CN120815187A

CN120815187A - Drug combination of HDAC6 inhibitor and BTK inhibitor and use thereof

Info

Publication number: CN120815187A
Application number: CN202511242433.2A
Authority: CN
Inventors: 邵颖
Original assignee: Hongxing Xianghe Taicang Biotechnology Co ltd
Current assignee: Hongxing Xianghe Taicang Biotechnology Co ltd
Priority date: 2025-09-02
Filing date: 2025-09-02
Publication date: 2025-10-21

Abstract

The present disclosure belongs to the technical field of biological medicine, and in particular relates to a pharmaceutical combination of an HDAC6 inhibitor and a BTK inhibitor and uses thereof. The BTK inhibitor and the HDAC6 inhibitor are combined to exert a synergistic effect, so that the tumor inhibition effect is obviously enhanced, the dosage and the period of the drug can be improved, the side effect of the drug can be reduced, and the compliance of patients to the drug can be improved.

Description

Pharmaceutical combination of HDAC6 inhibitor and BTK inhibitor and application thereof

Technical Field

The present disclosure is in the field of biomedical technology, in particular to pharmaceutical combinations of HDAC6 inhibitors and BTK inhibitors and their use in the treatment of cancer.

Background

At the heart of epigenetics are various covalent modifications of histones and nucleic acids that synergistically regulate chromatin structure and gene expression. Deregulation of the epigenetic group drives aberrant transcription processes, promoting the development and progression of cancer. Small molecule inhibitors of epigenetic regulators have great potential in the development of anticancer drugs.

Histone deacetylases (Histone deacetylase, HDAC) are involved in tumorigenesis and progression by removal of histone acetyl groups and other transcriptional regulation. Histone acetylation status depends on the competition of activity between histone acetyltransferase (Histone Acetyltransferase, HAT) and Histone Deacetylase (HDAC). HDAC aberrant binding to specific promoter regions, thereby inhibiting transcription of normally functioning genes, may be one of the mechanisms of malignancy occurrence.

HDAC6 (Histone deacetylase, histone deacetylase 6) is a special isoform in the HDAC family, and its substrates include histones and nonhistones (such as α -tubulin, peroxidases, dermatoxerasins and heat shock proteins), etc., as an important deacetylase involved in various cellular functions, in particular, it can promote the generation and development of tumor cells through different signaling pathways to assist their functional expression, while inhibiting HDAC6 can inhibit the development of cancer cells from many aspects.

The mechanism of action of HDAC inhibitors is explained by their antagonistic properties towards histone deacetylases involved in regulating processes related to apoptosis, cell growth, tumor development, cancer metastasis, cell adhesion, etc. These properties prevent the binding of HDAC to its natural ligand, which may be a histone or a cytoplasmic protein (e.g., tubulin), and its normal catalytic activation, i.e., deacetylation of epsilon-N-acetyllysine residues present in these proteins.

Chemotherapy is the gold standard for the treatment of a variety of cancers, however, the development of drug resistance and/or side effects can limit the therapeutic utility and clinical compliance of chemotherapeutic agents. "combination therapy" utilizes the combined use of individual potent chemotherapeutic agents (with different mechanisms of action) to reduce the incidence of drug resistance by expanding the selective pressure exerted on individual tumor cells. Combination therapy also allows for reduced individual doses of chemotherapeutic agents, thereby reducing the occurrence of side effects in a dose-dependent manner.

In tumor therapy, there is still a great unmet clinical need for novel combination therapies.

Disclosure of Invention

The present disclosure aims to provide a new combination drug regimen, which improves the anti-tumor efficacy of HDAC6 inhibitors through the synergistic effect between the drugs.

To achieve the above technical object, in one aspect, the present disclosure provides a pharmaceutical combination or kit comprising a first agent that is a histone deacetylase 6 (HDAC 6) inhibitor or a derivative thereof and a second agent that is a Bruton's Tyrosine Kinase, BTK inhibitor or a derivative thereof.

In another aspect, the present disclosure provides the use of the above pharmaceutical combination or kit for the preparation of a medicament for the prevention and/or treatment of cancer.

In yet another aspect, the present disclosure provides the use of the above pharmaceutical combination or kit for the prevention and/or treatment of cancer.

In yet another aspect, the present disclosure provides the use of an HDAC6 inhibitor or derivative thereof and a BTK inhibitor or derivative thereof in the manufacture of a medicament, pharmaceutical combination or kit for the prevention and/or treatment of cancer.

In yet another aspect, the present disclosure provides the use of an HDAC6 inhibitor or derivative thereof and a BTK inhibitor or derivative thereof in the prevention and/or treatment of cancer.

In yet another aspect, the present disclosure provides a method of preventing and/or treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of an HDAC6 inhibitor or derivative thereof and a therapeutically effective amount of a BTK inhibitor or derivative thereof.

The BTK inhibitor and the HDAC6 inhibitor are combined to exert a synergistic effect, the tumor inhibition effect is obviously enhanced, the tumor inhibition rate of lymphoma can reach 79.86%, the dosage and the period of administration can be improved, and the development of side effects generally related to the use of a higher dosage of a single chemotherapeutic agent is overcome, so that the compliance of patients to medicines is improved.

Drawings

In order to more clearly illustrate the specific embodiments of the present disclosure or the prior art, the drawings that are required in the description of the specific embodiments or the prior art will be briefly described, it being apparent that the drawings in the following description are some embodiments of the present disclosure and that other drawings may be obtained from these drawings without inventive effort for a person of ordinary skill in the art. The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the specification and together with the description, serve to explain the principles of the specification.

