WO2023280244A1 - 西奥罗尼及其联合用药治疗乳腺癌的用途 - Google Patents

西奥罗尼及其联合用药治疗乳腺癌的用途 Download PDF

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WO2023280244A1
WO2023280244A1 PCT/CN2022/104251 CN2022104251W WO2023280244A1 WO 2023280244 A1 WO2023280244 A1 WO 2023280244A1 CN 2022104251 W CN2022104251 W CN 2022104251W WO 2023280244 A1 WO2023280244 A1 WO 2023280244A1
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breast cancer
derivatives
use according
chidamide
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PCT/CN2022/104251
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French (fr)
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鲁先平
宁志强
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深圳微芯生物科技股份有限公司
成都微芯药业有限公司
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Priority to CN202280047251.8A priority Critical patent/CN117597124A/zh
Publication of WO2023280244A1 publication Critical patent/WO2023280244A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
    • Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

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  • the invention relates to the field of biomedicine, in particular to the use of ciorone and its combination medicine for treating breast cancer.
  • stage I stage II
  • stage III stage III
  • stage IV stage IV
  • the number of female breast cancer cases and deaths accounted for 11.2% and 9.2% of global morbidity and death respectively, ranking among the top in the world, ranking first in the incidence and mortality of female malignant tumors in my country 1st and 5th place.
  • the number of new breast cancer cases reached 269,000, accounting for 15% of all new malignant tumors in women, and 69,500 women died of breast cancer, and the trend is younger.
  • Breast cancer has become an important factor threatening the health of Chinese women.
  • breast cancer classification methods There are two types of breast cancer classification methods, one is pathological classification, and the other is molecular classification.
  • breast cancer can usually be divided into non-invasive cancer, early invasive cancer, invasive cancer and so on.
  • Non-invasive cancers belong to the early stage, including common ductal carcinoma in situ, and usually have a good prognosis. On the contrary, the overall prognosis of invasive cancers is poorer. To achieve good results, more comprehensive treatment is usually required.
  • Invasive carcinoma is the most common, accounting for more than 80%, it can be subdivided into invasive ductal carcinoma, invasive lobular carcinoma and so on.
  • Molecular typing refers to the detection of breast cancer at the gene and protein level, and grouping according to the characteristics of gene mutation and protein expression.
  • ER estrogen receptor
  • PR progesterone receptor
  • HER2 proteins Depending on how positive and negative they are, different combinations are formed, which also lead to different subtypes of breast cancer. For example: if a breast cancer is ER positive or PR positive, HER2 negative (ER+PR+HER2-), then we call it hormone receptor positive breast cancer. If a breast cancer is ER-negative, PR-negative, but HER2-positive (ER-PR-HER2+), then we call it HER2-positive breast cancer. If a breast cancer is ER negative, PR negative, HER2 negative (ER-PR-HER2-), then we call it triple negative breast cancer.
  • Immunotherapy is an emerging field of breast cancer treatment, especially for triple-negative breast cancer for which no specific targeted therapy exists. Studies have shown that the PD-L1 checkpoint inhibitor atezolizumab combined with nano nab-paclitaxel in the first line can prolong the survival of patients. Targeted therapy includes the application of anti-angiogenic drugs, PARP inhibitors, etc., but it is still in the clinical exploration stage, and it is urgent to find new methods for the treatment of this type of breast cancer after chemotherapy failure.
  • HR-positive/HER2-negative breast cancer is by far the most common subtype across racial/ethnic groups.
  • the American Society of Clinical Oncology (ASCO) clinical practice guidelines on chemotherapy and targeted therapy for HER2-negative breast cancer recommend that, for women with hormone receptor-positive advanced breast cancer, except for immediately life-threatening lesions (such as symptomatic visceral metastases) or endocrine
  • endocrine therapy should be used as the first-line standard treatment.
  • endocrine therapy is prone to primary or secondary drug resistance, which limits its application.
  • systemic chemotherapy should be considered if three consecutive endocrine therapy regimens fail to benefit or symptomatic visceral metastases occur.
  • Theoroni is a brand-new molecule independently developed by Shenzhen Microchip Biotechnology Co., Ltd. with global patent protection. There is no indication approved for marketing at home and abroad. It is a small molecule anti-tumor drug targeting multiple protein kinases Targeted drugs, through high selective inhibitory activity on VEGFR/PDGFR/c-Kit, Aurora B, and CSF-1R targets, have three anti-tumor pathways, including anti-tumor angiogenesis, inhibition of tumor cell mitosis, and regulation of tumor inflammatory microenvironment The synergistic mechanism exerts a comprehensive anti-tumor effect; at the same time, its high target selectivity also reduces the risk of side effects caused by off-target effects.
