dosing regimen G1 Vehicle (Blank Group) 8 N / A N / A G2 HID-1121 8 100mg / kg IV, QD*7 days G3 Olapalli 8 100mg / kg po, QD*28 days G4 HID-1121 + Olaparib 8 100mg / kg + 100mg / kg IV, QD*7+PO, QD*28 days

[0196] 2.2 Evaluation Indicators and Statistical Analysis

[0197] Animal weight: Mouse weight was measured and recorded three times a week during the administration period, grouped (before the first dose) and during the administration period.

[0198] Tumor volume (TV): For the subcutaneous xenograft model, tumor volume was measured three times a week after grouping. Tumor volume (V) was calculated as follows: V = (length × width) 2 ) / 2.

[0199] The relative tumor volume (RTV) is calculated as follows: RTV = Vt / V0, where Vt is the volume measured each time and V0 is the volume at the start of treatment.

[0200] Relative tumor inhibition rate (TGI): TGI% = (1-T / C) × 100%. Where T and C are the relative tumor volumes (RTV) of the experimental group and the negative control group at a specific time point, respectively.

[0201] 3. Results

[0202] 3.1 Weight

[0203] During the experiment, the weight of the animals in each group remained relatively stable. During the drug administration period, all animals were in normal physical condition, moved freely, and no adverse reactions or deaths occurred. The weight changes of the animals in each group at each time point are as follows: Figure 7 .

[0204] 3.2 Tumor volume and relative tumor volume

[0205] During the experiment, the tumor volume in the G1 control group mice continued to increase (see...). Figure 8 On day 0, the average tumor volume was 115.47 ± 2.88 mm. 3On day 28, the average tumor volume reached 971.95 ± 74.92 mm. 3 The mean RTV rose to 8.39 ± 0.59 (see...) Figure 9 This indicates that the human pancreatic cancer Capan-1 cell line was successfully established in the BALB / c nude mouse subcutaneous ectopic xenograft model in this experiment.

[0206] The mean tumor volume on day 0 in group G2 was 115.18 ± 2.88 mm. 3 On day 28, the average tumor volume reached 881.99 ± 46.81 mm. 3 The relative tumor volume was 7.64 ± 0.30. Compared with the G1 control group at the same time point, the tumor volume and relative tumor volume were significantly reduced during the period from day 3 to day 10 (p < 0.05).

[0207] The mean tumor volume on day 0 in group G3 was 114.18 ± 2.20 mm. 3 On day 28, the average tumor volume reached 437.41 ± 50.05 mm. 3 The relative tumor volume was 3.83 ± 0.43. Compared with the G1 control group at the same time point, the tumor volume and relative tumor volume were significantly reduced during days 3 and 14–28 (p < 0.05 or p < 0.01).

[0208] The mean tumor volume on day 0 in group G4 was 115.58 ± 3.09 mm. 3 On day 28, the average tumor volume reached 371.10 ± 30.55 mm. 3 The relative tumor volume was 3.19 ± 0.21. Compared with the G1 control group at the same time point, the tumor volume and relative tumor volume were significantly reduced during the period from day 3 to day 28 (p < 0.01).

[0209] 3.3 Relative tumor inhibition rate (%)

[0210] The relative tumor inhibition rates of each group at each time point are shown in Table 7. After administration, the relative tumor inhibition rates of groups G2-G4 on day 28 were 8.93%, 54.31%, and 61.98%, respectively.

[0211] Table 7. Relative Tumor Inhibition Rate (TGI) (%)

[0212] Grouping Day 3 Day 7 Day 11 Day 14 Day 18 Day 21 Day 25 Day 28 G2 23.03 27.13 21.10 6.51 2.71 7.32 7.74 8.93 G3 15.30 8.98 17.22 27.45 31.50 42.92 48.31 54.31 G4 23.49 27.79 30.91 37.43 39.74 49.38 58.68 61.98

[0213] 4. Discussion of Results

[0214] This experiment successfully established a subcutaneous ectopic xenograft model of human pancreatic cancer Capan-1 cell line in BALB / c nude mice. The tumor volume in the G1 control group mice steadily increased, with a mean tumor volume of 115.47 mm on day 0.3 At the end of the experiment (day 28), the average tumor volume reached 971.95 mm. 3 The relative tumor volume reached 8.39.

