CN115052594A - 化合物和其用途 - Google Patents
化合物和其用途 Download PDFInfo
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- CN115052594A CN115052594A CN202180011624.1A CN202180011624A CN115052594A CN 115052594 A CN115052594 A CN 115052594A CN 202180011624 A CN202180011624 A CN 202180011624A CN 115052594 A CN115052594 A CN 115052594A
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Abstract
本公开特征在于可用于治疗BAF复合物相关病症的化合物。
Description
背景技术
病症可能会受到BAF复合物的影响。BRD9是BAF复合物的组成部分。本发明涉及用于治疗BAF复合物相关病症,例如癌症和感染的有用组合物和方法。
发明内容
含溴结构域蛋白9(BRD9)是由5号染色体上的BRD9基因编码的蛋白质。BRD9是BAF(BRG1或BRM相关因子)复合物(一种SWI/SNF ATP酶染色质重塑复合物)的组成部分,属于含溴结构域蛋白的IV家族。BRD9存在于数种SWI/SNF ATP酶染色质重塑复合物中,并在多种癌细胞系中上调。因此,降低BRD9的水平和/或活性的剂可提供用于治疗例如癌症和感染的疾病和病症的新方法。本发明人已发现使细胞中的BRD9耗尽会引起那些细胞中SS18-SSX融合蛋白的耗尽。在超过95%滑膜肉瘤肿瘤中检测到SS18-SSX融合蛋白,并且通常是滑膜肉瘤中唯一的细胞遗传学异常。此外,有证据表明,BAF复合物与细胞抗病毒活性有关。因此,降解BRD9的剂(例如化合物)可用于治疗与BAF、BRD9和/或SS18-SSX有关的病症(例如癌症或感染)。
本公开特征在于可用于治疗BAF相关病症(例如癌症或感染)的化合物和方法。
在一个方面,本发明特征在于一种具有表1中化合物D1、S-D1、R-D1和D2中的任一者的结构的化合物,或其药学上可接受的盐。
在一些实施方案中,化合物具有化合物D1的结构,或其药学上可接受的盐。在一些实施方案中,化合物具有化合物S-D1的结构,或为其药学上可接受的盐。在一些实施方案中,化合物具有化合物R-D1的结构,或为其药学上可接受的盐。在其它实施方案中,化合物具有化合物D2的结构,或其药学上可接受的盐。
在一个方面,本发明特征在于具有表1中化合物D1的结构的化合物,或其药学上可接受的盐。
在一个方面,本发明特征在于具有表1中化合物S-D1的结构的化合物,或其药学上可接受的盐。
在一个方面,本发明特征在于具有表1中化合物R-D1的结构的化合物,或其药学上可接受的盐。
在另一方面,本发明特征在于具有表1中化合物D2的结构的化合物,或其药学上可接受的盐。
表1.本发明的化合物
在另一方面,本公开特征在于一种药物组合物,其包括上述化合物中的任一者或其药学上可接受的盐和药学上可接受的赋形剂。
在一个方面,本公开特征在于一种抑制细胞中的BRD9的水平和/或活性的方法,所述方法包括使所述细胞与有效量的上述化合物中的任一者或其药学上可接受的盐或其药物组合物接触。
在另一方面,本公开特征在于一种降低细胞中的BRD9的水平和/或活性的方法,所述方法包括使所述细胞与有效量的上述化合物中的任一者或其药学上可接受的盐或其药物组合物接触。
在一些实施方案中,细胞为癌细胞。
在一些实施方案中,癌症为恶性横纹肌样瘤、CD8+T细胞淋巴瘤、子宫内膜癌、卵巢癌、膀胱癌、胃癌、胰腺癌、食道癌、前列腺癌、肾细胞癌、黑色素瘤、结肠直肠癌、肉瘤(例如软组织肉瘤、滑膜肉瘤、尤文氏肉瘤(Ewing's sarcoma)、骨肉瘤、横纹肌肉瘤、成人纤维肉瘤、腺泡状软组织肉瘤、血管肉瘤、透明细胞肉瘤、促纤维组织增生性小圆细胞肿瘤、上皮样肉瘤、纤维粘液样肉瘤、胃肠道基质瘤、卡波西肉瘤(Kaposi sarcoma)、脂肪肉瘤、平滑肌肉瘤、恶性间叶瘤恶性外周神经鞘膜瘤、粘液纤维肉瘤、低级别横纹肌肉瘤)、非小细胞肺癌(例如鳞状或腺癌)、胃癌或乳腺癌。在一些实施方案中,癌症为恶性横纹肌样瘤、CD8+T细胞淋巴瘤、子宫内膜癌、卵巢癌、膀胱癌、胃癌、胰腺癌、食道癌、前列腺癌、肾细胞癌、黑色素瘤或结肠直肠癌。在一些实施方案中,癌症为肉瘤(例如滑膜肉瘤或尤文氏肉瘤)、非小细胞肺癌(例如鳞状或腺癌)、胃癌或乳腺癌。在一些实施方案中,癌症为肉瘤(例如滑膜肉瘤或尤文氏肉瘤)。在一些实施方案中,肉瘤为滑膜肉瘤。
在一个方面,本公开特征在于一种治疗有需要的受试者的BAF复合物相关病症的方法,所述方法包括向所述受试者施用有效量的上述化合物中的任一者或其药学上可接受的盐或其药物组合物。在一些实施方案中,BAF复合物相关病症为癌症。在一些实施方案中,BAF复合物相关病症为感染。
在另一方面,本公开特征在于一种治疗有需要的受试者的SS18-SSX融合蛋白相关病症的方法,所述方法包括向所述受试者施用有效量的上述化合物中的任一者或其药学上可接受的盐或其药物组合物。在一些实施方案中,SS18-SSX融合蛋白相关病症为癌症。在一些实施方案中,SS18-SSX融合蛋白相关病症为感染。在前述方法中的任一者的一些实施方案中,SS18-SSX融合蛋白为SS18-SSX1融合蛋白、SS18-SSX2融合蛋白或SS18-SSX4融合蛋白。
在另一方面,本公开特征在于一种治疗有需要的受试者的BRD9相关病症的方法,所述方法包括向所述受试者施用有效量的上述化合物中的任一者或其药学上可接受的盐或其药物组合物。在一些实施方案中,BRD9相关病症为癌症。在一些实施方案中,BRD9相关病症为感染。
在一些实施方案中,癌症为鳞状细胞癌、基底细胞癌、腺癌、肝细胞癌和肾细胞癌;膀胱、肠、乳腺、宫颈、结肠、食道、头、肾脏、肝脏、肺、颈部、卵巢、胰腺、前列腺和胃的癌症;白血病;良性和恶性淋巴瘤,尤其伯基特淋巴瘤(Burkitt's lymphoma)和非霍奇金淋巴瘤(Non-Hodgkin's lymphoma);良性和恶性黑色素瘤;骨髓增生性疾病;肉瘤,包括尤文氏肉瘤、血管内皮瘤、卡波西肉瘤、脂肪肉瘤、肌肉瘤、外周神经上皮瘤、滑膜肉瘤、神经胶质瘤、星形细胞瘤、少突胶质细胞瘤、室管膜瘤、胶质母细胞瘤、神经母细胞瘤、神经节细胞瘤、神经节神经胶质瘤、髓母细胞瘤、松果体细胞肿瘤、脑膜瘤、脑膜肉瘤、纤维神经瘤和神经鞘瘤;肠癌、乳腺癌、前列腺癌、宫颈癌、子宫癌、肺癌、卵巢癌、睪丸癌、甲状腺癌、星形细胞瘤、食道癌、胰腺癌、胃癌、肝癌、结肠癌、黑色素瘤;癌肉瘤、霍奇金病、威尔姆斯氏瘤(Wilms'tumor)和畸胎癌。可使用根据本发明的所公开化合物治疗的另外的癌症包括例如急性粒细胞性白血病、急性淋巴细胞性白血病(ALL)、急性骨髓性白血病(AML)、腺癌、腺肉瘤、肾上腺癌、肾上腺皮质癌、肛门癌、间变性星形细胞瘤、血管肉瘤、阑尾癌、星形细胞瘤、基底细胞癌、B细胞淋巴瘤、胆管癌、膀胱癌、骨癌、骨髓癌、肠癌、脑癌、脑干神经胶质瘤、乳腺癌、三(雌激素、黄体酮和HER-2)阴性乳腺癌、双阴性乳腺癌(雌激素、黄体酮和HER-2中的两者呈阴性)、单阴性(雌激素、黄体酮和HER-2中的一者呈阴性)、雌激素受体阳性、HER2阴性乳腺癌、雌激素受体阴性乳腺癌、雌激素受体阳性乳腺癌、转移性乳腺癌、管腔A型乳腺癌、管腔B型乳腺癌、Her2阴性乳腺癌、HER2阳性或阴性乳腺癌、黄体酮受体阴性乳腺癌、黄体酮受体阳性乳腺癌、复发性乳腺癌、类癌瘤肿瘤、宫颈癌、胆管细胞癌、软骨肉瘤、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)、结肠癌、结肠直肠癌、颅咽管瘤、皮肤淋巴瘤、皮肤黑色素瘤、弥漫性星形细胞瘤、导管原位癌(DCIS)、子宫内膜癌、室管膜瘤、上皮样肉瘤、食道癌、尤文氏肉瘤、肝外胆管癌、眼癌、输卵管癌、纤维肉瘤、胆囊癌、胃癌、胃肠癌、胃肠道类癌、胃肠道基质瘤(GIST)、生殖细胞肿瘤多形性胶质母细胞瘤(GBM)、神经胶质瘤、毛细胞白血病、头颈癌、血管内皮瘤、霍奇金淋巴瘤、下咽癌、浸润性导管癌(IDC)、浸润性小叶癌(ILC)、炎性乳腺癌(IBC)、肠癌、肝内胆管癌、侵袭性/浸润性乳腺癌、胰岛细胞癌、颌癌、卡波西肉瘤、肾癌、喉癌、平滑肌肉瘤、软脑膜转移、白血病、唇癌、脂肪肉瘤、肝癌、小叶原位癌、低级别星形细胞瘤、肺癌、淋巴结癌、淋巴瘤、男性乳腺癌、髓样癌、髓母细胞瘤、黑色素瘤、脑膜瘤、默克尔细胞癌(Merkel cell carcinoma)、间叶性软骨肉瘤、间叶瘤、间皮瘤转移性乳腺癌、转移性黑色素瘤转移性鳞状颈癌、混合性胶质细胞瘤、单胚层畸胎瘤、口腔癌粘液癌、粘膜黑色素瘤、多发性骨髓瘤、蕈样真菌病、骨髓增生异常综合征、鼻腔癌、鼻咽癌、颈癌、神经母细胞瘤、神经内分泌肿瘤(NET)、非霍奇金淋巴瘤、非小细胞肺癌(NSCLC)、燕麦细胞癌、眼癌、眼睛黑色素瘤、少突胶质细胞瘤、口癌、口腔癌、口咽癌、骨原性肉瘤、骨肉瘤、卵巢癌、卵巢上皮癌卵巢生殖细胞肿瘤、卵巢原发性腹膜癌、卵巢性索基质肿瘤、佩吉特病(Paget's disease)、胰腺癌、乳头状癌、鼻窦癌、甲状旁腺癌、骨盆癌、阴茎癌、外周神经癌、腹膜癌、咽癌、嗜铬细胞瘤、毛细胞型星形细胞瘤、松果体区肿瘤、松果体母细胞瘤、垂体腺癌、原发性中枢神经系统(CNS)淋巴瘤、前列腺癌、直肠癌、肾细胞癌、肾盂癌、横纹肌肉瘤、唾液腺癌、软组织肉瘤、骨骼肉瘤、肉瘤、鼻窦癌、皮肤癌、小细胞肺癌(SCLC)、小肠癌、脊椎癌、脊柱癌、脊髓癌、鳞状细胞癌、胃癌、滑膜肉瘤、T细胞淋巴瘤、睪丸癌、咽喉癌、胸腺瘤/胸腺癌、甲状腺癌、舌癌、扁桃体癌、移行细胞癌、输卵管癌、管状癌、未诊断癌、输尿管癌、尿道癌、子宫腺癌、子宫癌、子宫肉瘤、阴道癌、外阴癌、T细胞谱系急性淋巴母细胞性白血病(T-ALL)、T细胞谱系淋巴母细胞性淋巴瘤(T-LL)、外周T细胞淋巴瘤、成人T细胞白血病、前BALL、前B淋巴瘤、大B细胞淋巴瘤、伯基特淋巴瘤、B细胞ALL、费城染色体(Philadelphiachromosome)阳性ALL、费城染色体阳性CML、幼年型粒-单核细胞白血病(JMML)、急性早幼粒细胞白血病(AML亚型)、大颗粒淋巴细胞白血病、成人T细胞慢性白血病、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤;粘膜相关的淋巴组织淋巴瘤(MALT)、小细胞淋巴细胞性淋巴瘤、纵隔大B细胞淋巴瘤、结节边缘区B细胞淋巴瘤(NMZL);脾边缘区淋巴瘤(SMZL);血管内大B细胞淋巴瘤;原发性渗出性淋巴瘤;或淋巴瘤样肉芽肿病;B细胞幼淋巴细胞白血病;未分类脾淋巴瘤/白血病、脾弥漫性红髓小B细胞淋巴瘤;淋巴浆细胞性淋巴瘤;重链病(例如α重链病、γ重链病、μ重链病)、浆细胞骨髓瘤、骨孤立性浆细胞瘤;骨外浆细胞瘤;原发性皮肤滤泡中心淋巴瘤、富含T细胞/组织细胞的大B细胞淋巴瘤、与慢性炎症相关的DLBCL;老年人爱泼斯坦-巴尔病毒(Epstein-Barr virus,EBV)+DLBCL;原发性纵隔(胸腺)大B细胞淋巴瘤、原发性皮肤DLBCL、腿型、ALK+大B细胞淋巴瘤、浆母细胞性淋巴瘤;在HHV8相关的多中心卡斯尔门病(Castleman disease)中出现的大B细胞淋巴瘤;具有介于弥漫性大B细胞淋巴瘤中间的特征的未分类B细胞淋巴瘤,或具有介于弥漫性大B细胞淋巴瘤与经典霍奇金淋巴瘤中间的特征的未分类B细胞淋巴瘤。
在一些实施方案中,癌症为恶性横纹肌样瘤、CD8+T细胞淋巴瘤、子宫内膜癌、卵巢癌、膀胱癌、胃癌、胰腺癌、食道癌、前列腺癌、肾细胞癌、黑色素瘤、结肠直肠癌、肉瘤(例如软组织肉瘤、滑膜肉瘤、尤文氏肉瘤、骨肉瘤、横纹肌肉瘤、成人纤维肉瘤、腺泡状软组织肉瘤、血管肉瘤、透明细胞肉瘤、促纤维组织增生性小圆细胞肿瘤、上皮样肉瘤、纤维粘液样肉瘤、胃肠道基质瘤、卡波西肉瘤、脂肪肉瘤、平滑肌肉瘤、恶性间叶瘤恶性外周神经鞘膜瘤、粘液纤维肉瘤、低级别横纹肌肉瘤)、非小细胞肺癌(例如鳞状或腺癌)、胃癌或乳腺癌。在一些实施方案中,癌症为恶性横纹肌样瘤、CD8+T细胞淋巴瘤、子宫内膜癌、卵巢癌、膀胱癌、胃癌、胰腺癌、食道癌、前列腺癌、肾细胞癌、黑色素瘤或结肠直肠癌。在一些实施方案中,癌症为肉瘤(例如滑膜肉瘤或尤文氏肉瘤)、非小细胞肺癌(例如鳞状或腺癌)、胃癌或乳腺癌。在一些实施方案中,癌症为肉瘤(例如滑膜肉瘤或尤文氏肉瘤)。在一些实施方案中,肉瘤为滑膜肉瘤。