  • CN200910223861.5 discloses Theoroni compound, which specifically discloses a derivative of naphthylamide, its preparation method and application.
  • This type of compound has both protein kinase inhibitory activity and histone deacetylase inhibitory activity, and can be used to treat diseases related to abnormal protein kinase activity or abnormal histone deacetylase activity, including inflammation, autoimmune disease, cancer , nervous system and neurodegenerative diseases, cardiovascular diseases, metabolic diseases, allergies, asthma and hormone-related diseases.
  • CN201610856945.2 discloses the non-solvated crystals A, B, and C of Theoroni and their preparation methods, and also relates to pharmaceutical compositions containing the crystals, and the preparation of the crystals for the treatment of abnormal protein kinase activity Or the application of drugs for diseases related to abnormal histone deacetylase activity.
  • Chidamide is also a new molecular body with global patent protection independently developed by Shenzhen Microchip Biotechnology Co., Ltd. It has been approved for two indications in China and is a new generation of subtype-selective histone deacetylase inhibitors , mainly targeting the I major HDAC subtypes (HDAC1, 2, 3) closely related to the occurrence and development of tumors. Studies have shown that Chidamide inhibits specific HDAC subtypes and the resulting chromatin Remodeling and gene transcription regulation (i.e.
  • T cells T cells
  • CTL tumor killing effect mediated by T cells (CTL) and the inhibition of the inflammatory response of tumor pathological tissues may not only directly contribute to the curative effect on circulating tumor cells and local lesions in T lymphoma, but also may be used to induce and enhance the effect on other tumors.
  • chidamide has the functions of inducing tumor stem cell differentiation and reversing the epithelial-mesenchymal phenotype transition (EMT) of tumor cells through the epigenetic regulation mechanism, and then in It plays a potential role in restoring the sensitivity of drug-resistant tumors to drugs and inhibiting tumor metastasis and recurrence.
  • EMT epithelial-mesenchymal phenotype transition
  • CN03139760.3 discloses chidamide compounds, specifically a preparation method and application of a benzamide histone deacetylase inhibitor with differentiation and anti-proliferation activity and its pharmaceutical preparations, which discloses the structure The general formula defines the substituents.
  • the compounds, as histone deacetylase inhibitors, can be used to treat diseases related to differentiation and proliferation, such as cancer and psoriasis.
  • CN201210489178.8 discloses two crystalline forms of chidamide, ie, crystal form A and crystal form B of chidamide, and a preparation method of a new crystal form of chidamide.
  • the chidamide crystal form A and chidamide crystal form B have excellent performance in oral absorption and inhibition of cell differentiation and proliferation, and are weakly toxic, have good storage and handling stability, and can be used to prepare Drugs that treat diseases related to cell differentiation and proliferation.
  • CN201410136761.X discloses an E-configuration benzamide compound and its pharmaceutical preparation and application.
  • the E-configuration benzamide compound is chidamide, and its chemical name is N-(2-amino- 4-fluorophenyl)-4-[N-[(E)-3-(3-pyridine)acryloyl]aminomethyl]benzamide, in its structural formula, the configuration of 3-pyridineacryloyl is E type.
  • the E-configuration chidamide has subtype-selective histone deacetylase inhibitory activity, mainly inhibiting HDAC1, HDAC2, HDAC3 in class I HDACs and HDAC10 in class IIb HDACs.
  • the E-configuration chidamide can be used to treat diseases related to abnormal activity of histone deacetylase, such as cancer, including lymphoma, solid tumor and hematological tumor.
  • the purpose of the present invention is to provide a drug and drug combination composition that can effectively prevent and/or treat breast cancer after first-line, especially multi-line treatment.
  • the present invention proposes the use of cioloni or its derivatives or a pharmaceutical composition comprising it and chidamide or its derivatives in the preparation of medicaments for treating and/or preventing breast cancer.
  • the breast cancer is triple-negative breast cancer.
  • the cioloni derivatives include its pharmaceutically acceptable salts and non-solvated crystals A, B and C
  • the chidamide derivatives include its pharmaceutically acceptable salts, enantiomers, and crystal forms A and B.