Fig. 1 shows tumor growth curves for mice from each test group, data points represent the mean tumor size for each group, error bars represent standard errors, P <0.05, P <0.01, P <0.001, and all groups are compared to group 5 (G5).

Detailed Description

In order to make the objects, technical solutions, and advantages of the present disclosure more apparent, the present disclosure is further described in detail below by means of specific embodiments. It will be apparent that the described embodiments are merely some, but not all embodiments of the present disclosure. All other embodiments, which can be made by one of ordinary skill in the art without undue burden based on the examples in this disclosure, are within the scope of this disclosure.

The present disclosure may be embodied in other specific forms without departing from its essential attributes. It is to be understood that any and all embodiments of the present disclosure may be combined with any other embodiment or features of multiple other embodiments to yield yet further embodiments without conflict. The present disclosure includes additional embodiments resulting from such combinations.

(I) Definition and description

For easier understanding of the present disclosure, certain technical and scientific terms are specifically defined below. In this disclosure, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, compositions, or biological systems, as such may, of course, vary. It is also to be understood that the terminology used in the present disclosure is for the purpose of describing particular embodiments only, and is not intended to be limiting.

All publications and patents mentioned in this disclosure are incorporated herein by reference in their entirety. If a use or term used in any of the publications and patents incorporated by reference conflicts with the use or term used in the present disclosure, the use or term of the present disclosure controls. The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter.

As used in this specification and the appended claims, the singular forms "a," "an," "the," and similar referents include the plural referents unless the content clearly dictates otherwise.

As used herein, the conjunctive term "and/or" between various elements is meant to include both "and" or "meaning, e.g., the phrase" A, B and/or C "is intended to cover each of A, B and C, A, B or C, a or B, B or C, a and B, B and C, a (alone), B (alone), and C (alone).

As used herein, the terms "comprising," "including," "having," and "containing," as well as any variations thereof, are intended to cover a non-exclusive inclusion. The term is intended to be open ended to specify the presence of any stated features, elements, integers, steps, or components, but does not preclude the presence or addition of one or more other features, elements, integers, steps, components, or groups thereof. Thus, the term "comprising" includes the more restrictive terms "consisting of" and "consisting essentially of.

The numerical ranges used herein should be understood to have enumerated all numbers within the range. For example, a range of 1 to 20 should be understood to include any number, combination of numbers, or subrange from the group 1,2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

As used herein, the term "about" means a range of ±20% of the numerical value thereafter. In some embodiments, the term "about" means a range of ±10% of the numerical value following that. In some embodiments, the term "about" means a range of ±5% of the numerical value thereafter.

In the description herein, reference is made to "some embodiments," "some implementations," or "some implementations," which describe a subset of all possible embodiments, but it is to be understood that "some embodiments" may be the same subset or different subsets of all possible embodiments and may be combined with one another without conflict.

As used herein, the terms "histone deacetylase," "histone deacetylase," and "HDAC" are used interchangeably and are intended to include any of a family of enzymes that remove acetyl groups from the epsilon-amino group of a lysine residue at the N-terminus of a histone or tubulin. HDAC6 is the largest protein in the HDAC family and can play a role in cells by modulating histone, non-histone substrates and signaling pathways.

As used herein, the term "BTK" refers to Bruton's tyrosine kinase (Bruton's Tyrosine Kinase, BTK), an enzyme in mammals that catalyzes the phosphorylation of specific proteins, is one of the Tec family of tyrosine kinases specifically expressed in B cells, plays an important role in the mediation of B cell receptor signals within the cells, and plays an important role in the survival, proliferation, activation and differentiation of B cells.

As used herein, the term "kit" refers to one or more components of a package that may be packaged separately or placed in a container, such as a tube, bottle, vial, pouch, blister, syringe, or other suitable container device. The kits described herein can also include instructions for using the components of the kit to perform the subject methods (e.g., instructions for preparing and/or using the pharmaceutical combinations described herein). The instructions for implementing the subject methods are typically recorded on a suitable recording medium. For example, the instructions may be printed on a substrate such as paper or plastic. Thus, the instructions may be in the form of a package insert in the kit, in the label of the container of the kit or parts thereof (i.e., parts associated with the package or the packet). In some embodiments, the instructions exist as electronically stored data documents residing on suitable computer readable storage media (e.g., CD-ROM, magnetic disk, etc.). In other embodiments, the actual instructions are not present in the kit, but means are provided for obtaining the instructions from a remote source, such as through the Internet, an example of such an embodiment being a kit that includes a website from which the instructions can be viewed and/or from which the instructions can be downloaded.

As used herein, the terms "cancer," "tumor," and "tumor" are used interchangeably to refer to a disease characterized by uncontrolled growth of abnormal cells, including pre-cancerous lesions as well as malignant tumors. Tumor cells can spread locally or through the blood stream and lymphatic system to other parts of the body, including solid tumors and hematological tumors. Examples of various cancers are described herein, including but not limited to pancreatic cancer, prostate cancer, bladder cancer, liver cancer, skin cancer, glioma, breast cancer, melanoma, glioblastoma, rhabdomyosarcoma, ovarian cancer, astrocytoma, ewing's sarcoma, retinoblastoma, epithelial cell cancer, colon cancer, renal cancer, gastrointestinal stromal tumor, leukemia, lymphoma, lung cancer, nasopharyngeal cancer, and the like.