[0215] Compared with the G1 blank group, the G2 to G4 groups of the test substance all reduced tumor volume (TV) and relative tumor volume (RTV) during the administration period, with significant differences (p<0.05 or p<0.01).

[0216] In summary, all treatment groups showed significant tumor-inhibiting effects. Among them, the HID-1121 (100 mg / kg) + olaparib (100 mg / kg) combination group had smaller tumor volume and higher TGI% than other treatment groups, showing greater advantages and better tumor growth inhibition.

[0217] Example 4: The efficacy of HID-1121 and olaparib in the treatment of drug-resistant pancreatic cancer

[0218] 1. Experimental Materials

[0219] HID-1121 (purchased from QUIMATRYX, SL, batch number CC-5570.0-02, purity 99.3%), and related experimental reagents and equipment were all commercially available products. Weigh 13.90g of β-cyclodextrin powder, add 30.00mL of sterile water for injection, stir until completely dissolved, continue stirring and add 5.0mL of 1N NaOH dropwise, then add sterile water for injection to bring the volume to 100mL for later use.

[0220] A total of 50 BALB / c nude mice (18 spares) were purchased from the supplier to study the effect of the test substance on the growth of subcutaneous ectopic xenografts of human pancreatic cancer Capan-1 in BALB / c nude resistant mouse models.

[0221] 2. Experimental Methods

[0222] 2.1 Tumor tissue resuscitation in the Capan-1 model

[0223] 1) After removing the cryovial from liquid nitrogen, place it in a 37°C water bath and shake it continuously to thaw until it is almost completely thawed (leaving a small ice crystal).

[0224] 2) Transfer the tumor mass in the cryopreservation tube to fresh DMEM medium containing 1% penicillin and antibiotics and wash it twice. Dilute the DMSO in the cryopreservation solution (this can be done in a sterile 10-cm dish).

[0225] 3) Cut the tumor into 2×2×2mm pieces, mix with Matrigel glue and place in a pre-cooled cannula.

[0226] 4) Before inoculation, anesthetize the mice with 3-4% isoflurane, shave and disinfect the injection site, and inoculate the tumor at 1-4 injection sites on the upper and lower backs of the left and right sides of the mice. Each model is inoculated with 2-4 immunodeficient mice.

[0227] 5) Observe the mice's condition after inoculation until the mice wake up.

[0228] 2.2 Passage and inoculation of Capan-1 model tumor tissue

[0229] 1) When the volume of a single tumor in a model mouse reaches 500-1000 mmHg 3 The mouse tumors were removed in a sterile environment, and the tumors were washed in a sterile culture dish with PBS containing 1% penicillin and antibiotics. Useless tissues such as fat, fascia, connective tissue, and necrotic tissue were removed. The trimmed tumor pieces were then transferred to DMEM medium containing 1% penicillin and antibiotics and washed again.

[0230] 2) Trim the tumor fragments to a size of 2×2×2mm, and inoculate each fragment into the right back of each immunodeficient mouse near the armpit using a cannula. Anesthetize the mice with 3-4% isoflurane before inoculation.

[0231] 2.3 Animal grouping and dosing regimen

[0232] When the tumor grew to an average size of approximately 132 mm 3 At approximately [time missing], 32 tumor-bearing mice were randomly divided into 4 groups of 8 mice each using E-WorkBook software based on tumor volume and body weight. The day of grouping and drug administration was defined as day 0. Grouping and administration regimens are shown in Table 8.

[0233] Table 8. Grouping and Dosing Regimens

[0234] Group test drug Number Dosage (mg / kg) Dosing regimen G1 Vehicle (Blank Group) 8 N / A N / A G2 HID-1121 8 100mg / kg IV, QD*7 days G3 Olapalli 8 100mg / kg po, QD*28 days G4 HID-1121 + Olaparib 8 100mg / kg + 100mg / kg IV, QD*7+PO, QD*28 days

[0235] 2.4 Evaluation Indicators and Statistical Analysis

[0236] Animal weight: Mouse weight was measured and recorded three times a week during the administration period, grouped (before the first dose) and during the administration period.

[0237] Tumor volume (TV): For the subcutaneous xenograft model, tumor volume was measured three times a week after grouping. Tumor volume (V) was calculated as follows: V = (length × width) 2 ) / 2.

[0238] The relative tumor volume (RTV) is calculated as follows: RTV = Vt / V0, where Vt is the volume measured each time and V0 is the volume at the start of treatment.