  • the content of the ciorone or its derivatives is 10-80mg, preferably 20-50mg, more preferably 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, the content of chidamide or its derivatives is 5-60mg, preferably 10-30mg, more preferably 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg.
  • the drug is a first-line, second-line, third-line, fourth-line, fifth-line or sixth-line drug.
  • compositions of the present invention include compound preparations or kits.
  • kits refers to a complete set of packaging that includes therapeutic drugs. Usually the correct proportions of the various drugs are provided in kits and packaged in a form that optimizes and saves those expensive and difficult to obtain drugs, where each drug has a precise dosage and can be used as a set when treating a disease.
  • the compound preparation includes solid preparation and liquid preparation.
  • the solid preparations include tablets, capsules, granules, pills, powders and suppositories, and the liquid preparations include oral liquids and injections.
  • the kit is the unit preparations of Theoronib or its derivatives and Chidamide or its derivatives with the same or different specifications respectively, wherein the unit preparations are placed in separate containers or in the same container.
  • the present invention also provides a method for treating and/or preventing breast cancer, which comprises administering Theoloni or its derivatives or simultaneously or sequentially administering Theocronib or its derivatives and Chidamide or its derivatives A step of.
  • the breast cancer is triple-negative breast cancer.
  • the cioloni derivatives include its pharmaceutically acceptable salts and non-solvated crystals A, B and C
  • the chidamide derivatives include its pharmaceutically acceptable salts, enantiomers, and crystal forms A and B.
  • the content of the ciorone or its derivatives is 10-80mg, preferably 20-50mg, more preferably 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, the content of chidamide or its derivatives is 5-60mg, preferably 10-30mg, more preferably 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg.
  • the present invention proves through the animal efficacy test that different doses of Theoronib alone have significant tumor growth inhibitory activity, and the efficacy models of different tumor donor sources have slight differences in the curative effect of Theoronib, showing that more or less dose dependent.
  • the combination of cioloni and chidamide has a stronger inhibitory effect on tumor growth than the two drugs used alone, that is, the combination of the two drugs can produce a better therapeutic effect.
  • Figure 1 represents the tumor inhibitory activity of cioronib on TNBC (triple negative breast cancer)-PDX (human tumor xenograft) model 1 at different doses.
  • the abscissa represents the number of days after the completion of treatment, and the ordinate represents the tumor volume (mm 3 ).
  • Figure 2 represents the tumor inhibitory activity of cioronib on TNBC (triple negative breast cancer)-PDX (human tumor xenograft) model 2 at different doses.
  • the abscissa represents the number of days after the completion of treatment, and the ordinate represents the tumor volume (mm 3 ).
  • Figure 3 represents the tumor inhibitory activity of cioloni and chidamide alone and in combination on the 4T1 (mouse triple-negative breast cancer cell line) model.
  • the abscissa represents the number of days after the completion of treatment
  • the ordinate represents the tumor volume (mm 3 ).
  • Example 1 Drug efficacy test of cioronib on tumor xenograft model (PDX) derived from triple negative breast cancer patients
  • BR1458 and BR1282 were tumors from Asian triple-negative breast cancer (TNBC) patients.
  • TNBC Asian triple-negative breast cancer
  • Inoculate BR1458 into BALB/c nude mice purchased from Beijing Weitong Lihua Biotechnology Co., Ltd.
  • inoculate BR1282 into BALB/c nude mice until they grow to About 100mm 3 , recorded as model 2.
  • Model 1 mice were divided into 4 groups: solvent control group, Theoroni low-dose group (5mg/kg), Theoroni middle-dose group (10mg/kg), Theoroni high-dose group (20mg/kg). kg), administered once a day (QD), and administered continuously for 3 weeks, the changes in tumor volume were monitored, and the results are shown in Figure 1.
  • Model 2 mice were administered in groups in the same way as model 1 mice, and the changes in tumor volume were monitored. The results are shown in Figure 2.
  • Example 2 Drug efficacy test of cioronib and its combination with chidamide on xenograft tumor model derived from triple-negative breast cancer cell lines
  • mice inoculate the mouse triple-negative breast cancer cell line 4T1 (purchased from Crown Biotechnology (Beijing) Co., Ltd.) into normal BALB/c mice (purchased from Beijing Weitong Lihua Biotechnology Co., Ltd. Technology Co., Ltd.) until it grows to about 100mm 3 .
  • 4T1 purchased from Crown Biotechnology (Beijing) Co., Ltd.
  • BALB/c mice purchased from Beijing Weitong Lihua Biotechnology Co., Ltd. Technology Co., Ltd.