在一些实施方案中,感染为病毒感染(例如以下病毒感染:逆转录病毒科(Retroviridae),例如慢病毒(例如人类免疫缺乏病毒(HIV)和δ逆转录病毒(例如人类T细胞白血病病毒I(HTLV-I)、人类T细胞白血病病毒II(HTLV-II));肝脱氧核糖核酸病毒科(Hepadnaviridae)(例如乙型肝炎病毒(HBV));黄病毒科(Flaviviridae)(例如丙型肝炎病毒(HCV));腺病毒科(Adenoviridae)(例如人类腺病毒);疱疹病毒科(Herpesviridae)(例如人类巨细胞病毒(HCMV)、爱泼斯坦-巴尔病毒、单纯疱疹病毒1(HSV-1)、单纯疱疹病毒2(HSV-2)、人类疱疹病毒6(HHV-6)、疱疹病毒K*、CMV、水痘-带状疱疹病毒);乳头瘤病毒科(Papillomaviridae)(例如人类乳头瘤病毒(HPV、HPV E1));细小病毒科(Parvoviridae)(例如细小病毒B19);多瘤病毒科(Polyomaviridae)(例如JC病毒和BK病毒);副粘病毒科(Paramyxoviridae)(例如麻疹病毒);或披膜病毒科(Togaviridae)(例如风疹病毒))。在一些实施方案中,病症为科芬西里斯病(Coffin Siris)、神经纤维瘤(例如NF-1、NF-2或神经鞘瘤(Schwannomatosis))或多发性脑膜瘤。在一个方面,本公开特征在于一种治疗有需要的受试者的癌症的方法,所述方法包括向所述受试者施用有效量的上述化合物中的任一者或其药学上可接受的盐或上述药物组合物中的任一者。
在一些实施方案中,癌症为鳞状细胞癌、基底细胞癌、腺癌、肝细胞癌和肾细胞癌;膀胱、肠、乳腺、宫颈、结肠、食道、头、肾脏、肝脏、肺、颈部、卵巢、胰腺、前列腺和胃的癌症;白血病;良性和恶性淋巴瘤,尤其是伯基特淋巴瘤和非霍奇金淋巴瘤;良性和恶性黑色素瘤;骨髓增生性疾病;肉瘤,包括尤文氏肉瘤、血管内皮瘤、卡波西肉瘤、脂肪肉瘤、肌肉瘤、外周神经上皮瘤、滑膜肉瘤、神经胶质瘤、星形细胞瘤、少突胶质细胞瘤、室管膜瘤、胶质母细胞瘤、神经母细胞瘤、神经节细胞瘤、神经节神经胶质瘤、髓母细胞瘤、松果体细胞肿瘤、脑膜瘤、脑膜肉瘤、纤维神经瘤和神经鞘瘤;肠癌、乳腺癌、前列腺癌、宫颈癌、子宫癌、肺癌、卵巢癌、睪丸癌、甲状腺癌、星形细胞瘤、食道癌、胰腺癌、胃癌、肝癌、结肠癌、黑色素瘤;癌肉瘤、霍奇金病、威尔姆斯氏瘤和畸胎癌。可使用根据本发明的所公开化合物治疗的另外的癌症包括例如急性粒细胞性白血病、急性淋巴细胞性白血病(ALL)、急性骨髓性白血病(AML)、腺癌、腺肉瘤、肾上腺癌、肾上腺皮质癌、肛门癌、间变性星形细胞瘤、血管肉瘤、阑尾癌、星形细胞瘤、基底细胞癌、B细胞淋巴瘤、胆管癌、膀胱癌、骨癌、骨髓癌、肠癌、脑癌、脑干神经胶质瘤、乳腺癌、三(雌激素、黄体酮和HER-2)阴性乳腺癌、双阴性乳腺癌(雌激素、黄体酮和HER-2中的两者呈阴性)、单阴性(雌激素、黄体酮和HER-2中的一者呈阴性)、雌激素受体阳性HER2阴性乳腺癌、雌激素受体阴性乳腺癌、雌激素受体阳性乳腺癌、转移性乳腺癌、管腔A型乳腺癌、管腔B型乳腺癌、Her2阴性乳腺癌、HER2阳性或阴性乳腺癌、黄体酮受体阴性乳腺癌、黄体酮受体阳性乳腺癌、复发性乳腺癌、类癌瘤肿瘤、宫颈癌、胆管细胞癌、软骨肉瘤、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)、结肠癌、结肠直肠癌、颅咽管瘤、皮肤淋巴瘤、皮肤黑色素瘤、弥漫性星形细胞瘤、导管原位癌(DCIS)、子宫内膜癌、室管膜瘤、上皮样肉瘤、食道癌、尤文氏肉瘤、肝外胆管癌、眼癌、输卵管癌、纤维肉瘤、胆囊癌、胃癌、胃肠癌、胃肠道类癌、胃肠道基质瘤(GIST)、生殖细胞肿瘤多形性胶质母细胞瘤(GBM)、神经胶质瘤、毛细胞白血病、头颈癌血管内皮瘤、霍奇金淋巴瘤、下咽癌、浸润性导管癌(IDC)、浸润性小叶癌(ILC)、炎性乳腺癌(IBC)、肠癌、肝内胆管癌、侵袭性/浸润性乳腺癌、胰岛细胞癌、颌癌、卡波西肉瘤、肾癌、喉癌、平滑肌肉瘤、软脑膜转移、白血病、唇癌、脂肪肉瘤、肝癌、小叶原位癌、低级别星形细胞瘤、肺癌、淋巴结癌、淋巴瘤、男性乳腺癌、髓样癌、髓母细胞瘤、黑色素瘤、脑膜瘤、默克尔细胞癌、间叶性软骨肉瘤、间叶瘤、间皮瘤转移性乳腺癌、转移性黑色素瘤转移性鳞状颈癌、混合性胶质细胞瘤、单胚层畸胎瘤、口腔癌粘液癌、粘膜黑色素瘤、多发性骨髓瘤、蕈样真菌病、骨髓增生异常综合征、鼻腔癌、鼻咽癌、颈癌、神经母细胞瘤、神经内分泌肿瘤(NET)、非霍奇金淋巴瘤、非小细胞肺癌(NSCLC)、燕麦细胞癌、眼癌、眼睛黑色素瘤、少突胶质细胞瘤、口癌、口腔癌、口咽癌、骨原性肉瘤、骨肉瘤、卵巢癌、卵巢上皮癌卵巢生殖细胞肿瘤、卵巢原发性腹膜癌、卵巢性索基质肿瘤、佩吉特病、胰腺癌、乳头状癌、鼻窦癌、甲状旁腺癌、骨盆癌、阴茎癌、外周神经癌、腹膜癌、咽癌、嗜铬细胞瘤、毛细胞型星形细胞瘤、松果体区肿瘤、松果体母细胞瘤、垂体腺癌、原发性中枢神经系统(CNS)淋巴瘤、前列腺癌、直肠癌、肾细胞癌、肾盂癌、横纹肌肉瘤、唾液腺癌、软组织肉瘤、骨骼肉瘤、肉瘤、鼻窦癌、皮肤癌、小细胞肺癌(SCLC)、小肠癌、脊椎癌、脊柱癌、脊髓癌、鳞状细胞癌、胃癌、滑膜肉瘤、T细胞淋巴瘤、睪丸癌、咽喉癌、胸腺瘤/胸腺癌、甲状腺癌、舌癌、扁桃体癌、移行细胞癌、输卵管癌、管状癌、未诊断癌、输尿管癌、尿道癌、子宫腺癌、子宫癌、子宫肉瘤、阴道癌、外阴癌、T细胞谱系急性淋巴母细胞性白血病(T-ALL)、T细胞谱系淋巴母细胞性淋巴瘤(T-LL)、外周T细胞淋巴瘤、成人T细胞白血病、前B ALL、前B淋巴瘤、大B细胞淋巴瘤、伯基特淋巴瘤、B细胞ALL、费城染色体阳性ALL、费城染色体阳性CML、幼年型粒-单核细胞白血病(JMML)、急性早幼粒细胞白血病(AML亚型)、大颗粒淋巴细胞白血病、成人T细胞慢性白血病、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤;粘膜相关的淋巴组织淋巴瘤(MALT)、小细胞淋巴细胞性淋巴瘤、纵隔大B细胞淋巴瘤、结节边缘区B细胞淋巴瘤(NMZL);脾边缘区淋巴瘤(SMZL);血管内大B细胞淋巴瘤;原发性渗出性淋巴瘤;或淋巴瘤样肉芽肿病;B细胞幼淋巴细胞白血病;未分类脾淋巴瘤/白血病、脾弥漫性红髓小B细胞淋巴瘤;淋巴浆细胞性淋巴瘤;重链病(例如α重链病、γ重链病、μ重链病)、浆细胞骨髓瘤、骨孤立性浆细胞瘤;骨外浆细胞瘤;原发性皮肤滤泡中心淋巴瘤、富含T细胞/组织细胞的大B细胞淋巴瘤、与慢性炎症相关的DLBCL;老年人爱泼斯坦-巴尔病毒(Epstein-Barr virus,EBV)+DLBCL;原发性纵隔(胸腺)大B细胞淋巴瘤、原发性皮肤DLBCL、腿型、ALK+大B细胞淋巴瘤、浆母细胞性淋巴瘤;在HHV8相关的多中心卡斯尔门病(Castleman disease)中出现的大B细胞淋巴瘤;具有介于弥漫性大B细胞淋巴瘤中间的特征的未分类B细胞淋巴瘤,或具有介于弥漫性大B细胞淋巴瘤与经典霍奇金淋巴瘤中间的特征的未分类B细胞淋巴瘤。
在一些实施方案中,癌症为恶性横纹肌样瘤、CD8+T细胞淋巴瘤、子宫内膜癌、卵巢癌、膀胱癌、胃癌、胰腺癌、食道癌、前列腺癌、肾细胞癌、黑色素瘤、结肠直肠癌、肉瘤(例如软组织肉瘤、滑膜肉瘤、尤文氏肉瘤、骨肉瘤、横纹肌肉瘤、成人纤维肉瘤、腺泡状软组织肉瘤、血管肉瘤、透明细胞肉瘤、促纤维组织增生性小圆细胞肿瘤、上皮样肉瘤、纤维粘液样肉瘤、胃肠道基质瘤、卡波西肉瘤、脂肪肉瘤、平滑肌肉瘤、恶性间叶瘤恶性外周神经鞘膜瘤、粘液纤维肉瘤、低级别横纹肌肉瘤)、非小细胞肺癌(例如鳞状或腺癌)、胃癌或乳腺癌。在一些实施方案中,癌症为恶性横纹肌样瘤、CD8+T细胞淋巴瘤、子宫内膜癌、卵巢癌、膀胱癌、胃癌、胰腺癌、食道癌、前列腺癌、肾细胞癌、黑色素瘤或结肠直肠癌。在一些实施方案中,癌症为肉瘤(例如滑膜肉瘤或尤文氏肉瘤)、非小细胞肺癌(例如鳞状或腺癌)、胃癌或乳腺癌。在一些实施方案中,癌症为肉瘤(例如滑膜肉瘤或尤文氏肉瘤)。在一些实施方案中,肉瘤为滑膜肉瘤。
在任一上述方法的一些实施方案中,癌症为前列腺癌。在任一上述方法的一些实施方案中,癌症为前列腺癌。
在任一上述方法的一些实施方案中,癌症为BRCA突变癌症。
在另一方面,本公开特征在于一种用于治疗有需要的受试者的病毒感染的方法。该方法包括向所述受试者施用有效量的上述化合物中的任一者,或其药学上可接受的盐,或上述药物组合物中的任一者。在一些实施方案中,病毒感染为以下病毒感染:逆转录病毒科,例如慢病毒(例如人类免疫缺乏病毒(HIV)和δ逆转录病毒(例如人类T细胞白血病病毒I(HTLV-I)、人类T细胞白血病病毒II(HTLV-II));肝脱氧核糖核酸病毒科(例如乙型肝炎病毒(HBV))、黄病毒科(例如丙型肝炎病毒(HCV))、腺病毒科(例如人类腺病毒)、疱疹病毒科(例如人类巨细胞病毒(HCMV)、爱泼斯坦-巴尔病毒、单纯疱疹病毒1(HSV-1)、单纯疱疹病毒2(HSV-2)、人类疱疹病毒6(HHV-6)、疱疹病毒K*、CMV、水痘-带状疱疹病毒)、乳头瘤病毒科(例如人类乳头瘤病毒(HPV、HPV E1))、细小病毒科(例如细小病毒B19)、多瘤病毒科(例如JC病毒和BK病毒)、副粘病毒科(例如麻疹病毒)、披膜病毒科(例如风疹病毒)。
在任一上述方法的另一实施方案中,所述方法还包括向所述受试者施用另外的抗癌疗法(例如化学治疗剂或细胞毒性剂或放射疗法)。
在一些实施方案中,另外的抗癌疗法为PARP抑制剂(例如尼拉帕尼(niraparib)、奥拉帕尼(olaparib)、卢卡帕尼(rucaparib)、他拉唑帕尼(talazoparib)、维利帕尼(veliparib)、帕米帕利(pamiparib)、CK-102或E7016)。在特定实施方案中,另外的抗癌疗法为:化学治疗剂或细胞毒性剂(例如多柔比星(doxorubicin)或异环磷酰胺(ifosfamide))、诱导分化剂(例如视黄酸、维生素D、细胞因子)、激素药剂、免疫药剂或抗血管生成剂。化学治疗剂和细胞毒性剂包括(但不限于)烷基化剂、细胞毒性抗生素、抗代谢物、长春花生物碱、依托泊苷(etoposide)和其它(例如太平洋紫杉醇(paclitaxel)、紫杉醇(taxol)、多烯紫杉醇(docetaxel)、泰索帝(taxotere)、顺铂(cis-platinum))。具有抗癌活性的另外化合物的清单可见于L.Brunton,B.Chabner和B.Knollman(编辑).Goodman andGilman’s The Pharmacological Basis of Therapeutics,第十二版,2011,McGraw HillCompanies,New York,NY。
在特定实施方案中,本发明的化合物和另外的抗癌疗法和上述化合物或药物组合物中的任一者彼此在28天内(例如在21天、14天、10天、7天、5天、4天、3天、2天或1天内)或在24小时(例如12小时、6小时、3小时、2小时或1小时;或伴随)内,各呈一同有效治疗受试者的量。
化学术语