As used herein, the term "treatment" is intended to include prophylaxis and treatment, methods by which beneficial or desired results, including clinical results, can be obtained, including, for purposes of the present application, beneficial or desired clinical results including, but not limited to, one or more of alleviating one or more symptoms caused by the disease, alleviating the extent of the disease, stabilizing the disease (e.g., preventing or delaying exacerbation of the disease), preventing or delaying the spread of the disease (e.g., metastasis), preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, improving the disease state, providing remission (part or all) of the disease, reducing the dosage of one or more other drugs required to treat the disease, delaying the progression of the disease, improving or ameliorating the quality of life, increasing weight gain and/or prolonging survival. "treatment" also includes reduction of pathological consequences (e.g., tumor volume) of cancer. In the context of cancer, "treatment" includes any or all of inhibiting the growth of cancer cells, inhibiting the replication, metastasis of cancer cells, alleviating overall tumor burden, and ameliorating one or more symptoms associated with the disease.

As used herein, the term "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount is also meant to be an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on such factors as the condition to be treated, the general health of the patient, the route and dosage of administration, and the severity of the side effects. An effective amount may be the maximum dose or regimen that avoids significant side effects or toxic effects.

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

The amount of drug administered may depend on the subject being treated, the age, health, sex and weight of the subject, the type of concurrent therapy (if any), the severity of the condition, the nature of the effect desired, the manner and frequency of treatment, and the discretion of the prescribing physician. The frequency of administration may also depend on the pharmacodynamic effect on the arterial oxygen partial pressure. However, the most preferred dosage may be adjusted according to the individual subject, as understood by those skilled in the art and can be determined without undue experimentation. This typically involves adjusting a standard dose (e.g., reducing the dose if the patient is low in weight).

In the present disclosure, the term "administering" refers to a method of administering a dose of a pharmaceutical composition (e.g., a pharmaceutical combination or kit of a first agent and a second agent as described in the present disclosure) to a subject (e.g., a patient). Administration may be by any suitable route, for example by injection, such as intravenous or subcutaneous injection, depending in part on whether administration is brief or chronic.

In some embodiments, the pharmaceutical combination or kit is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Various dosing regimens are contemplated herein, including but not limited to a single administration or multiple administrations at different time points.

As used herein, the term "injection" refers to any form of injection known to those of skill in the art, such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intra-articular, subarachnoid and intrasternal. Injection may refer to an infusion process (e.g., continuous administration) and bolus (discontinuous) administration.

As used herein, the term "combination", "combination" or "combination" is a mode of administration that includes the various instances of simultaneous, separate or sequential administration of two, three or more different agents. The term "simultaneous" administration includes administration of two, three or more different drugs within the same administration period, e.g., within 2 days, or within 1 day. The term "sequential" administration refers to administration such that two, three or more different drugs may act therapeutically within the same time frame. "sequential" administration may allow one drug to be administered within 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, or several hours after the other drug is provided, provided that the circulatory half-life of the first administered drug is such that both are present in a therapeutically effective amount. The time delay of administration between ingredients will vary depending on the exact nature of the ingredients, the interactions between them, and their respective half-lives. The term "separate" means that the separation between the administration of one drug and another is significant, i.e., the first administered drug may no longer be present in the blood stream in a therapeutically effective amount when the second drug is administered. The above modes of administration all pertain to the combination administration described in the present disclosure. Such administration includes co-administration of the therapeutic agents in a substantially simultaneous manner, e.g., in a single liquid with a fixed ratio of active ingredients. Or such administration includes co-administration of the individual active ingredients in multiple or separate containers (e.g., tablets, capsules, powders, and liquids). The powder and/or liquid may be reconstituted or diluted to the desired dosage prior to administration. In addition, such administration also includes the use of each type of therapeutic agent in a sequential manner at about the same time or at different times. In either case, the treatment regimen will provide a beneficial effect of the pharmaceutical composition in treating the disorders or conditions described herein.

(II) detailed technical scheme

The HID-1121 can specifically inhibit HDAC6 to a large extent, in order to enhance the anti-tumor activity of the HID-1121, the inventor proposes and verifies the combined effect of the HID-1121 and a plurality of anti-tumor drugs, and finds that the combined use of the HID-1121 and a BTK inhibitor such as zebutinib has remarkable synergistic effect when being used for treating cancers, remarkably enhances the tumor inhibition effect, can reach 79.86% on the tumor inhibition rate of lymphoma, can improve the dosage and the dosage period, and is beneficial to overcoming the development of side effects generally related to the use of higher doses of single chemotherapeutic agents, thereby improving the compliance of patients to drugs.

In one aspect, the present disclosure provides a pharmaceutical combination or kit comprising a first agent that is a histone deacetylase 6 (HDAC 6) inhibitor or a derivative thereof and a second agent that is a Bruton's Tyrosine Kinase (BTK) inhibitor or a derivative thereof.

As used herein, the term "histone deacetylase 6 inhibitor" or "HDAC6 inhibitor" is used to refer to a compound that is capable of interacting with histone deacetylase 6 and inhibiting its activity, more specifically 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 lower than those required to produce some other unrelated biological effect. The term "HDAC6 inhibitor" is intended to include all known or future-discovered compounds and derivatives thereof capable of inhibiting the enzymatic activity of HDAC 6.

In some embodiments, the HDAC6 inhibitor is selected from one or more of HID-1121, ACY-1215 (CAS number 1316214-52-4), ACY241 (CAS number 1316215-12-9), KA2507 (CAS number 1636894-46-6), WT161 (CAS number 1206731-57-8), tubacin (CAS number 537049-40-4), and Tubacstatin (CAS number 1252003-15-8).