  • the model mice obtained above are divided into 6 groups: solvent control group, Theoroni low dose group (5mg/kg), Theoroni middle dose group (10mg/kg), Theoroni high dose group ( 20mg/kg), Chidamide (25mg/kg) single-drug group, two-drug combination (Cioronib 10mg/kg+Chidamide 25mg/kg) group, administered once a day (QD), continuous administration After 3 weeks, the changes in tumor volume were monitored, and the results are shown in Figure 3.
  • the tumor volume in the chidamide (25mg/kg) single drug group decreased to some extent, that is, it also had a certain tumor inhibitory effect.
  • the two-drug combination (Cioronib 10mg/kg+Chioronib 25mg/kg) group had the largest reduction in tumor volume, which represented that the combination of Chioronib and Cioronib had a significant effect.
  • the stronger anti-tumor effect is stronger than that of chidamide monotherapy group and the 3 dosage groups of cioronib monotherapy, resulting in an unexpected synergistic effect.

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Abstract

涉及生物医药领域，具体涉及西奥罗尼及其联合用药治疗乳腺癌的用途。提供了西奥罗尼或其衍生物或者包含其与西达本胺或其衍生物的药物组合物在制备用于治疗和/或预防乳腺癌的药物中的用途。通过动物药效试验证明，西奥罗尼和西达本胺单药均有抑瘤活性，联合应用可以产生更好的协同治疗效果。

Description

西奥罗尼及其联合用药治疗乳腺癌的用途 技术领域
本发明涉及生物医药领域，具体涉及西奥罗尼及其联合用药治疗乳腺癌的用途。
背景技术
乳腺癌是全球及我国发病率最高的女性恶性肿瘤，占全部女性恶性肿瘤发病人数30％，在女性恶性肿瘤死亡率第二。世界卫生组织统计2018年乳腺癌新增210万，占女性所有癌症的1/4。据美国癌症协会统计，2019年新增病例31.7万，4.2万女性死于该疾病。根据激素受体(HR)和人表皮生长因子受体(HER2)分型，发病率最高的为HR+/HER2-乳腺癌约占66％，侵袭性最高的三阴性乳腺癌约占10％。乳腺癌的存活率因诊断阶段不同而有很大差异，临床分期越高5年生存率越低，I期98％、II期92％、III期75％、IV期27％。2018年我国最新乳腺癌数据报告，女性乳腺癌发病例数和死亡例数分别占全球发病和死亡的11.2％和9.2％，在世界范围位居前列，位居我国女性恶性肿瘤发病率和死亡率第1位和第5位。全国肿瘤登记2015年年报数据显示，乳腺癌新发病例数达26.9万，占女性全部新发恶性肿瘤的15％，6.95万女性因乳腺癌死亡，并且呈现年轻化趋势。乳腺癌已经成为威胁中国女性健康的重要因素。
乳腺癌的分型有两大类方法，一类是病理分型，二类是分子分型。