本文所述的化合物可具有一个或多个不对称碳原子并且可呈光学纯对映异构物、对映异构物的混合物(例如外消旋体)、光学纯非对映异构物、非对映异构物的混合物、非对映异构物外消旋体或非对映异构物外消旋体的混合物形式存在。光学活性形式可例如通过拆分外消旋体、通过不对称合成或不对称色谱法(利用手性吸附剂或洗提液的色谱法)获得。即,某些所公开的化合物可呈多种立体异构形式存在。立体异构物是仅空间排列不同的化合物。对映异构物为镜像不可重叠的立体异构物对,最通常是因为它们含有用作手性中心的被不对称取代的碳原子。“对映异构物”意指彼此呈镜像并且不可重叠的一对分子中的一者。非对映异构物为非镜像相关的立体异构物,最通常是因为它们含有两个或更多个被不对称取代的碳原子并且表示一个或多个手性碳原子周围的取代基的构型。化合物的对映异构物可例如通过使用一种或多种众所周知的技术和方法,例如手性色谱法和基于手性色谱法的分离方法从外消旋体分离对映异构物来制备。适用于从外消旋混合物分离本文所述的化合物的对映异构物的技术和/或方法可容易地由本领域的技术人员决定。“外消旋体”或“外消旋混合物”意指含有两种对映异构物的化合物,其中这类混合物不展现光学活性;即,它们不会使偏振光平面旋转。“几何异构物”意指在与碳-碳双键、环烷基环或桥接双环系统相关的取代基原子的方向上不同的异构物。碳-碳双键每一侧的原子(除H以外)可呈E(取代基在碳-碳双键的对侧)或Z(取代基在同一侧上取向)构型。“R”、“S”、“S*”、“R*”、“E”、“Z”、“顺式”和“反式”指示相对于核心分子的构型。某些所公开的化合物可呈阻转异构物形式存在。阻转异构物是由围绕单键的旋转受阻引起的立体异构物,其中旋转的空间张力阻碍高至足以允许分离构象异构物。本文所述的化合物可通过异构物特异性合成制成个别异构物,或者从异构物混合物拆分。常规的拆分技术包括使用光学活性酸形成异构物对的各异构物的游离碱的盐(然后分步结晶和游离碱再生),使用光学活性胺形成异构物对的各异构物的酸形式的盐(然后分步结晶和游离酸再生),使用光学纯的酸、胺或醇形成异构物对的各异构物的酯或酰胺(然后色谱分离和去除手性助剂),或者使用多种众所周知的色谱法拆分起始物质或最终产物的异构物混合物。当所公开的化合物的立体化学通过结构来命名或描绘时,所命名或描绘的立体异构物相对于其它立体异构物按重量计至少60%、70%、80%、90%、99%或99.9%。当单一对映异构物通过结构来命名或描绘时,所描绘或命名的对映异构物按重量计至少60%、70%、80%、90%、99%或99.9%光学纯。当单一非对映异构物通过结构来命名或描绘时,所描绘或命名的非对映异构物按重量计至少60%、70%、80%、90%、99%或99.9%纯。光学纯度百分比是对映异构物的重量与对映异构物的重量加其光学异构物的重量的比率。按重量计的非对映异构物纯度是一种非对映异构物与所有非对映异构物的重量的比率。当所公开的化合物的立体化学通过结构来命名或描绘时,所命名或描绘的立体异构物相对于其它立体异构物按摩尔分数计至少60%、70%、80%、90%、99%或99.9%纯。当单一对映异构物通过结构来命名或描绘时,所描绘或命名的对映异构物按摩尔分数计至少60%、70%、80%、90%、99%或99.9%纯。当单一非对映异构物通过结构来命名或描绘时,所描绘或命名的非对映异构物按摩尔分数计至少60%、70%、80%、90%、99%或99.9%纯。按摩尔分数计的纯度百分比是对映异构物的摩尔数与对映异构物的摩尔数加其光学异构物的摩尔数的比率。类似地,按摩尔分数计的纯度百分比是非对映异构物的摩尔数与非对映异构物的摩尔数加其异构物的摩尔数的比率。当在不指示立体化学下通过结构来命名或描绘所公开的化合物并且化合物具有至少一个手性中心时,应了解,名称或结构涵盖不含对应光学异构物的化合物的对映异构物、化合物的外消旋混合物或一种对映异构物相对于对应光学异构物富集的混合物。当在不指示立体化学下通过结构来命名或描绘所公开的化合物并且化合物具有两个或更多个手性中心时,应了解,名称或结构涵盖不含其它非对映异构物的非对映异构物、不含其它非对映异构物对的许多非对映异构物、非对映异构物的混合物、非对映异构物对的混合物、一种非对映异构物相对于其它非对映异构物富集的非对映异构物的混合物或者一种或多种非对映异构物相对于其它非对映异构物富集的非对映异构物的混合物。本发明涵盖所有这些形式。
本公开的化合物还包括中间体或最终化合物中存在的原子的所有同位素。“同位素”是指具有相同原子序数但由于原子核中的中子数不同而引起质量数不同的原子。举例来说,氢同位素包括氚和氘。
除非另有说明,本文中描绘的结构还意指包括不同之处仅在于存在一个或多个同位素富集原子的化合物。可并入本发明化合物中的示例性同位素包括氢、磷、氮、氧、磷、硫、氟、氯和碘的同位素,例如2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、32P、33P、35S、18F、36Cl、123I和125I。同位素标记化合物(例如用3H和14C标记的化合物)可用于化合物或底物组织分布测定中。氚化(即3H)和碳14(即14C)同位素因它们容易制备和可检测性而为有用的。此外,用较重同位素如氘(即2H)取代可提供由更大的代谢稳定性产生的某些治疗优点(例如体内半衰期延长或剂量需求降低)。在一些实施方案中,一个或多个氢原子经2H或3H置换,或者一个或多个碳原子经13C或14C富集碳置换。正电子发射同位素如15O、13N、11C和18F可用于正电子发射断层摄影(PET)研究中以检查底物受体占有率。同位素标记化合物的制备是本领域的技术人员已知的。举例来说,同位素标记化合物通常可通过根据与针对本文所述的本发明化合物所公开的程序类似的程序,通过用同位素标记试剂代替非同位素标记试剂来制备。
如本领域中已知,许多化学实体可采用多种不同的固体形式,例如无定形或结晶形式(例如多晶型物、水合物、溶剂化物)。在一些实施方案中,本发明的化合物可呈任何这类形式,包括呈任何固体形式利用。在一些实施方案中,本文中描述或描绘的化合物可呈水合物或溶剂化物形式提供或利用。
除非另外定义,否则本文中使用的所有技术和科学术语均具有与本发明所属领域的一般技术人员通常所了解的含义相同的含义。本文中描述了用于本公开中的方法和材料;还可使用本领域中已知的其它合适的方法和材料。材料、方法和实例只是例示性的,不意图限制。本文中提到的所有公布、专利申请、专利、序列、数据库登录和其它参考文献均以引用的方式整体并入本文中。万一发生矛盾,将以本说明书为准,包括定义在内。
定义
在本申请中,除非另外从上下文清楚可见,否则(i)术语“一”可理解为意指“至少一种”;(ii)术语“或”可理解为意指“和/或”;以及(iii)术语“包括”可理解为涵盖详细列举的组分或步骤,无论单独还是连同一种或多种另外的组分或步骤一起呈现。
如本文所用,术语“约”和“大约”是指比所述值高或低10%内的值。举例来说,术语“约5nM”指示4.5至5.5nM的范围。
如本文所用,术语“施用”是指向受试者或系统施用组合物(例如,如本文所述的化合物或包括如本文所述的化合物的制剂)。可通过任何适当的途径施用于动物受试者(例如人)。举例来说,在一些实施方案中,施用可经支气管(包括通过支气管灌注)、经颊、经肠、皮间(interdermal)、动脉内、皮内、胃内、髓内、肌内、鼻内、腹膜内、鞘内、肿瘤内、静脉内、心室内、经粘膜、经鼻、经口、经直肠、皮下、舌下、表面、经气管(包括通过气管内灌注)、经皮、经阴道和经玻璃体。
如本文所用,术语“成人软组织肉瘤”是指通常在青少年和成人受试者(例如至少10岁、11岁、12岁、13岁、14岁、15岁、16岁、17岁、18岁或19岁的受试者)中在体内软组织中显现的肉瘤。成人软组织肉瘤的非限制性实例包括(但不限于)滑膜肉瘤、纤维肉瘤、恶性纤维组织细胞瘤、皮肤纤维肉瘤、脂肪肉瘤、平滑肌肉瘤、血管内皮瘤、卡波西肉瘤、淋巴管肉瘤、恶性外周神经鞘膜瘤/神经纤维肉瘤、骨外软骨肉瘤、骨外骨肉瘤、骨外粘液样软骨肉瘤和骨外间叶性软骨肉瘤。
如本文所用,术语“BAF复合物”是指人类细胞中的BRG1或HRBM相关因子复合物。
如本文所用,术语“BAF复合物相关病症”是指由BAF复合物的水平和/或活性引起或受其影响的病症。
如本文所用,术语“GBAF复合物”和“GBAF”是指人类细胞中SWI/SNF ATP酶染色质重塑复合物。GBAF复合物亚基可包括(但不限于)ACTB、ACTL6A、ACTL6B、BICRA、BICRAL、BRD9、SMARCA2、SMARCA4、SMARCC1、SMARCD1、SMARCD2、SMARCD3和SS18。术语“癌症”是指由恶性赘生性细胞增殖引起的疾患,例如肿瘤、赘生物、癌瘤、肉瘤、白血病和淋巴瘤。
如本文所用,术语“BRD9”是指含溴结构域蛋白9,BAF(BRG1或BRM相关因子)复合物(一种SWI/SNF ATP酶染色质重塑复合物)的组成部分,属于含溴结构域蛋白的IV家族。BRD9由BRD9基因编码,核酸序列在SEQ ID NO:1中示出。术语“BRD9”还指野生型BRD9蛋白的天然变体,例如与SEQ ID NO:2中所示的野生型BRD9的氨基酸序列具有至少85%序列同一性(例如85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.9%同一性或更多)的蛋白质。
如本文所用,术语“BRD9相关病症”是指由BRD9的水平和/或活性引起或受其影响的病症。术语“癌症”是指由恶性赘生性细胞增殖引起的疾患,例如肿瘤、赘生物、癌瘤、肉瘤、白血病和淋巴瘤。
如本文所用,“组合疗法”或“组合施用”意指两种(或更多种)不同剂或治疗作为定义的用于特定疾病或疾患的治疗方案的一部分施用于受试者。治疗方案定义了每种剂的施用剂量和周期,使得单独剂对受试者的作用重叠。在一些实施方案中,两种或更多种剂的递送是同时的或同时发生的,这些剂可共同配制。在一些实施方案中,两种或更多种剂不共同配制,而是作为指定方案的一部分以连续方式施用。在一些实施方案中,两种或更多种剂或治疗组合施用,使得症状或与病症有关的其它参数减少,程度超过在单独递送的一种剂或治疗下或在缺乏其它剂或治疗下将观察到的症状或参数。两种治疗的作用可部分累加,整体累加,或超过累加(例如协同)。每种治疗剂的连续或基本上同时施用可通过任何适当的途径实现,包括(但不限于)口服途径、静脉内途径、肌内途径和穿过粘膜组织直接吸收。治疗剂可通过相同的途径或通过不同的途径施用。举例来说,组合的治疗剂可通过静脉内注射施用,而组合的第二治疗剂可经口施用。
如本文所用,“本发明的化合物”和类似术语,无论是否明确指示,均是指可用于治疗本文所述的BAF相关病症(例如癌症或感染)的化合物,例如化合物D1、化合物S-D1、化合物R-D1或化合物D2,以及其盐(例如药学上可接受的盐)、溶剂化物、水合物、立体异构物(包括阻转异构物)和互变异构物。本领域的技术人员将了解,本文所述的某些化合物可呈一种或多种不同异构物(例如立体异构物、几何异构物、阻转异构物和互变异构物)或同位素(例如其中一个或多个原子已被该原子的不同同位素取代,例如氘取代氢)形式存在。除非另外指示或从上下文清楚可见,否则所描绘的结构可理解为代表个别或组合的任何这类异构物或同位素形式。本文所述的化合物可为不对称的(例如具有一个或多个立构中心)。除非另外指示,否则意图例如对映异构物和非对映异构物的所有立体异构物。含有被不对称取代的碳原子的本公开的化合物可呈光学活性或外消旋形式分离。本领域中已知由光学活性的起始物质制备光学活性形式的方法,例如通过拆分外消旋混合物或通过立体选择性合成。烯烃、C=N双键等的许多几何异构物也可存在于本文所述的化合物中,本公开中涵盖所有这类稳定异构物。描述了本公开的化合物的顺式与反式几何异构物并且可呈异构物混合物或呈单独异构物形式分离。在一些实施方案中,本文中描绘的一种或多种化合物可呈不同的互变异构形式存在。如从上下文清楚可见,除非明确排除,否则提及这类化合物涵盖所有这类互变异构形式。在一些实施方案中,互变异构形式由单键与相邻双键交换和伴随质子迁移产生。在某些实施方案中,互变异构形式可为质子移变互变异构物,它是具有与参考形式相同的经验式和总电荷的异构物质子化状态。具有质子移变互变异构形式的部分的实例为酮-烯醇对、酰胺-亚氨酸对、内酰胺-内酰亚胺对、烯胺-亚氨酸对、烯胺-亚胺对和环状形式,其中质子可占据杂环系统的两个或更多个位置,例如1H-和3H-咪唑、1H-、2H-和4H-1,2,4-三唑、1H-和2H-异吲哚、以及1H-和2H-吡唑。在一些实施方案中,互变异构形式可处于平衡中或通过适当取代而在空间上锁定成一种形式。在某些实施方案中,互变异构形式由缩醛互变产生。
如本文所用,术语“降解剂”是指包括降解部分的小分子化合物,其中所述化合物与蛋白质(例如BRD9)以引起蛋白质降解的方式相互作用,例如化合物的结合引起例如细胞或受试者中的蛋白质水平减少至少5%。
如本文所用,术语“降解部分”是指结合引起例如BRD9的蛋白质降解的部分。在一个实例中,该部分结合于代谢例如BRD9的蛋白质的蛋白酶或泛素连接酶。
“测定蛋白质水平”意指通过本领域中已知的方法直接或间接检测蛋白质或编码蛋白质的mRNA。“直接测定”意指执行一种获得物理实体或值的方法(例如对样品执行测定或测试或者“分析样品”,如该术语在本文中定义时)。“间接测定”是指接受来自另一方或来源(例如直接获得物理实体或值的第三方实验室)的物理实体或值。测量蛋白质水平的方法一般包括(但不限于)蛋白质印迹法、免疫印迹法、酶联免疫吸附测定(ELISA)、放射免疫测定(RIA)、免疫沉淀、免疫荧光、表面等离子共振、化学发光、荧光偏振、磷光、免疫组织化学分析、基质辅助激光解吸/电离飞行时间(MALDI-TOF)质谱法、液体色谱(LC)-质谱法、微流式细胞术、显微术、荧光激活细胞分选(FACS)和流式细胞术,以及基于包括(但不限于)酶活性或与其它蛋白质搭配物的相互作用的蛋白质特性的测定。本领域中已知测量mRNA水平的方法。