As used herein, the terms "HID1121", "HID-1121" include havingThe compound of the structure shown or a derivative thereof is a compound which specifically inhibits HDAC 6. The term "HID-1121" is referred to herein to include crystalline forms of HID-1121 and adducts thereof, as well as pharmaceutically acceptable salts of the compounds of formula (I), such as trifluoroacetate salts thereof. Methods for preparing compounds of formula (I) and signs of their biological activity for use in various medical treatments are described, for example, in WO 2011/039353 and WO 2018/087082, the contents of which are incorporated herein by reference. Advantageous pharmaceutical formulations comprising HID-1121 are further described in CN202210325433.9, the contents of which are incorporated herein by reference. In some preferred embodiments, the HDAC6 inhibitor is HID-1121. It will be appreciated by those skilled in the art that other HDAC6 inhibitors can be substituted for HID-1121 to synergistically enhance anticancer effects with BTK inhibitors, so long as they have the effect of inhibiting HDAC6 activity, and such technical solutions are within the scope of the present disclosure.

As used herein, the terms "BTK inhibitor" and "bruton's tyrosine kinase inhibitor" are used interchangeably to refer to a compound that is capable of interacting with and inhibiting the activity of bruton's tyrosine kinase. In some embodiments, the BTK inhibitor is selected from one or more of zebutinib (Zanubrutinib), ibrutinib (Ibrutinib), acartinib (Acalabrutinib), tiratinib (Tirabrutinib), obutinib (Orelabrutinib), s Bei Tini (Spebrutinib), and elvan (Evobrutinib). In some preferred embodiments, the BTK inhibitor is zebutinib. It will be appreciated by those skilled in the art that other BTK inhibitors can be substituted for the synergistic enhancement of anticancer effects of zebutinib and HDAC6 inhibitors, provided that they have the effect of inhibiting BTK activity, and that these solutions should also be within the scope of the equivalent protection of the present disclosure.

In some embodiments, the derivatives include pharmaceutically acceptable salts, stereoisomers, solvates, and prodrugs.

In the present disclosure, compounds that include one or more asymmetric centers, such as HID-1121 or zebutinib, may exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, a compound of the present disclosure, such as HID-1121 or zebutinib, may be an individual enantiomer, diastereomer, or geometric isomer (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, including a racemic mixture and a mixture enriched in one or more stereoisomers. The isomers may be separated from the mixtures by methods known to those skilled in the art, including chiral High Pressure Liquid Chromatography (HPLC) and formation and crystallization of chiral salts, or the preferred isomers may be prepared by asymmetric synthesis.

In the present disclosure, the term "solvate" refers to a form of a compound that is bound to a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. "solvate" includes both solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates and methanolates. When the solvent is water, the complex is referred to as a "hydrate". The present disclosure encompasses all solvates of HID-1121 and zebutinib.

In the present disclosure, the HID-1121 or zebutinib may be in an amorphous or crystalline form (crystalline or polymorphic), and the HID-1121 or zebutinib may exist in one or more crystalline forms. Accordingly, the present disclosure includes all amorphous or crystalline forms of HID-1121 and zebutinib. The term "polymorph" refers to a crystalline form (or salt, hydrate or solvate thereof) of a particular crystal stacking 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, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to a crystalline form predominating.

In the present disclosure, the HID-1121 or zebutinib also includes isotopically labeled HID-1121 or zebutinib, which are identical to HID-1121 or zebutinib, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number common in nature. Examples of isotopes that can be incorporated into HID-1121 or zebutinib described in the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. HID-1121 or zebutinib of the present disclosure, as well as prodrugs and pharmaceutically acceptable salts thereof, containing the above isotopes and/or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically labeled HIDs-1121 or zebutinib of the present disclosure, such as those incorporating radioisotopes (e.g., ³ H and ¹⁴ C), are useful in drug and/or substrate tissue distribution assays. Tritium, i.e., ³ H, and carbon-14, i.e., ¹⁴ C isotopes are particularly preferred because they are easy to prepare and detect. Further, substitution with heavier isotopes, such as deuterium, i.e., ² H, may be preferred in some circumstances because greater metabolic stability may afford therapeutic benefits such as increased in vivo half-life or reduced dosage requirements.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt that, when administered to a subject, can provide (directly or indirectly) a compound as described in the present disclosure. "pharmaceutically acceptable" preferably refers to compositions and molecular entities that are physiologically tolerable and do not typically produce allergic or similar untoward reactions such as stomach disorders, dizziness, and the like when administered to a human or animal. Preferably, the term "pharmaceutically acceptable" means that it is approved by a government regulatory agency or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. The preparation of the salt may be achieved by methods known in the art. For example, pharmaceutically acceptable salts can be synthesized from the original compounds containing basic residues by conventional chemical methods. In general, the salts are prepared, for example, by reacting the free base form of the compound with an appropriate 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 the acid addition salts include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate. Examples of the base addition salt include inorganic salts such as sodium salt, potassium salt, calcium salt, ammonium salt, magnesium salt, aluminum salt and lithium salt, and organic salts such as ethylenediamine, ethanolamine, N-dialkylene ethanolamine, triethanolamine, glucosamine and basic salts of amino acids.

As used herein, the term "pharmaceutical combination" refers to a combination of one or more pharmaceutical components suitable for combined administration of the different pharmaceutical components, which may be administered simultaneously, separately or sequentially. The different pharmaceutical components may together form a composition (e.g., a pharmaceutical composition) or may be present separately, e.g., with separate formulations and/or packages.