乳腺癌病理分型，是通过在显微镜下观察肿瘤细胞特征，从而判断它的性质。按照这个系统，通常可以把乳腺癌分为非浸润性癌，早期浸润性癌，浸润性癌等。非浸润性癌属于早期，包括常见的原位导管癌，通常预后很好，相反，浸润性癌整体预后就要差一些，要想达到好的效果，通常需要比较综合的治疗。浸润性癌最常见，占了80％以上，它又可以再细分为浸润性导管癌，浸润性小叶癌等。
分子分型，是指对乳腺癌进行基因和蛋白水平检测，根据基因突变和蛋白表达的特性来进行分组。乳腺癌的分子分型不止一种系统，最经典的是通过癌细胞是否表达ER(雌激素受体)，PR(孕酮受体)和HER2三种蛋白来分类。根据它们的阳性和阴性，形成了不同的组合，也带来了不同的乳腺癌亚型。比如：如果一个乳腺癌是ER阳性或PR阳性，HER2阴性(ER+PR+HER2-)，那么我们称它为激素受体阳性乳腺癌。如果一个乳腺癌是ER阴性，PR阴性，但HER2阳性(ER-PR-HER2+)，那么我们称它为HER2阳性乳腺癌。如果一个乳腺癌是ER阴性，PR阴性，HER2阴性(ER-PR-HER2-)，那么我们称它为三阴性乳腺癌。
5-10％的乳腺癌患者确诊时已发生远处转移，而接受治疗的早期患者中，仍有20-50％会 出现复发转移。研究显示，晚期转移性乳腺癌患者中位生存期为2-3年，五年生存率仅25％，尤其是HER2阴性的晚期乳腺癌，因缺乏有效的靶向治疗药物，其科学的治疗方案确立显得更加重要。
HR阴性/HER2阴性乳腺癌的治疗进展落后于其它分子亚型，迄今仅限于非转移性疾病的化疗，但该病理类型呈现高侵袭性，易发生远处转移。复发转移晚期乳腺癌一线、二线、后线化疗尚未确定最优方案，包括蒽环类药物、紫杉烷、和卡培他滨等，治疗采用单药化疗或联合化疗的方式。大量证据表明紫衫类和蒽环类药物优选作为一线治疗。后线治疗方案的选择应综合考量之前的治疗、药物毒性、共存疾病、病人意愿等。经多线化疗，患者疗效获益呈现逐渐递减趋势，如连续3个化疗方案无效或ECOG评分≥3，不再考虑使用细胞毒药物，改用姑息治疗。免疫治疗是乳腺癌治疗的一个新兴领域，特别是针对没有特效靶向治疗的三阴性乳腺癌。研究表明PD-L1检查点抑制剂atezolizumab与纳米白蛋白结合型紫杉醇在一线联合使用可以延长患者的生存期。靶向治疗包括抗血管生成药，PARP抑制剂等的应用，但仍处于临床探索阶段，亟待寻求新的方法用于化疗失败后该类乳腺癌的治疗。
HR阳性/HER2阴性乳腺癌是目前各个种族/民族组中最常见的亚型。美国临床肿瘤学会(ASCO)关于HER2阴性乳腺癌化疗和靶向治疗临床实践指南推荐，对于激素受体阳性晚期乳腺癌女性，除了有立即危及生命的病变(如有症状的内脏转移)或者对内分泌治疗产生耐药，应将内分泌疗法作为一线标准治疗方案。但内分泌治疗容易出现原发或继发耐药，导致其应用受限。美国NCCN指南指出，连续3个内分泌治疗方案无获益或出现有症状的内脏转移，则需考虑系统化疗。但大多数抗肿瘤药物同时又会诱发不良反应，影响病人生活质量，内分泌治疗耐药的分子机制和相关靶向药物研究是当前亟待解决的问题。现阶段，内分泌联合用药方案在内分泌耐药受试者中的研究包括联合CDK4/6抑制剂、联合PI3Kα抑制剂、联合AKT抑制剂、联合HDAC抑制剂均能有效延长无进展生存期，在过去30年间提高了转移性疾病的生存率，对于激素受体阳性内分泌治疗耐药的受试者是一个新的契机。其它联合用药方案是否对内分泌耐药患者有效，是否可以为该部分人群提供一种新的治疗选择，这是领域内一个值得研究的课题。
西奥罗尼是深圳微芯生物科技股份有限公司自主研发的具全球专利保护的全新分子体，在国内外尚无适应症获批上市，是一个以多蛋白激酶为靶点的小分子抗肿瘤靶向药物，通过对VEGFR/PDGFR/c-Kit、Aurora B、CSF-1R靶点的高选择抑制活性，具有抗肿瘤血管生成、抑制肿瘤细胞有丝分裂、调控肿瘤炎性微环境等三通路抗肿瘤协同作用机制，发挥综合抗肿瘤作用；同时其高的靶标选择性也降低了因脱靶效应带来的副作用风险。