如本文所用,术语本文所述的降低BRD9的水平和/或活性(例如细胞或受试者中)的剂的“有效量”、“治疗有效量”和“足够量”是指当向包括人在内受试者施用时足以实现有益或期望的结果,包括临床结果的量,因而,“有效量”或其同义词取决于其应用的背景。举例来说,在治疗癌症的背景下,它为降低BRD9的水平和/或活性的剂与在不施用降低BRD9的水平和/或活性的剂下获得的反应相比足以实现治疗反应的量。与这类量对应的所给定的本文所述的降低BRD9的水平和/或活性的剂的量将视多种因素而变化,这些因素例如所给定的剂、医药制剂、施用途径、疾病或病症类型、所治疗的受试者或宿主的特性(例如年龄、性别和/或体重)等,然而可通过本领域的技术人员按常规确定。此外,如本文所用,本公开的降低BRD9的水平和/或活性的剂的“治疗有效量”是与对照物相比中受试者中产生有益或期望的结果的量。如本文中所定义,本公开的降低BRD9的水平和/或活性的剂的治疗有效量容易由本领域的一般技术人员通过本领域中已知的常规方法测定。可调整给药方案以提供最佳治疗反应。
如本文所用,术语“抑制剂”是指降低蛋白质(例如BRD9)的水平和/或活性的任何剂。抑制剂的非限制性实例包括小分子抑制剂、降解剂、抗体、酶或多核苷酸(例如siRNA)。
“水平”意指蛋白质或编码蛋白质的mRNA与参考相比的水平。参考可以是如本文中定义的任何有用的参考。“降低水平”或“增加水平”的蛋白质意指蛋白质水平与参考相比降低或增加(例如降低或增加约5%、约10%、约15%、约20%、约25%、约30%、约35%、约40%、约45%、约50%、约55%、约60%、约65%、约70%、约75%、约80%、约85%、约90%、约95%、约100%、约150%、约200%、约300%、约400%、约500%或更多;与参考相比降低或增加超过约10%、约15%、约20%、约50%、约75%、约100%或约200%;降低或增加小于约0.01倍、约0.02倍、约0.1倍、约0.3倍、约0.5倍、约0.8倍或更小;或增加超过约1.2倍、约1.4倍、约1.5倍、约1.8倍、约2.0倍、约3.0倍、约3.5倍、约4.5倍、约5.0倍、约10倍、约15倍、约20倍、约30倍、约40倍、约50倍、约100倍、约1000倍或更多)。蛋白质水平可以呈相对于样品中的总蛋白质或mRNA的质量/体积(例如g/dL、mg/mL、μg/mL、ng/mL)或百分比表述。
“调节BAF复合物的活性”意指改变与BAF复合物(例如GBAF)有关的活性的水平,或相关下游效应。BAF复合物的活性水平可使用本领域中已知的任何方法,例如Kadoch等人,Cell 153:71-85(2013)中所述的方法测量,所述方法以引用的方式并入本文中。
关于参考多核苷酸或多肽序列的“序列同一性百分比(%)”定义为在比对序列和必要时引入空位以实现最大序列同一性百分比后,候选序列中与参考多核苷酸或多肽序列中的核酸或氨基酸一致的核酸或氨基酸的百分比。用于测定核酸或氨基酸序列同一性百分比的比对可用在本领域的技术人员能力范围内的多种方式,例如使用公众可获得的计算机软件,例如BLAST、BLAST-2或Megalign软件来实现。本领域的技术人员可确定用于比对序列的适当参数,包括实现所比较的全长序列上的最大比对所需的任何算法。举例来说,可使用序列比较计算机程序BLAST产生序列同一性百分比值。作为例证,所给定的核酸或氨基酸序列A相对于、与或对比所给定的核酸或氨基酸序列B的序列同一性百分比(其可替代地用短语表达为相对于、与或对比所给定的核酸或氨基酸序列B具有一定序列同一性百分比的A)如下计算:
100乘以(分数X/Y)
其中X为在序列比对程序(例如BLAST)对A和B进行比对中,通过程序评分为相同匹配的核苷酸或氨基酸数目,且其中Y为B中的核酸总数。应了解,在核酸或氨基酸序列A的长度与核酸或氨基酸序列B的长度不等的情况下,A对B的序列同一性百分比不等于B对A的序列同一性百分比。
如本文所用,“药学上可接受的赋形剂”是指除本文所述的化合物以外(例如能够使活性化合物悬浮或溶解的媒介物)并且在患者中具有基本上无毒和非炎性的特性的任何成分。赋形剂可包括例如:抗粘剂、抗氧化剂、粘合剂、包衣、压缩助剂、崩解剂、染料(着色剂)、软化剂、乳化剂、填充剂(稀释剂)、成膜剂或包衣、调味剂、香料、助流剂(流动增强剂)、润滑剂、防腐剂、印刷油墨、吸附剂、悬浮或分散剂、甜味剂和水合水。
如本文所用,术语“药学上可接受的盐”意指本文所述的化合物中的任何化合物的任何药学上可接受的盐。举例来说,本文所述的任何化合物的药学上可接受的盐包括在合理医学判断范围内,适于与人和动物的组织接触使用,没有过度毒性、刺激、过敏反应,并且与合理益处/风险比相称的盐。药学上可接受的盐是本领域中众所周知的。举例来说,药学上可接受的盐描述于以下中:Berge等人,J.Pharmaceutical Sciences 66:1-19,1977和Pharmaceutical Salts:Properties,Selection,and Use,(P.H.Stahl和C.G.Wermuth编辑),Wiley-VCH,2008。盐可在本文所述的化合物的最终分离和纯化期间当场制备,或者通过游离碱基团与合适的有机酸反应而单独制备。本文所述的化合物可具有可离子化基团以便能够制备成药学上可接受的盐。这些盐可以是涉及无机酸或有机酸的酸加成盐,或者在本文所述的化合物的酸性形式的情况下,盐可以由无机碱或有机碱制备。化合物常制备成呈药学上可接受的酸或碱的加成产物制备的药学上可接受的盐或呈药学上可接受的盐使用。合适的药学上可接受的酸和碱以及适当盐的制备方法是本领域中众所周知的。盐可以由包括无机酸和有机酸以及无机碱和有机碱的药学上可接受的无毒酸和碱制备。
如本文所用,术语“药物组合物”表示含有与药学上可接受的赋形剂一起配制的本文所述的化合物并经政府管理机构批准作为用于治疗哺乳动物的疾病的治疗方案的一部分制造或出售的组合物。药物组合物可例如配制用于呈单位剂型(例如片剂、胶囊、囊片、明胶胶囊或糖浆)口服;用于表面施用(例如呈乳膏、凝胶、洗剂或软膏);用于静脉内施用(例如呈不含微粒栓子并在适合于静脉内使用的溶剂系统中的无菌溶液);或呈任何其它药学上可接受的制剂。
“降低BRD9活性”意指降低与BRD9有关的活性的水平或相关下游效应。抑制BRD9活性的一非限制性实例为降低细胞中的BAF复合物(例如GBAF)的水平。BRD9的活性水平可使用本领域中已知的任何方法测量。在一些实施方案中,降低BRD9活性的药剂为小分子BRD9抑制剂。在一些实施方案中,降低BRD9活性的药剂为小分子BRD9降解剂。
“降低BRD9水平”意指降低细胞或个体中的BRD9的水平。BRD9的水平可使用本领域中已知的任何方法测量。
“参考”意指用于比较蛋白质或mRNA水平的任何有用参考。参考可为用于达成比较目的的任何样品、标准、标准曲线或水平。参考可为正常参考样品或参考标准或水平。“参考样品”可为例如对照物,例如预先确定的阴性对照值,例如取自同一受试者的“正常对照物”或先前样品;来自正常健康受试者的样品,例如正常细胞或正常组织;来自未患病的受试者的样品(例如细胞或组织);来自被诊断为患有疾病但未用本文所述的化合物治疗的受试者的样品;来自已用本文所述的化合物治疗的受试者的样品;或在已知标准浓度下的纯化蛋白质(例如本文所述的任一者)的样品。“参考标准或水平”意指源自于参考样品的值或数值。“正常对照值”为指示非疾病病况的预测定值,例如在健康对照受试者中预期的值。通常,正常对照值可表述为范围(“介于X与Y之间”)、高阈值(“不高于X”)或低阈值(“不低于X”)。对特定生物标志物的测量值在正常对照值内的受试者通常称为在该生物标志物的“正常界限内”。正常参考标准或水平可为源自于未患疾病或病症(例如癌症)的正常受试者的值或数值;已用本文所述的化合物治疗的受试者。在优选的实施方案中,通过以下标准中的至少一者,参考样品、标准或水平与样品受试样品匹配:年龄、体重、性别、疾病阶段和总体健康状态。在正常参考范围内的纯化蛋白质,例如本文所述的任一者的水平的标准曲线也可用作参考。
如本文所用,术语“受试者”是指根据可施用本发明的组合物以例如达成实验、诊断、预防性和/或治疗性目的的任何生物体。典型的受试者包括任何动物(例如哺乳动物,例如小鼠、大鼠、兔、非人类灵长类动物和人)。受试者可寻求或需要治疗,需要治疗,正接受治疗,将来接受治疗,或为接受训练有素的专业人员针对特定疾病或疾患进行照护的人或动物。
如本文所用,术语“SS18-SSX融合蛋白相关病症”是指由SS18-SSX融合蛋白的水平和/或活性引起或受其影响的病症。
如本文所用,术语“治疗(treat/treated/treating)”意指治疗性治疗与预防性或预防措施,其中目标是预防或减慢(减轻)不希望有的生理疾患、病症或疾病,或获得有益或期望的临床结果。有益或期望的临床结果包括(但不限于)减轻症状;降低疾患、病症或疾病的程度;疾患、病症或疾病的状态稳定(即未恶化);疾患、病症或疾病进展的发作延迟或减慢;改善疾患、病症或疾病病况或症状缓解(无论部分还是总体),无论可检测还是不可检测;改善至少一种可测量的物理参数,患者不一定能够辨别;或者疾患、病症或疾病改善或好转。治疗包括引起临床显著反应,没有过度水平的副作用。治疗还包括与未接受治疗下的预期生存期相比延长生存期。
如本文所用,术语“变体”和“衍生物”可互换使用,是指本文所述的化合物、肽、蛋白质或其它物质的天然存在的、合成的和半合成的类似物。本文所述的化合物、肽、蛋白质或其它物质的变体或衍生物可保留或改善原始物质的生物活性。
在以下描述中阐明了本发明的一个或多个实施方案的细节。将从描述中和从权利要求书中显而易见本发明的其它特征、对象和优点。
附图说明
图1是示出滑膜肉瘤细胞系(SYO1)中在BRD9降解剂存在下BRD9水平的剂量依赖性耗尽的图像。
图2是示出滑膜肉瘤细胞系(SYO1)中在BRD9降解剂存在下72小时内BRD9水平的持续抑制的图像。
图3是示出两种细胞系(293T和SYO1)中在BRD9降解剂存在下5天内BRD9水平的持续抑制的图像。
图4是示出与用CRISPR试剂治疗的细胞中的水平相比,在滑膜肉瘤细胞系(SYO1和Yamato)中在BRD9降解剂存在下7天内BRD9水平的持续抑制的图像。
图5是示出在BRD9降解剂和BRD9抑制剂存在下对六种细胞系(SYO1、Yamato、A549、HS-SY-II、ASKA和293T)的细胞生长的作用的图像。
图6是示出在BRD9降解剂存在下对两种细胞系(SYO1和G401)的细胞生长的作用的图像。
图7是示出在BRD9降解剂、BRD9结合剂和E3连接酶结合剂存在下对三种滑膜肉瘤细胞系(SYO1、HS-SY-II和ASKA)的细胞生长的作用的图像。
图8是示出在BRD9降解剂、BRD9结合剂和E3连接酶结合剂存在下对三种非滑膜肉瘤细胞系(RD、HCT116和Calu6)的细胞生长的作用的图像。
图9是示出在用DMSO、200nM化合物1或1μM化合物1处理8或13天之后多个细胞周期阶段中SYO1的百分比的图。
图10是示出在用DMSO、200nM化合物1、1μM化合物1或200nM来那度胺(lenalidomide)处理8天之后多个细胞周期阶段中SYO1细胞的百分比的一系列等高线图。与每个等高线图相对应的数值见于以下表中。
图11是示出在用DMSO、200nM化合物1、1μM化合物1或200nM来那度胺处理13天之后多个细胞周期阶段中SYO1细胞的百分比的一系列等高线图。与每个等高线图相对应的数值见于以下表中。
图12是示出在用DMSO、200nM化合物1、1μM化合物1或200nM来那度胺处理8天之后早期和晚期细胞凋亡SYO1细胞的百分比的一系列等高线图。与每个等高线图相对应的数值见于以下表中。
图13是示出包括SS18-SSX融合蛋白在内的BAF复合物中存在的蛋白质的图。
图14是展示在SOY-1异种移植小鼠模型中化合物D1的功效的图。用化合物D1处理引起肿瘤生长的抑制。
图15是展示对照组和处理组(化合物D1)中的BRD9检测的蛋白质印迹法的图像。用化合物D1处理引起BRD9抑制。