In some embodiments, the pharmaceutical combination or kit comprises a single daily dose of HDAC6 inhibitor and BTK inhibitor, the molar ratio of HDAC6 inhibitor to BTK inhibitor, based on the amount of HDAC6 inhibitor or BTK inhibitor, is from 1:40 to 1:0.01, e.g. may be 1:40、1:35、1:30、1:25、1:20、1:15、1:10、1:9、1:8、1:7、1:6、1:5、1:4、1:3、1:2.5、1:2、1:1.5、1:1、1:0.9、1:0.8、1:0.7、1:0.6、1:0.5、1:0.4、1:0.3、1:0.2、1:0.1、1:0.09、1:0.08、1:0.07、1:0.06、1:0.05、1:0.04、1:0.03、1:0.02 or 1:0.01, preferably from 1:20 to 1:0.1, more preferably from 1:1 to 1:0.5, even more preferably from 1:0.8 to 1:0.7. In clinical practice, the skilled artisan can flexibly adjust the content of the HDAC6 inhibitor or the BTK inhibitor according to the specific condition, physical condition and other relevant factors of the patient, so as to achieve the aim of clinical treatment.

In some embodiments, the pharmaceutical combination or kit comprises a single daily dose of HID-1121 and zebutinib, the molar ratio of HID-1121 to zebutinib, based on the content of HID-1121 and zebutinib, may be, for example, from 1:40 to 1:0.01, and may be, for example, 1:40、1:35、1:30、1:25、1:20、1:15、1:10、1:9、1:8、1:7、1:6、1:5、1:4、1:3、1:2.5、1:2、1:1.5、1:1、1:0.9、1:0.8、1:0.7、1:0.6、1:0.5、1:0.4、1:0.3、1:0.2、1:0.1、1:0.09、1:0.08、1:0.07、1:0.06、1:0.05、1:0.04、1:0.03、1:0.02 or 1:0.01, preferably from 1:20 to 1:0.1, more preferably from 1:1 to 1:0.5, and even more preferably from 1:0.8 to 1:0.7. In clinical practice, the skilled artisan can flexibly adjust the content of the HDAC6 inhibitor or the BTK inhibitor according to the specific condition, physical condition and other relevant factors of the patient, so as to achieve the aim of clinical treatment.

In some embodiments, the final concentration of HID-1121 in the pharmaceutical combination or kit is 1-50mg/mL, e.g. 1mg/mL、2mg/mL、3mg/mL、4mg/mL、5mg/mL、6mg/mL、7mg/mL、8mg/mL、8.5mg/mL、9mg/mL、9.5mg/mL、10mg/mL、11mg/mL、12mg/mL、13mg/mL、14mg/mL、15mg/mL、16mg/mL、17mg/mL、18mg/mL、19mg/mL、20mg/mL、25mg/mL、30mg/mL、35mg/mL、40mg/mL、45mg/mL or 50mg/mL, preferably 2-30mg/mL, preferably 5-20mg/mL, preferably 8-15mg/mL, more preferably 10-12mg/mL, based on the content of HID-1121. In clinical practice, the content of HID-1121 can be flexibly adjusted by those skilled in the art according to the specific condition, physical condition and other relevant factors of the patient, so as to achieve the goal of clinical treatment.

In some embodiments, the pharmaceutical combinations or kits of the present disclosure may include optionally one or more pharmaceutically acceptable carriers, such as antioxidants, preservatives, wetting agents, emulsifying agents, dispersing agents, and the like. As used herein, the term "pharmaceutically acceptable carrier" refers to nontoxic solid, semisolid or liquid fillers, diluents, encapsulating materials, formulation aids or carriers, excipients, adjuvants, buffers, pH adjusting agents, preservatives, antioxidants, bacteriostats, stabilizers, suspending agents, solubilizing agents, surfactants (e.g., wetting agents), colorants, isotonic agents (i.e., render the formulation isotonic with the blood or other relevant body fluid of the intended recipient) and the like, which together constitute a medicament or combination of medicaments for administration to an individual, as is conventional in the art for use with therapeutic agents. Suitable carriers, diluents, excipients, and the like can be found in standard pharmaceutical literature. The pharmaceutically acceptable carrier is non-toxic to the recipient at the dosage and concentration employed and is compatible with the other ingredients of the formulation. Pharmaceutically acceptable carriers are suitable for the formulation employed. 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, polymeric micelles or inorganic nanocarriers and the like.

In some embodiments, the pharmaceutical combinations or kits of the present disclosure further comprise a buffer (i.e., comprise a buffer salt dissolved therein). Optionally, the buffer may be selected from the group ：MES、Bis-Tris、ADA、ACES、PIPES、MOPSO、BES、MOPS、TES、HEPES、DIPSO、MOBS、TAPSO、Tris-HCl、HEPPSO、POPSO、TEA、EPPS、 tris (hydroxymethyl) methylglycine (Tricine), gly-Gly, N-dihydroxyethylglycine (Bicine), HEPBS, TAPS, AMPD, TABS, AMPSO, CHES, CAPSO, APS, CHAPS, CABS, phosphate and histidine or a combination of the above. Without wishing to be bound by theory, it is believed that the use of buffers may help stabilize the drug or drug combination at physiological pH. The concentration of buffer salt in the aqueous drug or drug combination may range from 1mM to 1M, preferably from 1mM to 100mM, preferably from 5mM to 50mM, preferably from 5mM to 20mM.