CN200910223861.5公开了西奥罗尼化合物，其具体公开了一种萘酰胺的衍生物、其制备方法及应用。该类化合物同时具有蛋白激酶抑制活性和组蛋白去乙酰化酶抑制活性，可以用于治疗与蛋白激酶活性异常或组蛋白去乙酰化酶活性异常相关的疾病，包括炎症、自身免疫性疾病、癌症、神经系统疾病和神经退化性疾病、心血管疾病、代谢病、过敏、哮喘以及与激素相关的疾病。CN201610856945.2公开了西奥罗尼的的非溶剂化晶体A、B、C及其制备方法，还涉及含有所述晶体的药物组合物，以及所述晶体在制备用于治疗与蛋白激酶活性异常或组蛋白去乙酰化酶活性异常相关的疾病的药物中的应用。
西达本胺也是深圳微芯生物科技股份有限公司自主研发的具全球专利保护的全新分子体，在国内已获批两个适应症，是新一代亚型选择性组蛋白去乙酰化酶抑制剂，主要针对与肿瘤发生和发展密切相关的第I大类HDAC亚型(HDAC1、2、3)，已有研究表明，西达本胺通过对特定HDAC亚型的抑制及由此产生的染色质重构与基因转录调控作用(即表观遗传调控作用)，明显抑制淋巴及血液肿瘤细胞于G0/G1周期并诱导肿瘤细胞凋亡；诱导和增强自然杀伤细胞(NK)和抗原特异性细胞毒T细胞(CTL)介导的肿瘤杀伤作用及抑制肿瘤病理组织的炎症反应，不仅可能直接贡献于对T淋巴瘤中循环肿瘤细胞及局部病灶的疗效作用，同时也可能应用于诱导和增强针对其他类型肿瘤的抗肿瘤细胞免疫的整体调节活性；此外，西达本胺通过表观遗传调控机制，具有诱导肿瘤干细胞分化、逆转肿瘤细胞的上皮间充质表型转化(EMT)等功能，进而在恢复耐药肿瘤对药物的敏感性和抑制肿瘤转移、复发等方面发挥潜在作用。
CN03139760.3公开了西达本胺化合物，具体公开了一种具有分化和抗增殖活性的苯甲酰胺类组蛋白去乙酰化酶抑制剂及其药用制剂的制备方法与应用，其公开了结构通式，对取代基进行了定义。该类化合物作为组蛋白去乙酰化酶抑制剂，可以用于治疗与分化和增殖相关的疾病如癌症和牛皮癣。CN201210489178.8公开了西达本胺的两种结晶形式，即西达本胺晶型A和西达本胺晶型B，以及西达本胺新的结晶形式的制备方法。所述西达本胺晶型A和西达本胺晶型B在口服吸收性和抑制细胞的分化和增殖的方面性能优异，并且其毒性弱，具有良好的储存和处理稳定性，可用于制备治疗与细胞分化和增殖相关的疾病的药物。CN201410136761.X公开了一种E构型苯甲酰胺类化合物及其药用制剂与应用，所述E构型苯甲酰胺类化合物为西达本胺，其化学名称为N-(2-氨基-4-氟苯基)-4-[N-[(E)-3-(3-吡啶)丙烯酰基]氨甲基]苯甲酰胺，在其结构式中，3-吡啶丙烯酰基的构型为E型。所述E构型西达本胺具有亚型选择性组蛋白去乙酰化酶抑制活性，主要抑制第I类HDAC中的HDAC1、HDAC2、HDAC3和第IIb类HDAC中的HDAC10。所述E构型西达 本胺可以用于治疗与组蛋白去乙酰化酶活性异常相关的疾病，如癌症，包括淋巴瘤、实体肿瘤和血液系统肿瘤等。
晚期乳腺癌患者一线治疗根据HR受体和HER2肿瘤标志物表达情况，有较明确的能够获益的系统内分泌治疗或化疗方案。但经过一线特别是多线治疗后，患者的受益率逐渐下降，毒性反应增加、耐受性降低，可选择治疗方案有限，常选择姑息治疗，以提高患者生存质量。因此，晚期乳腺癌治疗存在未能满足的临床需求。
发明内容
本发明的目的是提供一种在一线特别是多线治疗后能够有效预防和/或治疗乳腺癌的药物以及药物联用组合物。
为实现该目的，本发明提出了西奥罗尼或其衍生物或者包含其与西达本胺或其衍生物的药物组合物在制备用于治疗和/或预防乳腺癌的药物中的用途。优选地，其中所述乳腺癌为三阴性乳腺癌。
其中，所述西奥罗尼衍生物包括其可药用盐以及非溶剂化晶体A、B和C，所述西达本胺衍生物包括其可药用盐、对映异构体以及晶型A和B。
所述西奥罗尼或其衍生物的含量为10-80mg，优选为20-50mg，进一步优选为10mg，15mg，20mg，25mg，30mg，35mg，40mg，45mg，50mg，55mg，60mg，65mg，70mg，75mg，80mg，所述西达本胺或其衍生物的含量为5-60mg，优选为10-30mg，进一步优选为5mg，10mg，15mg，20mg，25mg，30mg，35mg，40mg，45mg，50mg，55mg，60mg。