[0239] Relative tumor inhibition rate (TGI): TGI% = (1-T / C) × 100%. Where T and C are the relative tumor volumes (RTV) of the experimental group and the negative control group at a specific time point, respectively.

[0240] 3. Results

[0241] 3.1 Weight

[0242] During the experiment, the weight of the animals in each group remained relatively stable. During the drug administration period, all animals were in normal physical condition, moved freely, and no adverse reactions or deaths occurred. The weight changes of the animals in each group at each time point are as follows: Figure 10 .

[0243] 3.2 Tumor volume and relative tumor volume

[0244] During the experiment, the tumor volume in the G1 control group mice continued to increase (see...). Figure 11 On day 0, the average tumor volume was 132.96 ± 4.86 mm. 3 On day 28, the average tumor volume reached 1846.59 ± 66.26 mm. 3 The mean RTV rose to 14.06 ± 0.82 (see...) Figure 12 This indicates that the Capan-1 subcutaneous ectopic xenograft model of human pancreatic cancer was successfully established in this experiment in BALB / c nude resistant mice.

[0245] The mean tumor volume on day 0 in group G2 was 132.86 ± 4.92 mm. 3 On day 28, the average tumor volume reached 1828.48 ± 109.73 mm. 3 The relative tumor volume was 1.94 ± 0.09. Compared with the G1 control group at the same time, there was no significant difference in tumor volume and relative tumor volume during the drug administration period.

[0246] The mean tumor volume on day 0 in group G3 was 131.03 ± 3.55 mm. 3 On day 28, the average tumor volume reached 1817.60 ± 119.31 mm. 3 The relative tumor volume was 13.88 ± 0.85. Compared with the G1 control group at the same time, there was no significant difference in tumor volume and relative tumor volume during the drug administration period.

[0247] The mean tumor volume on day 0 in group G4 was 131.94 ± 4.57 mm. 3 On day 28, the average tumor volume reached 1578.14 ± 112.39 mm. 3The relative tumor volume was 12.09 ± 1.02. Compared with the G1 control group at the same time, the tumor volume and relative tumor volume decreased significantly during the drug administration period, but the difference was not statistically significant.

[0248] 3.3 Relative tumor inhibition rate (%)

[0249] The relative tumor inhibition rates of each group at each time point are shown in Table 9. After administration, the relative tumor inhibition rates of groups G2-G4 on day 28 were 1.46%, 1.23%, and 14.03%, respectively.

[0250] Table 9. Relative Tumor Inhibition Rate (TGI) (%)

[0251] Grouping Day 3 Day 7 Day 10 Day 14 Day 17 Day 21 Day 24 Day 28 G2 4.39 2.24 6.17 5.36 1.97 3.12 2.91 1.46 G3 1.62 -1.01 0.62 2.92 1.72 -1.12 -1.70 1.23 G4 8.48 1.12 9.01 12.56 15.06 14.09 12.82 14.03

[0252] 5. Discussion of Results

[0253] This experiment successfully established a subcutaneous ectopic xenograft model of human pancreatic cancer in BALB / c nude mice with Capan-1 resistance. The tumor volume in the G1 control group mice steadily increased, with a mean tumor volume of 132.96 mm² on day 0. 3 At the end of the experiment (day 28), the average tumor volume reached 1846.59 mm. 3 The relative tumor volume reached 14.06.

[0254] All treatment groups showed effective tumor inhibition. Among them, the combination of HID-1121 (100 mg / kg) and olaparib (100 mg / kg) had smaller tumor volume and higher TGI% than other treatment groups, and thus had a greater advantage in inhibiting tumor growth.

Claims

1. A drug combination or kit comprising a first agent and a second agent, wherein the first agent is a histone deacetylase inhibitor, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof; The second agent is a PARP inhibitor, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof.

2. The drug combination or pillbox as described in claim 1, characterized in that, The first agent is a histone deacetylase 6 inhibitor, which is selected from one or more of HID-1121, ACY-1215, ACY241, KA2507, WT161, Tubacin, and Tubastatin.

3. The drug combination or pillbox as described in claim 1 or 2, characterized in that, The first agent is HID-1121, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof, wherein HID-1121 has the structure shown in formula (I):

4. The drug combination or pillbox as described in any one of claims 1-3, characterized in that, The PARP inhibitors include AZD2461, CEP8983, DR2313, E7016, E7449, NU1025, NU1064, IMP4297, fluzoparib, niraparib, olaparib, rucaparib, simenoparib, tapazolidinone, or veliparib. Preferably, the second agent is olaparib, its pharmaceutically acceptable salt, its stereoisomer, its solvate, or its prodrug.