In some embodiments, the pharmaceutical combinations of the present disclosure may further comprise a counter ion and a salt, such as a sodium counter ion, chloride ion, or NaCl dissolved in solution.

In some embodiments, the HDAC6 inhibitor is contained in the pharmaceutical combination or kit in an oral formulation or an injectable formulation, preferably in an injectable formulation. In some embodiments, the BTK inhibitor is contained in an oral formulation or an injectable formulation, preferably in an oral formulation.

In some embodiments, the HDAC6 inhibitor and the BTK inhibitor in the pharmaceutical combination or kit may be contained in the same formulation or in different formulations.

In some embodiments, the pharmaceutical combination or kit comprises HID-1121 or derivative thereof required for a single administration. In some embodiments, the pharmaceutical combination or kit comprises 25-4500mg HID-1121 or derivative thereof, preferably 50-3000mg, more preferably 200-2000mg, still more preferably 250-1500mg, based on the amount of HID-1121.

In some embodiments, the pharmaceutical combination or kit comprises the zebutinib required for a single administration. In some embodiments, the pharmaceutical combination or kit comprises, based on the amount of zebutinib, 10-3000mg, preferably 20-1500 mg, more preferably 100-600 mg of zebutinib or a derivative thereof.

In a further aspect, the present disclosure provides the use of the above pharmaceutical combination or kit for the prevention and/or treatment of cancer.

In some embodiments, the cancer comprises lymphoma, leukemia, myeloma, colorectal cancer, fibrosarcoma, gastric cancer, glioblastoma, renal cancer, liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, breast cancer, and/or prostate cancer.

In some embodiments, the cancer comprises mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, NK cell lymphoma, and/or hodgkin's lymphoma. In some preferred embodiments, the cancer is mantle cell lymphoma.

In some embodiments, the HDAC6 inhibitor is selected from one or more of HID-1121, ACY-1215, ACY241, KA2507, WT161, tubacin and Tubastatin, wherein HID-1121 is a compound having a structure represented by formula (I). In some preferred embodiments, the HDAC6 inhibitor is HID-1121.

In some embodiments, the BTK inhibitor is selected from one or more of zebutinib (Zanubrutinib), ibrutinib (Ibrutinib), acartinib (Acalabrutinib), tiratinib (Tirabrutinib), obutinib (Orelabrutinib), s Bei Tini (Spebrutinib), and elvan (Evobrutinib). In some preferred embodiments, the BTK inhibitor is zebutinib.

In yet another aspect, the present disclosure provides the use of a BTK inhibitor or derivative thereof in the manufacture of a medicament or kit for improving the effect of an HDAC6 inhibitor or derivative thereof in the prevention and/or treatment of cancer.

In a further aspect, the present disclosure provides the use of a BTK inhibitor or derivative thereof in a medicament or kit for improving the effect of an HDAC6 inhibitor or derivative thereof in the prevention and/or treatment of cancer.

In yet another aspect, the present disclosure provides a method of improving the therapeutic effect of an HDAC6 inhibitor or derivative thereof, comprising administering a BTK inhibitor or derivative thereof at any time before, during, or after the administration of the HDAC6 inhibitor.

The "drugs", "drug combinations" of the present disclosure may be administered to a patient or subject in need of such treatment in any suitable manner of administration, such as oral, intravenous, parenteral, rectal, pulmonary or topical administration, and the like. When used for oral administration, the medicament or pharmaceutical combination may be formulated into an oral preparation, for example, an oral solid preparation such as a tablet, capsule, pill, granule, etc., or an oral liquid preparation such as an oral solution, oral suspension, syrup, etc. When formulated into an oral formulation, the pharmaceutical formulation may further comprise suitable fillers, binders, disintegrants, lubricants, etc.

The medicaments or pharmaceutical combinations of the present disclosure may be formulated into any pharmaceutically acceptable dosage form for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration, e.g., may be formulated as tablets, troches, capsules, pills, powders, granules, solutions, suspensions, syrups, injections, suppositories, inhalants or sprays.

In some embodiments, the medicament or pharmaceutical combination of the present disclosure is in a solid dosage form, such as a capsule, tablet, granule, powder, or sachet. In some embodiments, the medicament or combination of medicaments of the present disclosure is in the form of a sterile injectable solution in one or more aqueous or non-aqueous non-toxic parenterally acceptable buffer systems, diluents, solubilizers, co-solvents or carriers. The sterile injectable preparation may also be a sterile injectable aqueous or oleaginous suspension or suspension in a non-aqueous diluent, carrier or co-solvent which may be formulated according to the known art using one or more suitable dispersing or wetting agents and suspending agents. The drug or drug combination may be a solution for intravenous (iv) bolus/infusion or a lyophilized system (alone or with excipients) reconstituted with a buffer system with or without other excipients. The freeze-dried material may be prepared from a non-aqueous solvent or an aqueous solvent. The dosage form may also be a concentrate that is further diluted for subsequent infusion.

In some embodiments, the BTK inhibitor or derivative thereof, e.g., zebutinib or derivative thereof, is administered orally. In some embodiments, HID-1121 or derivative thereof is administered by injection. The administration may be by infusion (continuous) or bolus (discontinuous) administration. Methods of administration by injection may be, for example, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid and intrasternal injection. Preferably, administration is by intravenous infusion or intravenous injection (bolus administration). More preferably, administration is by intravenous infusion.

In some embodiments, the HDAC6 inhibitor or derivative thereof is administered simultaneously, separately or sequentially with the BTK inhibitor or derivative thereof.