其中所述药物为一线、二线、三线、四线、五线或六线用药物。
本发明所述的药物组合物包括复方制剂或者药盒。
药盒是指包括有治疗用药物的成套包装。通常药盒中提供各种药物的正确比例，并以能使那些昂贵的和难以获得的药物以最好和节省的形式包装，其中各个药物具有精确的剂量，在治疗疾病时可成套使用。
其中，所述复方制剂包括固体制剂和液体制剂。所述固体制剂包括片剂、胶囊、颗粒剂、丸剂、散剂和栓剂，所述液体制剂包括口服液和注射剂。所述药盒为分别具有相同或不同规格的西奥罗尼或其衍生物和西达本胺或其衍生物单位制剂，其中所述单位制剂分别置于单独容器中或者置于同一容器中。
本发明同时还提供了治疗和/或预防乳腺癌的方法，其中包括施用西奥罗尼或其衍生物或者同时或依序施用西奥罗尼或其衍生物与西达本胺或其衍生物的步骤。
优选地，其中所述乳腺癌为三阴性乳腺癌。
其中，所述西奥罗尼衍生物包括其可药用盐以及非溶剂化晶体A、B和C，所述西达本胺衍生物包括其可药用盐、对映异构体以及晶型A和B。
所述西奥罗尼或其衍生物的含量为10-80mg，优选为20-50mg，进一步优选为10mg，15mg，20mg，25mg，30mg，35mg，40mg，45mg，50mg，55mg，60mg，65mg，70mg，75mg，80mg，所述西达本胺或其衍生物的含量为5-60mg，优选为10-30mg，进一步优选为5mg，10mg，15mg，20mg，25mg，30mg，35mg，40mg，45mg，50mg，55mg，60mg。
本发明的有益效果：
本发明通过动物药效试验证明：不同剂量的西奥罗尼单药均有显著的肿瘤生长抑制活性，且不同肿瘤供体来源的药效模型对西奥罗尼的疗效反应略有差异，呈现或多或少的剂量依赖性。西奥罗尼联合西达本胺相比两者单药使用，对肿瘤生长的抑制效果更强，即两药联合可以产生更好的治疗效果。
附图说明
图1代表西奥罗尼在不同剂量下对TNBC(三阴性乳腺癌)-PDX(人源肿瘤移植物)模型1的抑瘤活性。其中，横坐标代表治疗完成后天数，纵坐标代表肿瘤体积(mm 3)。
图2代表西奥罗尼在不同剂量下对TNBC(三阴性乳腺癌)-PDX(人源肿瘤移植物)模型2的抑瘤活性。其中，横坐标代表治疗完成后天数，纵坐标代表肿瘤体积(mm 3)。
图3代表西奥罗尼与西达本胺单药及两药联合在4T1(小鼠三阴性乳腺癌细胞株)模型上的抑瘤活性。其中，横坐标代表治疗完成后天数，纵坐标代表肿瘤体积(mm 3)。
具体实施方式
以下进一步通过非限制性实例来说明本发明，其不旨在限制本发明所涵盖的范围。
除非另有定义，否则本文中使用的所有技术和科学术语均具有与本领域一般技术人员通常所理解的含义相同的含义。
实施例一 西奥罗尼对三阴性乳腺癌患者来源的肿瘤移植物模型(PDX)的药效试验
建立人源PDX模型：选取两个不同供体来源的
Figure PCTCN2022104251-appb-000001
乳腺癌(购自中美冠科生物技术(北京)有限公司)，分别记为BR1458和BR1282，两个供体均来自亚裔三阴性乳腺癌(TNBC) 患者的肿瘤。将BR1458接种至BALB/c裸鼠(购自北京维通利华生物技术有限公司)，至其生长至100mm 3左右，记为模型1；将BR1282接种至BALB/c裸鼠，至其生长至100mm 3左右，记为模型2。
将模型1小鼠分为4组：溶剂对照组、西奥罗尼低剂量组(5mg/kg)、西奥罗尼中剂量组(10mg/kg)、西奥罗尼高剂量组(20mg/kg),每天给药一次(QD),连续给药3周，监测肿瘤体积变化，结果见图1。
将模型2小鼠按照模型1小鼠同样的方法进行分组给药，监测肿瘤体积变化，结果见图2。
由图1可知：在模型1中，相比溶剂对照组，西奥罗尼低剂量组中肿瘤体积显著减小，即西奥罗尼在最低剂量(5mg/kg)下就有显著的抑瘤活性；并且，西奥罗尼的3个不同剂量(5mg/kg、10mg/kg和20mg/kg)组差异不明显，推测其可能与此来源肿瘤对西奥罗尼较为敏感有关。