5. The drug combination or pillbox according to any one of claims 1-4, characterized in that, The drug combination or cassette may also contain one or more pharmaceutically acceptable carriers; Optionally, the HID-1121 in the drug combination or kit is included in one or more of the following formulations: powder, injection, tablet, capsule, pill, suspension, syrup, solution, lozenge, suppository, inhaler, and spray; and the second agent is included in one or more of the following formulations: powder, injection, tablet, capsule, pill, suspension, syrup, solution, lozenge, suppository, inhaler, and spray. Optionally, HID-1121 and the second agent in the drug combination or kit are included in the same formulation or in different formulations.

6. The use of the pharmaceutical combination or cassette according to any one of claims 1-5 in the preparation of a medicament for the prevention and / or treatment of cancer.

7. The application as described in claim 6, wherein the cancer includes pancreatic cancer, cervical cancer, seminoma, testicular lymphoma, prostate cancer, ovarian cancer, lung cancer, rectal cancer, breast cancer, colon cancer, liver cancer, esophageal cancer, thyroid cancer, transitional cell carcinoma of the bladder, leukemia, brain tumor, gastric cancer, peritoneal cancer, head and neck cancer, endometrial cancer, kidney cancer, female reproductive tract cancer, carcinoma in situ, neurofibroma, bone cancer, skin cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, and sarcoma; Preferably, the cancer is one or more of prostate cancer, breast cancer, and pancreatic cancer.

8. The application as described in claim 7, characterized in that, The prostate cancer mentioned includes adenocarcinoma, ductal adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, and adenosquamous carcinoma; Preferably, the breast cancer types include luminal A, luminal B, HER2 overexpression, and triple-negative breast cancer; Preferably, the pancreatic cancer includes drug-resistant pancreatic cancer; Preferably, the pancreatic cancer includes pancreatic head cancer, pancreatic neck cancer, pancreatic body cancer, and pancreatic tail cancer; Preferably, the pancreatic cancer includes ductal cell carcinoma, acinar cell carcinoma, islet cell carcinoma, and rare types of carcinoma.

9. The use of the first and second pharmaceutical agents in the preparation of medicaments, combinations of medicaments, or kits for the treatment, prevention, and / or treatment of cancer; wherein the first pharmaceutical agent is a histone deacetylase inhibitor, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof; and the second pharmaceutical agent is a PARP inhibitor, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof. Preferably, the first agent is HID-1121, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof, wherein HID-1121 has the structure shown in formula (I): Preferably, the PARP inhibitor includes AZD2461, CEP8983, DR2313, E7016, E7449, NU1025, NU1064, IMP4297, fluzoparib, niraparib, olaparib, rucaparib, simenoparib, tapazolidinone, or veliparib; preferably, the PARP inhibitor is olaparib. Preferably, the second agent is olaparib, its pharmaceutically acceptable salt, its stereoisomer, its solvate, or its prodrug.

10. The application as described in claim 9, wherein the cancer includes pancreatic cancer, cervical cancer, seminoma, testicular lymphoma, prostate cancer, ovarian cancer, lung cancer, rectal cancer, breast cancer, colon cancer, liver cancer, esophageal cancer, thyroid cancer, transitional cell carcinoma of the bladder, leukemia, brain tumor, peritoneal cancer, head and neck cancer, endometrial cancer, kidney cancer, female reproductive tract cancer, carcinoma in situ, neurofibroma, bone cancer, skin cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, and sarcoma; Preferably, the cancer is one or more of prostate cancer, breast cancer, and pancreatic cancer; Preferably, the prostate cancer includes adenocarcinoma, ductal adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, and adenosquamous carcinoma; Preferably, the types of breast cancer include luminal A, luminal B, HER2 overexpression, and triple-negative breast cancer; Preferably, the pancreatic cancer includes drug-resistant pancreatic cancer; Preferably, the pancreatic cancer includes pancreatic head cancer, pancreatic neck cancer, pancreatic body cancer, and pancreatic tail cancer; Preferably, the pancreatic cancer includes ductal cell carcinoma, acinar cell carcinoma, islet cell carcinoma, and rare types of carcinoma.

Images