In some embodiments, the HDAC6 inhibitor or derivative thereof and the BTK inhibitor or derivative thereof are administered in the same or different cycles. In some preferred embodiments, the HDAC6 inhibitor or derivative thereof and the BTK inhibitor or derivative thereof are administered in different cycles. In some embodiments, the HDAC6 inhibitor or derivative thereof is administered once every 0.5, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days, preferably once daily, for 7 days after a continuous administration, for 7 days after a stop, for a further continuous administration for 7 days. In some embodiments, the BTK inhibitor or derivative thereof, e.g., zebutinib or derivative thereof, is administered once or twice daily.

In some embodiments, the HDAC6 inhibitor or derivative thereof and the BTK inhibitor or derivative thereof are administered at the same or different dosages. In some preferred embodiments, the HDAC6 inhibitor or derivative thereof and the BTK inhibitor or derivative thereof are administered in different doses. In general, the effective amount of the drug to be administered will depend on a number of factors, such as the severity of the disease being treated, the weight of the subject, the route of administration, the side effect profile, and the like. In clinical practice, the content of the HDAC6 inhibitor or its derivative and the BTK inhibitor or its derivative can be flexibly adjusted by one skilled in the art according to the specific condition, physical condition and other relevant factors of the patient, so as to achieve the objective of clinical treatment.

In some embodiments, the HID-1121 or derivative thereof is administered one or more times per day, for example 1, 2, 3 or 4 times per day, wherein a typical total daily dose is in the range of 0.01 to 1000 mg/kg/day.

In some embodiments, the daily dosage of HID-1121 or derivative thereof administered to a human patient is 0.1 to 600mg/kg, e.g. 0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、3、4、5、6、7、8、9、10、15、20、30、40、50、60、70、80、90、100、110、120、130、140、150、200、250、300、400、500 or 600mg/kg, preferably 0.5 to 50mg/kg, more preferably 0.5-30mg/kg, even more preferably 5-10mg/kg, based on the HID-1121 content. In clinical practice, the daily dosage of HID-1121 or its derivatives can be flexibly adjusted by those skilled in the art according to the specific condition, physical condition and other relevant factors of the patient to achieve the goal of clinical treatment.

In some embodiments, the daily dosage of HID-1121 or derivative thereof administered to a human patient is 25mg to 4500mg, e.g. 25、30、35、40、45、50、60、70、80、90、100、150、200、250、300、350、400、450、500、600、700、800、900、1000、1500、2000、2500、3000、3500、4000 or 4500mg, preferably 50mg to 3000mg, more preferably 250mg to 1500mg, based on the content of HID-1121. In clinical practice, the daily dosage of HID-1121 or its derivatives can be flexibly adjusted by those skilled in the art according to the specific condition, physical condition and other relevant factors of the patient to achieve the goal of clinical treatment.

In some embodiments, the dose of the zebutinib or its derivative administered in a single dose is 1-50mg/kg, for example, may be 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 10mg/kg, 15mg/kg, 20mg/kg, 25mg/kg, 30mg/kg, 35mg/kg, 40mg/kg, 45mg/kg or 50mg/kg, preferably 2-30mg/kg, more preferably 2-25mg/kg, based on the content of the zebutinib. In some embodiments, for a human patient, the zebutinib or derivative thereof is administered to the human patient at a dose of 10-3000mg, preferably 20-1500 mg, more preferably 100-600 mg, per day, based on the content of zebutinib. In clinical practice, one skilled in the art can flexibly adjust the daily dosage of zebutinib or its derivatives to achieve the goals of clinical treatment, depending on the specific condition, physical condition, and other relevant factors of the patient.

Examples

For the purpose of making the objects, technical solutions and advantages of the embodiments of the present disclosure more apparent, the technical solutions in the embodiments of the present disclosure will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present disclosure, and it is apparent that the described embodiments are some, but not all embodiments of the present disclosure. The following embodiments and features of the embodiments may be combined with each other without conflict. The following examples are provided to further illustrate the disclosure, but are not to be construed as limiting the disclosure, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principles of the disclosure are intended to be equivalent substitutes.

The materials and equipment used in the specific examples of the present disclosure are all known products, and are obtained by purchasing commercially available products or by using the disclosed methods.

Common abbreviations

Abbreviations used herein are defined in the following tables.

Example 1 action of HID-1121 and Zebutinib on MNO cells in NOD SCID mice subcutaneously transplanted tumors

1. Experimental materials

NOD SCID (Non-Obese Diabetic/Severe Combined Immunodeficiency, non-obese diabetes/severe combined immunodeficiency) mice were female, 6-8 weeks old, purchased from Shanghai Ji Hui laboratory animal feeding Co.

Zebutinib was purchased from pottery, cat No. T7584, lot No. 156148.

HID-1121, purchased from QUIMATRYX, S.L, lot CC-5570.0-02, 99.3% purity.

2. Experimental method

2.1 Cell culture and administration

MINO cells were cultured in RPMI1640 medium containing 15% foetal calf serum, 100U/mL penicillin and 100. Mu.g/mL streptomycin and continuously in a 37℃cell incubator containing 5% CO ₂, passaged 2-3 times per week.

2.2 Grouping and administration of animals

NOD SCID mice of 6-8 weeks of age were inoculated subcutaneously on the right underarm of each mouse with 0.1mL of MINO tumor cell fluid (1.00X 10 ⁷/mouse) containing 50% matrigel, day of inoculation was day 0. When the mean tumor volume reached 109mm ³, 32 mice were selected and randomly grouped according to tumor size and body weight, 8 mice per group were dosed on the day of grouping, and the dosing schedule was as shown in table 1 below. After 21 days, the medicine was stopped and observed for 7 days.