由图2可知：在模型2中，相比溶剂组，西奥罗尼的3个不同剂量(5mg/kg、10mg/kg和20mg/kg)组中肿瘤体积均显著减小，即西奥罗尼在3种剂量下均有显著的抑瘤活性；并且，西奥罗尼的3个不同剂量(5mg/kg、10mg/kg和20mg/kg)组差异明显，显示出明显的剂量依赖特征，此肿瘤对西奥罗尼的敏感性相对较低。
实施例二 西奥罗尼及其联合西达本胺对三阴性乳腺癌细胞株来源的移植瘤模型的药效试验
建立小鼠来源的TNBC模型：将小鼠三阴性乳腺癌细胞株4T1(购自中美冠科生物技术(北京)有限公司)接种至正常BALB/c小鼠(购自北京维通利华生物技术有限公司)，至其生长至100mm 3左右。
将上述得到的模型小鼠分为6组：溶剂对照组、西奥罗尼低剂量组(5mg/kg)、西奥罗尼中剂量组(10mg/kg)、西奥罗尼高剂量组(20mg/kg)、西达本胺(25mg/kg)单药组、两药联合(西奥罗尼10mg/kg+西达本胺25mg/kg)组,每天给药一次(QD),连续给药3周，监测肿瘤体积变化，结果见图3。
由图3可知：相比溶剂对照组，西奥罗尼的3个不同剂量(5mg/kg、10mg/kg和20mg/kg)组中肿瘤体积均减小，即西奥罗尼在3种剂量下均有抑瘤活性；并且，西奥罗尼的低剂量(5mg/kg)组与中高剂量(10mg/kg和20mg/kg)组有一定差异，显示出一定的剂量依赖特征，而西奥罗尼中剂量(10mg/kg)组和高剂量(20mg/kg)组间则没有显著差异。相比溶剂对照 组，西达本胺(25mg/kg)单药组中肿瘤体积有所减小，即其也有一定的抑瘤效果。与其它各组相比，两药联合(西奥罗尼10mg/kg+西达本胺25mg/kg)组中肿瘤体积减小程度最大，代表西达本胺和西奥罗尼两药联合具有显著更强的抑瘤效果，强于西达本胺单药组以及西奥罗尼单用的3种剂量组，产生了预料不到的协同增效作用。
以上对本发明进行了详细的介绍，本文中应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想，包括最佳方式，并且也使得本领域的任何技术人员都能够实践本发明，包括制造和使用任何装置或系统，和实施任何结合的方法。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。本发明专利保护的范围通过权利要求来限定，并可包括本领域技术人员能够想到的其他实施例。如果这些其他实施例具有不是不同于权利要求文字表述的结构要素，或者如果它们包括与权利要求的文字表述无实质差异的等同结构要素，那么这些其他实施例也应包含在权利要求的范围内。

Claims (11)

  1. 西奥罗尼或其衍生物或者包含其与西达本胺或其衍生物的药物组合物在制备用于治疗和/或预防乳腺癌的药物中的用途。
  2. 根据权利要求1所述的用途，其中所述乳腺癌为三阴性乳腺癌。
  3. 根据权利要求1所述的用途，所述西奥罗尼衍生物包括其可药用盐以及非溶剂化晶体A、B和C。
  4. 根据权利要求1所述的用途，其中所述西达本胺衍生物包括其可药用盐、对映异构体以及晶型A和B。
  5. 根据权利要求1所述的用途，其中所述西奥罗尼或其衍生物的含量为10-80mg，优选为20-50mg，所述西达本胺或其衍生物的含量为5-60mg，优选为10-30mg。
  6. 根据权利要求1所述的用途，其中所述药物为一线、二线、三线、四线、五线或六线用药物。
  7. 根据权利要求1所述的用途，其中所述药物组合物包括复方制剂或者药盒。
  8. 根据权利要求7所述的用途，其中所述复方制剂包括固体制剂和液体制剂。
  9. 根据权利要求8所述的用途，其中所述固体制剂包括片剂、胶囊、颗粒剂、丸剂、散剂和栓剂，所述液体制剂包括口服液和注射剂。
  10. 根据权利要求7所述的用途，其中所述药盒为分别具有相同或不同规格的西奥罗尼或其衍生物和西达本胺或其衍生物单位制剂。
  11. 根据权利要求10所述的用途，其中所述单位制剂分别置于单独容器中或者置于同一容器中。
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