图16是展示在用DMSO、对映异构物1或外消旋化合物D1处理1小时或6小时的SYO-1细胞中的BRD9检测的蛋白质印迹法的图像。
图17是展示在用DMSO、对映异构物2或外消旋化合物D1处理1小时或6小时的SYO-1细胞中的BRD9检测的蛋白质印迹法的图像。
图18是展示与来自图16和17中所示的蛋白质印迹法图像的BRD9亮带强度数据点拟合的剂量反应曲线的图。
图19是展示在用对映异构物1、对映异构物2或外消旋化合物D1处理24小时的SYO-1细胞中的BRD9检测的蛋白质印迹法的图像。
图20是展示在ASKA细胞对照物和用对映异构物1或外消旋化合物D1处理0.5小时或2小时的ASKA细胞中的BRD9检测的蛋白质印迹法的图像。
图21是展示在ASKA细胞对照物和用对映异构物2或外消旋化合物D1处理0.5小时或2小时的ASKA细胞中的BRD9检测的蛋白质印迹法的图像。
图22是展示与来自图20和21中所示的蛋白质印迹法图像的BRD9亮带强度数据点拟合的剂量反应曲线的图。
图23是展示在用对映异构物1、对映异构物2或外消旋化合物D1处理的SYO-1Zenograft模型中的BRD9检测的一系列蛋白质印迹法的图像。
图24是定量在图23中所示的蛋白质印迹法中观察到的BRD9水平变化的条形图。
具体实施方式
本公开特征在于可用于治疗BAF相关病症(例如癌症和感染)的组合物和方法。本公开特征还在于可用于在有需要的受试者中抑制BRD9的水平和/或活性,例如用于治疗例如癌症(例如肉瘤)和感染(例如病毒感染)的病症的组合物和方法。
化合物
本文所述的化合物降低细胞或受试者中与BRD9有关的活性的水平或相关下游效应,或降低细胞或受试者中的BRD9水平。本文所述的示例性化合物具有表1中的化合物D1、S-D1、R-D1和D2的结构,或其药学上可接受的盐。
药物用途
本文所述的化合物可用于本发明的方法中,虽然不受理论束缚,但相信通过其调节BAF复合物的水平、状态和/或活性的能力,例如通过抑制哺乳动物中的细胞中BAF复合物内的BRD9蛋白的活性或水平,发挥它们理想的作用。
本发明的一方面涉及治疗有需要的受试者的与BRD9有关的病症,例如癌症的方法。在一些实施方案中,化合物以有效产生以下中的一者(或更多者,例如两者或更多者、三者或更多者、四者或更多者)的量和时间来施用:(a)减小肿瘤尺寸;(b)降低肿瘤生长速率;(c)增加肿瘤细胞死亡;(d)减慢肿瘤进展;(e)减少转移数目;(f)降低转移速率;(g)减少肿瘤复发;(h)增加受试者生存率;和(i)增加受试者的无进展生存期。
治疗癌症可引起肿瘤尺寸或体积减小。举例来说,在治疗后,肿瘤尺寸相对于其在治疗之前的尺寸减小5%或更大(例如10%、20%、30%、40%、50%、60%、70%、80%、90%或更大)。肿瘤尺寸可通过任何可再现的测量方式测量。举例来说,肿瘤尺寸可测量为肿瘤直径。
治疗癌症还可引起肿瘤数目减少。举例来说,在治疗后,肿瘤数目相对于在治疗之前的数目减少5%或更大(例如10%、20%、30%、40%、50%、60%、70%、80%、90%或更大)。肿瘤数目可通过任何可再现的测量方式测量,例如肿瘤数目可通过计数肉眼可见的或在指定放大率(例如2x、3x、4x、5x、10x或50x)下可见的肿瘤来测量。
治疗癌症可引起远离原发肿瘤部位的其它组织或器官中转移性结节的数目减少。举例来说,在治疗后,转移性结节的数目相对于在治疗之前的数目减少5%或更大(例如10%、20%、30%、40%、50%、60%、70%、80%、90%或更大)。转移性结节的数目可通过任何可再现的测量方式测量。举例来说,转移性结节的数目可通过计数肉眼可见的或在指定放大率(例如2x、10x或50x)下可见的转移性结节来测量。
治疗癌症可引起根据本发明治疗的受试者群体与未治疗的受试者群体相比平均生存时间增加。举例来说,平均生存时间增加超过30天(超过60天、90天或120天)。群体的平均生存时间增加可通过任何可再现的方法测量。群体的平均生存时间增加可例如通过计算群体在开始用本文所述的化合物治疗之后的平均生存时长来测量。群体的平均生存时间增加还可例如通过计算群体在结束第一轮用本文所述的化合物的药学上可接受的盐治疗之后的平均生存时长来测量。
治疗癌症还可引起所治疗受试者的群体与未治疗的群体相比死亡率下降。举例来说,死亡率下降超过2%(例如超过5%、10%或25%)。所治疗受试者的群体的死亡率下降可通过任何可再现的方法来测量,例如通过计算群体在开始用本文所述的化合物的药学上可接受的盐治疗之后每单位时间的疾病相关死亡的平均数目来测量。群体的死亡率下降还可通过计算群体在结束第一轮用本文所述的化合物的药学上可接受的盐治疗之后每单位时间的疾病相关死亡的平均数目来测量。
组合疗法
本发明的方法可单独,或与另外的治疗剂如治疗癌症或与癌症相关的症状的其它剂组合,或与其它类型的治疗癌症的疗法组合使用。在组合治疗中,治疗性化合物中的一者或多者的剂量可从单独施用时的标准剂量减少。举例来说,剂量可凭经验从药物组合和排列中确定,或可通过等辐射分析推导(例如Black等人,Neurology 65:S3-S6(2005))。在这种情况下,化合物在组合时的剂量将提供治疗作用。
在一些实施方案中,第二治疗剂为化学治疗剂(例如细胞毒性剂或可用于治疗癌症的其它化合物)。这些治疗剂包括烷基化剂、抗代谢物、叶酸类似物、嘧啶类似物、嘌呤类似物和有关抑制剂、长春花生物碱、表鬼臼毒素、抗生素、L-天冬酰胺酶、拓扑异构酶抑制剂、干扰素、铂配位复合物、蒽二酮取代的脲、甲基肼衍生物、肾上腺皮质抑制剂、肾上腺皮质类固醇、孕激素、雌激素、抗雌激素、雄激素、抗雄激素和促性腺激素释放激素类似物。还包括5-氟尿嘧啶(5-fluorouracil,5-FU)、甲酰四氢叶酸(leucovorin,LV)、依立替康(irenotecan)、奥沙利铂(oxaliplatin)、卡培他滨(capecitabine)、太平洋紫杉醇和多烯紫杉醇。化学治疗剂的非限制性实例包括烷基化剂,例如噻替派(thiotepa)和环磷酰胺;烷基磺酸酯,例如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶,例如苯佐替派(benzodopa)、卡巴醌(carboquone)、美妥替派(meturedopa)和乌瑞替派(uredopa);乙烯亚胺和甲基蜜胺,包括六甲蜜胺(altretamine)、曲他胺(triethylenemelamine)、三亚乙基磷酰胺(trietylenephosphoramide)、三亚乙基硫代磷酰胺(triethiylenethiophosphoramide)和三羟甲基蜜胺(trimethylolomelamine);多聚乙酰(acetogenin)(尤其布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱(包括合成类似物拓扑替康(topotecan));苔藓虫素(bryostatin);卡利斯他汀(callystatin);CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);念珠藻素(cryptophycin)(尤其念珠藻素1和念珠藻素8);多拉司他汀(dolastatin);多米卡新(duocarmycin)(包括合成类似物KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑素(spongistatin);氮芥类(nitrogen mustards),例如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、胆磷酰胺(cholophosphamide)、雌氮芥(estramustine)、异环磷酰胺(ifosfamide)、氮芥(mechlorethamine)、氮芥氧化物盐酸盐、美法仑(melphalan)、新恩比兴(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亚硝基脲,例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimnustine);抗生素,例如烯二炔抗生素(例如卡奇霉素(calicheamicin),尤其卡奇霉素γll和卡奇霉素ωll(参见例如Agnew,Chem.Intl.EdEngl.33:183-186(1994));达内霉素(dynemicin),包括达内霉素A;双膦酸盐(bisphosphonate),例如氯膦酸盐(clodronate);埃斯培拉霉素(esperamicin);以及新制癌菌素发色团和相关色蛋白烯二炔抗生素发色团)、阿克拉霉素(aclacinomysin)、放线菌素(actinomycin)、安曲霉素(authramycin)、氮杂丝氨酸(azaserine)、博来霉素(bleomycin)、放线菌素C(cactinomycin)、卡拉比星(carabicin)、洋红霉素(caminomycin)、嗜癌菌素(carzinophilin)、色霉素(chromomycinis)、放线菌素D(dactinomycin)、道诺霉素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-氧代基-L-正白氨酸、(多柔比星(doxorubicin),包括吗啉基-多柔比星、氰基吗啉基-多柔比星、2-吡咯啉基-多柔比星和脱氧多柔比星)、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(mitomycin)(例如丝裂霉素C(mitomycin C))、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、泊非霉素(potfiromycin)、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链脲霉素(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物,例如甲氨蝶呤(methotrexate)和5-氟尿嘧啶(5-FU);叶酸类似物,例如二甲叶酸(denopterin)、甲氨蝶呤、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,例如氟达拉滨(fludarabine)、6-巯基嘌呤(6-mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物,例如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、脱氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素,例如卡鲁睪酮(calusterone)、屈他雄酮丙酸盐(dromostanolone propionate)、表硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睪内酯(testolactone);抗肾上腺药,例如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,例如亚叶酸(frolinic acid);醋葡内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);倍曲布西(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);依洛尼塞(elfomithine);依利醋铵乙酸盐(elliptinium acetate);埃坡霉素(epothilone);依托格鲁(etoglucid);硝酸镓;羟基脲(hydroxyurea);蘑菇多糖(lentinan);洛尼达宁(lonidainine);美登素类(maytansinoids),例如美登素(maytansine)和安丝菌素(ansamitocin);丙脒腙(mitoguazone);米托蒽醌(mitoxantrone);莫皮达莫(mopidanmol);二胺硝吖啶(nitraerine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基酰肼;丙卡巴肼(procarbazine);多糖复合物(JHS