TABLE 1 dosing regimen for each group of subjects

2.2 Evaluation index and statistical analysis

The body weight of the mice was measured twice a week with an electronic balance. The tumor diameter was measured twice a week with a vernier caliper and the tumor volume was calculated as v=0.5×a×b ², where a and b are the length and width of the tumor, respectively.

Relative tumor proliferation rate T/C% = T _RTV/C_RTV x 100% (rtv=vt/V0), where T is the test group and C is the control group.

Tumor inhibition rate TGI% = (1-T/C) ×100%

Two-way ANOVA was used to compare body weight and tumor volume. All data will be analyzed using GRAPHPAD PRISM, p <0.05 indicating statistical differences.

3. Experimental results

The tumor volume change for each group of animals tested is shown in figure 1. The tumor inhibition effect evaluation of each group of subjects is shown in table 2, and all groups represent P <0.05, P <0.01, and P <0.001 compared with the control group.

TABLE 2 evaluation of tumor suppression Effect of test substances of each group

G2 (HID-112160 mg/kg 5ml/kg i.v for one week), G3 (zebutinib 25mg/kg 10ml/kg p.o BID) and G5 (HID-112160 mg/kg 5ml/kg i.v for one week) produced significant tumor inhibiting effects (P < 0.001), TGI of 63.95%, 56.39% and 79.86%, respectively, compared to the control group after 27 days of treatment. It can be seen that the G5 co-administration was significantly better than the G3 and G2 single drug groups (P <0.001 ) in terms of co-administration.

In conclusion, in the MINO cell NOD-SCID mouse subcutaneous transplantation tumor model, HID-1121 has good tumor inhibition effect, and can be used together with a zebutinib treatment scheme to enhance the tumor inhibition effect.

The foregoing descriptions of specific exemplary embodiments of the present disclosure are presented for purposes of illustration and description. The description is not intended to limit the disclosure to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain the specific principles of the present disclosure and its practical application to thereby enable one skilled in the art to make and utilize the present disclosure in various exemplary embodiments and with various modifications as are suited to the particular use contemplated. The scope of the disclosure is intended to be defined by the claims and equivalents thereof.

Claims

1. A pharmaceutical combination or kit comprising a first agent and a second agent, wherein the first agent is a histone deacetylase 6 (HDAC6) inhibitor or a derivative thereof, and the second agent is a Bruton's tyrosine kinase (BTK) inhibitor or a derivative thereof.

2. The pharmaceutical combination or kit according to claim 1, wherein the HDAC6 inhibitor is selected from one or more of HID-1121, ACY-1215, ACY241, KA2507, WT161, Tubacin and Tubastatin, and the HID-1121 is a compound having a structure represented by formula (I)

Preferably, the HDAC6 inhibitor is HID-1121.

3. The drug combination or kit according to claim 1 or 2, wherein the BTK inhibitor is selected from one or more of zanubrutinib, ibrutinib, acalabrutinib, telatinib, obeticholic acid, sbetinib and ivoflavone; preferably, the BTK inhibitor is zanubrutinib.

4. The pharmaceutical combination or kit according to any one of claims 1 to 3, further comprising one or more pharmaceutically acceptable carriers.

5. The pharmaceutical combination or kit according to any one of claims 1 to 3, wherein the HDAC6 inhibitor in the pharmaceutical combination or kit is contained in an oral preparation or an injectable preparation, preferably in an injectable preparation;

Preferably, the zanubrutinib is contained in an oral formulation or an injectable formulation, preferably in an oral formulation;

Preferably, the HDAC6 inhibitor and zanubrutinib in the pharmaceutical combination or kit may be contained in the same formulation or in different formulations.

6. Use of the pharmaceutical combination or kit according to any one of claims 1 to 5 in the preparation of a medicament for preventing and/or treating cancer;

Preferably, the cancer comprises lymphoma, leukemia, myeloma, colorectal cancer, fibrosarcoma, gastric cancer, glioblastoma, renal cancer, liver cancer, lung cancer, melanoma, nasopharyngeal cancer, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, breast cancer and/or prostate cancer;

Preferably, the cancer comprises mantle cell lymphoma, B cell lymphoma, T cell lymphoma, NK cell lymphoma and/or Hodgkin lymphoma;

More preferably, the cancer is mantle cell lymphoma.

7. Use of an HDAC6 inhibitor or its derivatives and a BTK inhibitor or its derivatives in the preparation of a drug, drug combination or drug kit for preventing and/or treating cancer.

8. The use according to claim 7, wherein the HDAC6 inhibitor is selected from one or more of HID-1121, ACY-1215, ACY241, KA2507, WT161, Tubacin and Tubastatin, and the HID-1121 is a compound having the structure represented by formula (I);

Preferably, the HDAC6 inhibitor is HID-1121.

9. The use according to claim 7 or 8, wherein the BTK inhibitor is selected from one or more of zanubrutinib, ibrutinib, acalabrutinib, telatinib, obeticholic acid, sbetinib and efavirenz; preferably, the BTK inhibitor is zanubrutinib.

10. The use according to any one of claims 7 to 9, wherein the cancer comprises lymphoma, leukemia, myeloma, colorectal cancer, fibrosarcoma, gastric cancer, glioblastoma, renal cancer, liver cancer, lung cancer, melanoma, nasopharyngeal cancer, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, breast cancer and/or prostate cancer;

More preferably, the cancer is mantle cell lymphoma.