Natural Products,Eugene,OR);雷佐生(razoxane);根霉素(rhizoxin);西佐喃(sizofuran);螺旋锗(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2',2”-三氯三乙胺;单端孢霉毒素(trichothecenes)(尤其T-2毒素、瓦鲁克林(verracurin A)、杆孢菌素A(roridin A)和蛇形菌素(anguidine));乌拉坦(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);加胞嘧啶(gacytosine);阿糖胞苷(arabinoside,“Ara-C”);环磷酰胺;噻替派;紫杉烷类(taxoids),例如(太平洋紫杉醇;Bristol-Myers SquibbOncology,Princeton,NJ)、无cremophor的白蛋白工程化太平洋紫杉醇纳米颗粒制剂(American Pharmaceutical Partners,Schaumberg,IL)和多烯紫杉醇(Rhone-Poulenc Rorer,Antony,France);瘤可宁(chloranbucil);吉西他滨;6-硫代鸟嘌呤(6-thioguanine);巯基嘌呤(mercaptopurine);甲氨蝶呤;铂配位复合物,例如顺铂、奥沙利铂和卡铂;长春花碱;铂;依托泊苷(etoposide,VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨(vinorelbine);诺消灵(novantrone);替尼泊苷(teniposide);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基蝶呤(aminopterin);希罗达(xeloda);伊班膦酸盐(ibandronate);伊立替康(irinotecan)(例如CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视色素,例如视黄酸;卡培他滨(capecitabine);和以上任一者的药学上可接受的盐、酸或衍生物。两种或更多种化学治疗剂可呈混合物形式使用以与本文所述的第一治疗剂组合施用。本领域中已知组合化学疗法的合适给药方案并描述于例如Saltz等人,Proc.Am.Soc.Clin.Oncol.18:233a(1999),和Douillard等人,Lancet 355(9209):1041-1047(2000)。
在一些实施方案中,第二治疗剂为DNA损伤剂(例如铂基抗瘤剂、拓扑异构酶抑制剂、PARP抑制剂、烷基化抗瘤剂和电离辐射)。
可用作本发明的组合物和方法中的第二治疗剂的铂基抗瘤剂的实例为顺铂、卡铂、奥沙利铂、双环铂(dicycloplatin)、依他铂(eptaplatin)、洛铂(lobaplatin)、米铂(miriplatin)、奈达铂(nedaplatin)、四硝酸三铂(triplatin tetranitrate)、苯奈铂(phenanthrilplatin)、吡铂(picoplatin)和沙曲铂(satraplatin)。在一些实施方案中,第二治疗剂为顺铂且所治疗癌症为睪丸癌、卵巢癌或膀胱癌(例如晚期膀胱癌)。在一些实施方案中,第二治疗剂为卡铂且所治疗癌症为卵巢癌、肺癌、头颈癌、脑癌或神经母细胞瘤。在一些实施方案中,第二治疗剂为奥沙利铂且所治疗癌症为结肠直肠癌。在一些实施方案中,第二治疗剂为双环铂且所治疗癌症为非小细胞肺癌或前列腺癌。在一些实施方案中,第二治疗剂为依他铂且所治疗癌症为胃癌。在一些实施方案中,第二治疗剂为洛铂且所治疗癌症为乳腺癌。在一些实施方案中,第二治疗剂为米铂且所治疗癌症为肝细胞癌。在一些实施方案中,第二治疗剂为奈达铂且所治疗癌症为鼻咽癌、食道癌、鳞状细胞癌或宫颈癌。在一些实施方案中,第二治疗剂为四硝酸三铂且所治疗癌症为肺癌(例如小细胞肺癌)或胰腺癌。在一些实施方案中,第二治疗剂为吡铂且所治疗癌症为肺癌(例如小细胞肺癌)、前列腺癌、膀胱癌或结肠直肠癌。在一些实施方案中,第二治疗剂为沙曲铂且所治疗癌症为前列腺癌、乳腺癌或肺癌。
可用作本发明的组合物和方法中的第二治疗剂的拓扑异构酶抑制剂的实例为依托泊苷、替尼泊苷、多柔比星、道诺霉素、米托蒽醌、安吖啶、玫瑰树碱、伊立替康、拓扑替康、喜树碱和二氟替康(diflomotecan)。在一些实施方案中,第二治疗剂为依托泊苷且所治疗癌症为肺癌(例如小细胞肺癌)或睪丸癌。在一些实施方案中,第二治疗剂为替尼泊苷且所治疗癌症为急性淋巴母细胞性白血病(例如儿童急性淋巴母细胞性白血病)。在一些实施方案中,第二治疗剂为多柔比星且所治疗癌症为急性淋巴母细胞性白血病、急性髓母细胞性白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、乳腺癌、威尔姆斯氏瘤、神经母细胞瘤、软组织肉瘤、骨肉瘤、卵巢癌瘤、膀胱移行细胞癌、甲状腺癌、胃癌或支气管癌。在一些实施方案中,第二治疗剂为道诺霉素且所治疗癌症为急性淋巴母细胞性白血病或急性髓系白血病。在一些实施方案中,第二治疗剂为米托蒽醌且所治疗癌症为前列腺癌或急性非淋巴细胞性白血病。在一些实施方案中,第二治疗剂为安吖啶且所治疗癌症为白血病(例如急性成人白血病)。在一些实施方案中,第二治疗剂为伊立替康且所治疗癌症为结肠直肠癌。在一些实施方案中,第二治疗剂为拓扑替康且所治疗癌症为肺癌(例如小细胞肺癌)。在一些实施方案中,第二治疗剂为二氟替康且所治疗癌症为肺癌(例如小细胞肺癌)。
可用作本发明的组合物和方法中的第二治疗剂的烷基化抗瘤剂的实例为环磷酰胺、尿嘧啶氮芥、美法仑、苯丁酸氮芥、异环磷酰胺、苯达莫司汀、卡莫司汀、洛莫司汀、氯脲菌素、福莫司汀、尼莫司汀、雷莫司汀、白消安、英丙舒凡、哌泊舒凡、萘氮芥、胆磷酰胺、雌氮芥、氮芥、氧化氮芥盐酸盐、新恩比兴、苯芥胆甾醇、泼尼莫司汀、曲磷胺、丙卡巴肼、六甲蜜胺、达卡巴嗪、米托唑胺(mitozolomide)和替莫唑胺(temozolomide)。在一些实施方案中,第二治疗剂为环磷酰胺且所治疗癌症为非霍奇金淋巴瘤。在一些实施方案中,第二治疗剂为美法仑且所治疗癌症为多发性骨髓瘤、卵巢癌或黑色素瘤。在一些实施方案中,第二治疗剂为苯丁酸氮芥且所治疗癌症为慢性淋巴细胞性白血病、恶性淋巴瘤(例如淋巴肉瘤、巨滤泡性淋巴瘤或霍奇金淋巴瘤)。在一些实施方案中,第二治疗剂为异环磷酰胺且所治疗癌症为睪丸癌。在一些实施方案中,第二治疗剂为苯达莫司汀且所治疗癌症为慢性淋巴细胞性白血病或非霍奇金淋巴瘤。在一些实施方案中,第二治疗剂为卡莫司汀且所治疗癌症为脑癌(例如胶质母细胞瘤、脑干神经胶质瘤、髓母细胞瘤、星形细胞瘤、室管膜瘤或转移性脑肿瘤)、多发性骨髓瘤、霍奇金病或非霍奇金淋巴瘤。在一些实施方案中,第二治疗剂为洛莫司汀且所治疗癌症为脑癌或霍奇金淋巴瘤。在一些实施方案中,第二治疗剂为福莫司汀且所治疗癌症为黑色素瘤。在一些实施方案中,第二治疗剂为尼莫司汀且所治疗癌症为脑癌。在一些实施方案中,第二治疗剂为雷莫司汀且所治疗癌症为慢性骨髓性白血病或真性红血球增多症。在一些实施方案中,第二治疗剂为白消安且所治疗癌症为慢性骨髓性白血病。在一些实施方案中,第二治疗剂为英丙舒凡且所治疗癌症为肉瘤。在一些实施方案中,第二治疗剂为雌氮芥且所治疗癌症为前列腺癌(例如前列腺癌)。在一些实施方案中,第二治疗剂为氮芥且所治疗癌症为皮肤T细胞淋巴瘤。在一些实施方案中,第二治疗剂为曲磷胺且所治疗癌症为肉瘤(例如软组织肉瘤)。在一些实施方案中,第二治疗剂为丙卡巴肼且所治疗癌症为霍奇金病。在一些实施方案中,第二治疗剂为六甲蜜胺且所治疗癌症为卵巢癌。在一些实施方案中,第二治疗剂为达卡巴嗪且所治疗癌症为黑色素瘤、霍奇金淋巴瘤或肉瘤。在一些实施方案中,第二治疗剂为替莫唑胺且所治疗癌症为脑癌(例如星形细胞瘤或胶质母细胞瘤)或肺癌(例如小细胞肺癌)。
可用作本发明的组合物和方法中的第二治疗剂的PARP抑制剂的实例为尼拉帕尼、奥拉帕尼、卢卡帕尼、他拉唑帕尼、维利帕尼、帕米帕利、CK-102或E7016。有利地,本发明的化合物和DNA损伤剂可协同用以治疗癌症。在一些实施方案中,第二治疗剂为尼拉帕尼且所治疗癌症为卵巢癌(例如BRCA突变卵巢癌)、输卵管癌(例如BRCA突变输卵管癌)或原发性腹膜癌(例如BRCA突变原发性腹膜癌)。在一些实施方案中,第二治疗剂为奥拉帕尼且所治疗癌症为肺癌(例如小细胞肺癌)、卵巢癌(例如BRCA突变卵巢癌)、乳腺癌(例如BRCA突变乳腺癌)、输卵管癌(例如BRCA突变输卵管癌)、原发性腹膜癌(例如BRCA突变原发性腹膜癌)、前列腺癌(例如去势抵抗性前列腺癌)或胰腺癌(例如胰腺癌)。在一些实施方案中,第二治疗剂为卢卡帕尼且所治疗癌症为卵巢癌(例如BRCA突变卵巢癌)、输卵管癌(例如BRCA突变输卵管癌)或原发性腹膜癌(例如BRCA突变原发性腹膜癌)。在一些实施方案中,第二治疗剂为他拉唑帕尼且所治疗癌症为乳腺癌(例如BRCA突变乳腺癌)。在一些实施方案中,第二治疗剂为维利帕尼且所治疗癌症为肺癌(例如非小细胞肺癌)、黑色素瘤、乳腺癌、卵巢癌、前列腺癌或脑癌。在一些实施方案中,第二治疗剂为帕米帕利且所治疗癌症为卵巢癌。在一些实施方案中,第二治疗剂为CK-102且所治疗癌症为肺癌(例如非小细胞肺癌)。在一些实施方案中,第二治疗剂为E7016且所治疗癌症为黑色素瘤。
不希望受理论束缚,本发明的化合物与DNA损伤剂之间的协同作用可归因于BRD9是DNA修复所必需的;BRD9的抑制可使癌症(例如癌细胞或癌组织)对DNA损伤剂敏感。
在一些实施方案中,第二治疗剂为JAK抑制剂(例如JAK1抑制剂)。可用作本发明的组合物和方法中的第二治疗剂的JAK抑制剂的非限制性实例包括托法替尼(tofacitinib)、鲁索替尼(ruxolitinib)、奥拉替尼(oclacitinib)、巴瑞替尼(baricitinib)、培非替尼(peficitinib)、非德替尼(fedratinib)、乌帕替尼(upadacitinib)、菲格替尼(filgotinib)、赛度替尼(cerdulatinib)、甘多替尼(gandotinib)、来他替尼(lestaurtinib)、莫洛替尼(momelotinib)、帕克替尼(pacritinib)、阿布罗替尼(abrocitinib)、索西替尼(solcitinib)、伊他替尼(itacitinib)或SHR0302。不希望受理论束缚,本发明的化合物与JAK抑制剂之间的协同作用可因其下调Foxp3+Treg细胞的组合效应而为SAGA复合物的抑制剂。在一些实施方案中,第二治疗剂为鲁索替尼且所治疗癌症为骨髓增生性赘生物(例如红细胞增多症或骨髓纤维化)、卵巢癌、乳腺癌、胰腺癌。在一些实施方案中,第二治疗剂为非德替尼且所治疗癌症为骨髓增生性赘生物(例如骨髓纤维化)。在一些实施方案中,第二治疗剂为赛度替尼且所治疗癌症为淋巴瘤(例如外周T细胞淋巴瘤)。在一些实施方案中,第二治疗剂为甘多替尼且所治疗癌症为骨髓增生性赘生物(例如红细胞增多症或骨髓纤维化)。在一些实施方案中,第二治疗剂为来他替尼且所治疗癌症为骨髓增生性赘生物(例如红细胞增多症或骨髓纤维化)、白血病(例如急性髓系白血病)、胰腺癌、前列腺癌或神经母细胞瘤。在一些实施方案中,第二治疗剂为莫洛替尼且所治疗癌症为骨髓增生性赘生物(例如红细胞增多症或骨髓纤维化)或胰腺癌(例如胰腺导管腺癌)。在一些实施方案中,第二治疗剂为莫洛替尼且所治疗癌症为骨髓增生性赘生物(例如红细胞增多症或骨髓纤维化)。在一些实施方案中,第二治疗剂为莫洛替尼且所治疗癌症为骨髓增生性赘生物(例如红细胞增多症或骨髓纤维化)或胰腺癌(例如胰腺导管腺癌)。
在一些实施方案中,第二治疗剂为SAGA复合物或其组分的抑制剂。SAGA复合物抑制剂可为例如CCDC101、Tada2B、Tada3、Usp22、Tada1、Taf6l、Supt5、Supt20或它们的组合的抑制抗体或小分子抑制剂。不希望受理论束缚,本发明的化合物与SAGA复合物的抑制剂之间的协同作用可归因于其下调Foxp3+Treg细胞的组合效应。在一些实施方案中,第二治疗剂为作为用于癌症治疗的生物制剂,例如细胞因子(例如干扰素或白细胞介素(例如IL-2))的治疗剂。在一些实施方案中,生物制剂为抗血管生成剂,例如抗VEGF剂,例如贝伐单抗(bevacizumab,)。在一些实施方案中,生物制剂为对靶有促效作用以刺激抗癌反应或拮抗对癌症有重要意义的抗原的基于免疫球蛋白的生物制剂,例如单克隆抗体(例如人源化抗体、完全人抗体、Fc融合蛋白或其功能片段)。这类药剂包括(利妥昔单抗(rituximab));(达利珠单抗(daclizumab));(巴利昔单抗(basiliximab));(帕利珠单抗(palivizumab));(英夫利昔单抗(infliximab));(曲妥珠单抗(trastuzumab));(吉奥单抗(gemtuzumab ozogamicin));(阿仑单抗(alemtuzumab));(替伊莫单抗(ibritumomabtiuxetan));(阿达木单抗(adalimumab));(奥马珠单抗(omalizumab));(托西莫单抗-I-131(tositumomab-I-131));(依法珠单抗(efalizumab));(西妥昔单抗(cetuximab));(贝伐单抗);(那他珠单抗(natalizumab));(托珠单抗(tocilizumab));(帕尼单抗(panitumumab));(兰尼单抗(ranibizumab));(依库珠单抗(eculizumab));(聚乙二醇结合的赛妥珠单抗(certolizumab pegol));(戈利木单抗(golimumab));(卡那津单抗(canakinumab));(优特克单抗(ustekinumab));(奥法木单抗(ofatumumab));(地诺单抗(denosumab));(莫维珠单抗(motavizumab));(瑞西巴库单抗(raxibacumab));(贝利单抗(belimumab));(伊匹单抗(ipilimumab));(维布妥昔单抗(brentuximab vedotin));(帕妥珠单抗(pertuzumab));(美坦辛曲妥珠单抗(ado-trastuzumabemtansine));和(阿托珠单抗(obinutuzumab))。还包括抗体药物缀合物。
第二药剂可为作为非药物治疗的治疗剂。举例来说,第二治疗剂为放射疗法、冷冻疗法、温热疗法和/或肿瘤组织的手术切除。
第二药剂可为检查点抑制剂。在一个实施方案中,检查点抑制剂为抑制抗体(例如单特异性抗体,例如单克隆抗体)。抗体可为例如人源化或完全人抗体。在一些实施方案中,检查点抑制剂为融合蛋白,例如Fc受体融合蛋白。在一些实施方案中,检查点抑制剂为与检查点蛋白相互作用的剂,例如抗体。在一些实施方案中,检查点抑制剂为与检查点蛋白的配体相互作用的剂,例如抗体。在一些实施方案中,检查点抑制剂为CTLA-4抑制剂(例如抑制抗体或小分子抑制剂)(例如抗CTLA4抗体或融合蛋白,例如伊匹单抗/或曲美目单抗)。在一些实施方案中,检查点抑制剂为PD-1抑制剂(例如抑制抗体或小分子抑制剂)(例如纳武单抗/派姆单抗/匹利珠单抗/CT-011)。在一些实施方案中,检查点抑制剂为PDL1抑制剂(例如抑制抗体或小分子抑制剂)(例如MPDL3280A/RG7446;MEDI4736;MSB0010718C;BMS 936559)。
在一些实施方案中,检查点抑制剂为PDL2抑制剂(例如抑制抗体或Fc融合物或小分子抑制剂)(例如PDL2/Ig融合蛋白,例如AMP 224)。在一些实施方案中,检查点抑制剂为B7-H3(例如MGA271)、B7-H4、BTLA、HVEM、TIM3、GAL9、LAG3、VISTA、KIR、2B4、CD160、CGEN-15049、CHK 1、CHK2、A2aR、B-7家族配体或它们的组合的抑制剂(例如抑制抗体或小分子抑制剂)。在一些实施方案中,第二治疗剂为伊匹单抗且所治疗癌症为黑色素瘤、肾癌、肺癌(例如非小细胞肺癌或小细胞肺癌)或前列腺癌。在一些实施方案中,第二治疗剂为曲美目单抗且所治疗癌症为黑色素瘤、间皮瘤或肺癌(例如非小细胞肺癌)。在一些实施方案中,第二治疗剂为纳武单抗且所治疗癌症为黑色素瘤、肺癌(例如非小细胞肺癌或小细胞肺癌)、肾癌、霍奇金淋巴瘤、头颈癌(例如头颈部鳞状细胞癌)、尿路上皮癌、肝细胞癌或结肠直肠癌。在一些实施方案中,第二治疗剂为派姆单抗且所治疗癌症为黑色素瘤、肺癌(例如非小细胞肺癌或小细胞肺癌)、霍奇金淋巴瘤、头颈癌(例如头颈部鳞状细胞癌)、原发性纵隔大B细胞淋巴瘤、尿路上皮癌、肝细胞癌、微卫星高度不稳定癌、胃癌、食道癌、宫颈癌、默克尔细胞癌、肾癌或子宫内膜癌。在一些实施方案中,第二治疗剂为MPDL3280A且所治疗癌症为肺癌(例如非小细胞肺癌或小细胞肺癌)、尿路上皮癌、肝细胞癌或乳腺癌。在一些实施方案中,第二治疗剂为MEDI4736且所治疗癌症为肺癌(例如非小细胞肺癌或小细胞肺癌)或尿路上皮癌。在一些实施方案中,第二治疗剂为MSB0010718C且所治疗癌症为尿路上皮癌。在一些实施方案中,第二治疗剂为MSB0010718C且所治疗癌症为黑色素瘤、肺癌(例如非小细胞肺癌)、结肠直肠癌、肾脏癌、卵巢癌、胰腺癌、胃癌和乳腺癌。
有利地,本发明的化合物和检查点抑制剂可协同用以治疗癌症。不希望受理论束缚,本发明的化合物与检查点抑制剂之间的协同作用可归因于与BRD9抑制诱导的Foxp3+Treg细胞下调相关的检查点抑制剂功效增强。
在一些实施方案中,抗癌疗法为T细胞过继转移(ACT)疗法。在一些实施方案中,T细胞为活化T细胞。T细胞可被修饰成表达嵌合抗原受体(CAR)。CAR修饰的T(CAR-T)细胞可通过本领域中已知的任何方法产生。举例来说,CAR-T细胞可通过将编码CAR的合适表达载体引入到T细胞中来产生。在T细胞扩增和基因修饰之前,从受试者获得T细胞来源。可从许多来源获得T细胞,包括外周血单个核细胞、骨髓、淋巴结组织、脐带血、胸腺组织、来自感染部位的组织、腹水、胸腔积液、脾组织和肿瘤。在本发明的某些实施方案中,可使用本领域中可利用的许多T细胞系。在一些实施方案中,T细胞为自体同源T细胞。无论在T细胞进行基因修饰以表达理想蛋白质(例如CAR)之前还是之后,一般可使用如例如以下中所述的方法活化和扩增T细胞:美国专利6,352,694;6,534,055;6,905,680;6,692,964;5,858,358;6,887,466;6,905,681;7,144,575;7,067,318;7,172,869;7,232,566;7,175,843;5,883,223;6,905,874;6,797,514;6,867,041;和美国专利申请公布号20060121005。
在本文所述的组合实施方案中的任一者中,第一治疗剂和第二治疗剂同时或以任一次序相继施用。第一治疗剂可在第二治疗剂之前或之后长达1小时、长达2小时、长达3小时、长达4小时、长达5小时、长达6小时、长达7小时、长达8小时、长达9小时、长达10小时、长达11小时、长达12小时、长达13小时、14小时、长达16小时、长达17小时、长达18小时、长达19小时、长达20小时、长达21小时、长达22小时、长达23小时、长达24小时或长达1-7天、1-14天、1-21天或1-30天立即施用。
药物组合物
本文所述的药物组合物优选地被配制成呈适合于体内施用的生物学上相容形式的药物组合物,用于施用于人类受试者。
本文所述的化合物可以呈游离碱形式、呈盐、溶剂化物形式和呈前药形式使用。所有形式均在本文所述的方法内。根据本发明的方法,如本领域的技术人员所了解,所述化合物或其盐、溶剂化物或前药可呈多种形式施用于患者,取决于所选的施用途径。本文所述的化合物可例如通过经口、肠胃外、经颊、舌下、经鼻、经直肠、贴片、泵、肿瘤内或经皮施用来施用,并相应地配制药物组合物。肠胃外施用包括静脉内、腹膜内、皮下、肌内、经上皮、经鼻、肺内、鞘内、经直肠和表面施用模式。肠胃外施用可通过在所选时间段内连续输注来进行。
本文所述的化合物可例如利用惰性稀释剂或利用可吸收的可食用运载体经口施用,或者它可装入硬壳或软壳明胶胶囊中,或者它可压缩成片剂,或者它可直接与食品合并。对于经口治疗性施用来说,本文所述的化合物可与赋形剂合并,且呈可摄取的片剂、颊含片、糖锭、胶囊、酏剂、悬浮液、糖浆和糯米纸形式使用。本文所述的化合物还可肠胃外施用。本文所述的化合物的溶液可在适合与表面活性剂(例如羟丙基纤维素)混合的水中制备。分散液还可在丙三醇、液体聚乙二醇、DMSO和它们的混合物中在有或者没有醇下以及油中制备。在正常的存储和使用条件下,这些制剂可含有防止微生物生长的防腐剂。用于选择和制备合适制剂的常规程序和成分描述于例如Remington's Pharmaceutical Sciences(2012,第22版)和The United States Pharmacopeia:The National Formulary(USP41NF36),2018年出版。适合于可注射使用的医药形式包括无菌水溶液或分散液和临用时制备无菌可注射溶液或分散液的无菌粉末。在所有情况下,形式必须无菌且必须为流体,达到容易经由注射器施用的程度。用于经鼻施用的组合物宜配制成气溶胶、滴剂、凝胶和粉末。气溶胶制剂通常包括活性物质于生理学上可接受的水性或非水溶剂中的溶液或微悬浮液,且通常呈无菌形式以单剂或多剂的量呈现于密封容器中,该密封容器可采用药筒或再装品的形式供雾化装置使用。可替代地,密封容器可为一体式分配装置,例如单剂量鼻用吸入器或装有意图使用后抛弃的计量阀的气溶胶分配器。在剂型包括气溶胶分配器的情况下,它将含有推进剂,推进剂可为压缩气体,例如压缩空气或有机推进剂,例如氟氯烃。气溶胶剂型还可采用泵式喷雾器的形式。适合于经颊或舌下施用的组合物包括片剂、含片和软片,其中活性成分与例如糖、阿拉伯胶、黄芪胶、明胶和甘油的运载体一起配制。用于直肠施用的组合物宜呈含有常规栓剂碱、例如可可脂的栓剂形式。本文所述的化合物可经肿瘤内,例如呈肿瘤内注射物施用。肿瘤内注射直接注射至肿瘤血管中,且具体考虑用于离散、实体、易接近的肿瘤。局部、区域或全身性施用也是适当的。本文所述的化合物宜通过施用注射物或多个注射物至肿瘤,例如相隔大约1cm时间间隔来接触。在外科手术情况下,本发明可在手术前使用,以便使不宜手术的肿瘤进行切除术。适当时,还可例如通过将导管植入肿瘤中或肿瘤血管中来连续施用。
如本文中所示,本文所述的化合物可单独或与药学上可接受的运载体组合施用于动物,例如人,其中比例由化合物的溶解性和化学性质、所选择的施用途径和标准医药实践决定。
剂量
本文所述的化合物和/或包括本文所述的化合物的组合物的剂量可视多种因素而变化,这些因素例如化合物的药效性;施用模式;接受者的年龄健康状态和体重;症状的性质和程度;治疗频率和同时进行的治疗的类型(如果有的话);和化合物在有待治疗的动物中的清除率。本领域的技术人员可基于上述因素确定适当剂量。本文所述的化合物可最初以合适的剂量施用,剂量可根据需要进行调整,取决于临床反应。一般来说,当本文所述的化合物以例如介于0.05mg与3000mg(呈固体形式测量)之间的日剂量施用于人时可获得令人满意的结果。剂量范围包括例如10-1000mg(例如50-800mg)之间。在一些实施方案中,施用50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg或1000mg化合物。
可替代地,可使用患者体重来计算剂量。举例来说,化合物或其药物组合物施用于患者的剂量可在0.1-100mg/kg范围内。
药盒
本发明特征还在于药盒,其包括(a)包括本文所述的降细胞或受试者中BRD9的水平和/或活性的剂的药物组合物,和(b)具有执行本文所述的方法中的任一者的说明书的包装插页。在一些实施方案中,药盒包括(a)包括本文所述的降低细胞或受试者中BRD9的水平和/或活性的剂的药物组合物,(b)另外的治疗剂(例如抗癌剂),和(c)具有执行本文所述的方法中的任一者的说明书的包装插页。
实施例
实施例1-BRD9降解剂使BRD9蛋白耗尽
以下实施例证明了用BRD9降解剂处理的滑膜肉瘤细胞中BRD9蛋白的耗尽。
程序:将细胞用DMSO或BRD9降解剂化合物1(又称dBRD9,参见Remillard等人,Angew.Chem.Int.Ed.Engl.56(21):5738-5743(2017);参见以下化合物1的结构)处理,剂量和时间点如所指示。
全细胞提取物通过SDS-PAGE分级分离并根据制造商方案(Bio-Rad)使用转移设备转移至聚偏二氟乙烯膜。在与含5%脱脂牛奶的TBST(10mM Tris pH 8.0、150mM NaCl、0.5%Tween 20)一起孵育60分钟之后,将膜与针对BRD9(1:1,000,Bethyl laboratoryA303-781A)、GAPDH(1:5,000,Cell Signaling Technology)和/或MBP(1:1,000,BioRad)的抗体在4℃下孵育过夜。将膜洗涤三次,历时10分钟,并与缀合辣根过氧化物酶(HRP,图2-3)或IRDye(图4,1:20,000,LI-COR)的抗小鼠或抗兔抗体一起孵育至少1小时。将印迹用TBST洗涤三次,并根据制造商的方案用ECL系统显影(图2-3)或在Odyssey CLx成像系统上扫描(图4)。
结果:用BRD9降解剂化合物1处理SYO1滑膜肉瘤细胞引起细胞中BRD9的剂量依赖性(图1)和时间依赖性(图2)耗尽。此外,如图3中所示,在非滑膜肉瘤细胞系(293T)中复制化合物1对BRD9的耗尽且可持续至少5天。
实施例2-BRD9抑制剂和BRD9降解剂对滑膜细胞系的生长的抑制
以下实施例证明了BRD9降解剂和抑制剂选择性地抑制滑膜肉瘤细胞的生长。
程序:
将细胞用DMSO或BRD9降解剂化合物1以所指示浓度处理,从第7天至第14天,通过使用IncuCyte活细胞分析系统测量随时间推移的汇合来监测增殖(图4)。每3-4天更新生长培养基和化合物。
将细胞接种到12孔板中,并用DMSO、1μM BRD9抑制剂、化合物2(又称BI-7273,参见Martin等人,J Med Chem.59(10):4462-4475(2016);参见以下化合物2的结构)或1μM BRD9降解剂化合物1处理。
针对每种细胞系优化细胞数目。每3-5天更新生长培养基和化合物。第11天将SYO1、Yamato、A549、293T和HS-SY-II细胞固定并染色。第23天将ASKA细胞固定并染色。通过与结晶紫溶液(0.5g结晶紫、27ml 37%甲醛、100mL 10X PBS、10mL甲醇、863dH20至1L)一起孵育30分钟,然后用水洗涤3次并在室温下干燥平板至少24小时来进行染色。随后在Odyssey CLx成像系统上扫描平板(图5)。
将细胞接种到96孔超低簇板(Costar,#7007)中的200μL完全培养基中,第2天用DMSO、星形孢菌素(Staurosporin)或BRD9降解剂化合物1以所指示剂量处理(图2C)。每5天更换培养基和化合物,第14天使细胞群落成像。
结果:如图4、5和6所示,用BRD9抑制剂化合物2或BRD9降解剂化合物1处理滑膜肉瘤细胞系(SYO1、Yamato、HS-SY-II和ASKA)引起细胞生长的抑制,但未引起非滑膜对照癌细胞系(293T、A549、G401)的生长的抑制。
实施例3-BRD9降解剂和BRD9结合剂对滑膜细胞系的生长的选择性抑制
以下实施例证明了BRD9降解剂和结合剂选择性地抑制滑膜肉瘤细胞的生长。
程序:将细胞接种到6孔或12孔板中并每日用BRD9降解剂(化合物1)、溴结构域BRD9结合剂(化合物2)、E3连接酶结合剂(来那度胺)、DMSO或星形孢菌素(细胞杀死的阳性对照物)在所指示浓度下处理。针对每种细胞系优化细胞数目。每5天更新生长培养基。到第14天,去除培养基,将细胞用PBS洗涤,并在室温下使用500μL于25%(v/v)甲醇中的0.005%(w/v)结晶紫溶液染色至少1小时。随后在Odyssey CLx成像系统上扫描平板。
结果:如图7和8所示,用化合物1或化合物2处理滑膜肉瘤细胞系(SYO1、HS-SY-II和ASKA)引起细胞生长的抑制,但未引起非滑膜对照癌细胞系(RD、HCT116和Calu6)的生长的抑制。总体上,化合物1在所有滑膜细胞系中均显示最显著的生长抑制。
实施例4-滑膜肉瘤细胞中细胞生长的抑制
以下实施例展示了BRD9降解剂在滑膜肉瘤细胞中抑制细胞生长并诱导细胞凋亡。
程序:将SYO1细胞用DMSO、200nM或1μM的BRD9降解剂(化合物1)或200nM E3连接酶结合剂(来那度胺)处理8或13天。每5天更新化合物。使用Click-iTTM Plus EdU流式细胞术测定(Invitrogen)执行细胞周期分析。使用膜联蛋白V-FITC细胞凋亡检测试剂盒(SigmaA9210)执行细胞凋亡测定。根据制造商的方案执行测定。
结果:如图9-12所示,用化合物1处理8或13天引起处于细胞周期S期的细胞数目与DMSO和来那度胺相比减少。用化合物1处理8天还引起早期和晚期细胞凋亡细胞数目与DMSO对照物相比增加。
实施例5-SS18-SSX1-BAF的组合物
以下实施例展示了对作为含SS18-SSX的BAF复合物的组成部分的BRD9的鉴定。
程序:使用慢病毒整合产生表达HA-SS18SSX1的稳定293T细胞系。含SS18-SSX1的BAF复合物进行亲和力纯化,随后质谱分析揭露了SS18-SSX1相互作用蛋白质。
结果:如图13所示,包括SS18-SSX融合蛋白的BAF复合物还包括BRD9。针对ARID1A(95种肽)、ARID1B(77种肽)、SMARCC1(69种肽)、SMARCD1(41种肽)、SMARCD2(37种肽)、DPF2(32种肽)、SMARCD3(26种肽)、ACTL6A(25种肽)、BRD9(22种肽)、DPF1同种型2(18种肽)、DPF3(13种肽)和ACTL6B(6种肽)鉴定出超过5种独特肽。
实施例6-制备4-[6-(氮杂环丁烷-1-基)-2-甲基-1-氧代基-2,7-萘啶-4-基]-2,6-二甲氧基苯甲醛(中间体H)
步骤1:制备6-氯-4-甲基吡啶-3-甲酰胺(中间体B)
向搅拌的6-氯-4-甲基吡啶-3-甲酸(20.00g,116.564mmol,1.00当量)和NH4Cl(62.35g,1.17mol,10.00当量)于二氯甲烷(DCM;400mL)中的混合物中添加DIEA(22.60g,174.846mmol,3.00当量)。在搅拌5分钟后,逐份添加HATU(66.48g,174.846mmol,1.50当量)。将所得混合物在室温下搅拌3小时。将所得混合物减压浓缩,并将残余物通过硅胶柱色谱法来纯化,用1/1至3/2的石油醚/乙酸乙酯(PE/EtOAc)洗提,得到呈黄色固体状的6-氯-4-甲基吡啶-3-甲酰胺(18.30g,61.3%)。LCMS(ESI)m/z:[M+H]+=171。
步骤2:制备6-氯-N-[(1E)-(二甲基氨基)亚甲基]-4-甲基吡啶-3-甲酰胺(中间体C)
在80℃下在氮气气氛下向搅拌的6-氯-4-甲基吡啶-3-甲酰胺(18.30g,107.268mmol,1.00当量)和于2-甲基四氢呋喃(100mL)中的混合物中添加DMF-DMA(19.17g,160.903mmol,1.50当量),并再搅拌1小时。然后使混合物冷却并浓缩,得到呈粗黄色固体状的6-氯-N-[(1E)-(二甲基氨基)亚甲基]-4-甲基吡啶-3-甲酰胺(26.3g,91.3%),其未经进一步纯化直接使用。LCMS(ESI)m/z:[M+H]+=226。
步骤3:制备6-氯-2H-2,7-萘啶-1-酮(中间体D)
向搅拌的6-氯-N-[(1E)-(二甲基氨基)亚甲基]-4-甲基吡啶-3-甲酰胺(26.30g)于THF(170.00mL)中的混合物中添加t-BuOK(174.00mL,THF中1mol/L)。将所得溶液在60℃下在氮气气氛下搅拌30分钟。然后使混合物冷却并减压浓缩。将粗固体用饱和NaHCO3溶液(100mL)洗涤并收集,得到呈粉色固体状的6-氯-2H-2,7-萘啶-1-酮(14.1g,67.0%),其未经进一步纯化直接使用。LCMS(ESI)m/z:[M+H]+=181。
步骤4:制备6-氯-2-甲基-2,7-萘啶-1-酮(中间体E)
在0℃下向搅拌的6-氯-2H-2,7-萘啶-1-酮(14.10g,78.077mmol,1.00当量)于无水THF(280.00mL)中的混合物中逐份添加NaH(9.37g,234.232mmol,3.00当量,60%)。10分钟后,在0℃下添加MeI(33.25g,234.232mmol,3.00当量),并将混合物在0℃下搅拌10分钟,然后将混合物在室温下搅拌12小时。将所得混合物减压浓缩。将粗固体用水(100mL)形成浆液,并过滤固体且收集,得到呈黄色固体状的6-氯-2-甲基-2,7-萘啶-1-酮(14.6g,94.1%),其未经进一步纯化直接使用。LCMS(ESI)m/z:[M+H]+=195。
步骤5:制备4-溴-6-氯-2-甲基-2,7-萘啶-1-酮(中间体F)
向搅拌的6-氯-2-甲基-2,7-萘啶-1-酮(8.00g,41.106mmol,1.00当量)于DMF(160.00mL)中的混合物中添加NBS(8.78g,49.327mmol,1.20当量),并将所得混合物在90℃下搅拌2小时。使反应混合物冷却并用DCM(150mL)稀释且用水(3×100mL)洗涤。将有机层干燥并浓缩。然后将残余物用EtOAc(20mL)形成浆液,并过滤浆液。将滤饼用EtOAc(20mL)洗涤,得到呈白色固体状的4-溴-6-氯-2-甲基-2,7-萘啶-1-酮(6.32g,55.7%),其未经进一步纯化直接使用。LCMS(ESI)m/z:[M+H]+=273。
步骤6:制备6-(氮杂环丁烷-1-基)-4-溴-2-甲基-2,7-萘啶-1-酮(中间体G)
向4-溴-6-氯-2-甲基-2,7-萘啶-1-酮(5.00g,18.281mmol,1.00当量)和氮杂环丁烷盐酸盐(3.2g,54.843mmol,3当量)于DMSO(50.00mL)中的溶液中添加K2CO3(12.6g,91.404mmol,5当量)。将所得溶液在130℃下搅拌2小时。使所得混合物冷却并用水(100mL)稀释,然后用EtOAc(3×100mL)萃取。将合并的有机层用饱和NaCl溶液(3×50mL)洗涤,经无水Na2SO4干燥,并减压浓缩,得到呈灰色固体状的6-(氮杂环丁烷-1-基)-4-溴-2-甲基-2,7-萘啶-1-酮(3.7g,68.8%),其未经进一步纯化直接使用。LCMS(ESI)m/z:[M+H]+=294。
步骤7:制备4-[6-(氮杂环丁烷-1-基)-2-甲基-1-氧代基-2,7-萘啶-4-基]-2,6-二甲氧基苯甲醛(中间体H)
向6-(氮杂环丁烷-1-基)-4-溴-2-甲基-2,7-萘啶-1-酮(1.42g,4.827mmol,1.00当量)和4-甲酰基-3,5-二甲氧基苯基硼酸(1.52g,7.241mmol,1.5当量)于二噁烷(16.00mL)和H2O(4.00mL)中的溶液中添加Pd(dppf)Cl2(353.2mg,0.483mmol,0.1当量)和Cs2CO3(3.15g,9.655mmol,2当量),并将所得溶液在70℃下搅拌2小时。使所得混合物冷却并减压浓缩。将残余物用水(30mL)形成浆液并过滤,并收集滤饼。将该固体进一步用MeOH(30mL)形成浆液并过滤。收集固体,得到呈灰色固体状的4-[6-(氮杂环丁烷-1-基)-2-甲基-1-氧代基-2,7-萘啶-4-基]-2,6-二甲氧基苯甲醛(1.42g,77.5%)。LCMS(ESI)m/z:[M+H]+=380。
实施例7-制备3-[1-氧代基-6-[7-(哌啶-4-基甲基)-2,7-二氮杂螺[3.5]壬烷-2-基]-3H-异吲哚-2-基]哌啶-2,6-二酮(中间体P)
步骤1:制备5-溴-2-(溴甲基)苯甲酸甲酯(中间体J).
向搅拌的5-溴-2-甲基苯甲酸甲酯(50.00g,218.271mmol,1.00当量)于CCl4(500.00mL)中的混合物中添加NBS(38.85g,218.271mmol,1.00当量)和BPO(5.59g,21.827mmol,0.10当量)。在80℃下搅拌过夜后,混合物通过硅胶柱色谱法来纯化,用PE/EtOAc(50:1)洗提,得到呈黄色油状的5-溴-2-(溴甲基)苯甲酸甲酯(67g,74.75%)。LCMS(ESI)m/z:[M+H]+=307。
步骤2:制备4-(6-溴-1-氧代基-3H-异吲哚-2-基)-4-氨甲酰基丁酸叔丁酯(中间体K)
向搅拌的5-溴-2-(溴甲基)苯甲酸甲酯(67.00g,217.554mmol,1.00当量)和(4S)-4-氨基-4-氨甲酰基丁酸叔丁酯盐酸盐(62.32g,261.070mmol,1.20当量)于DMF(100.00mL)中的混合物中添加DIEA(112.47g,870.217mmol,4当量)。在80℃下搅拌过夜后,将混合物减压浓缩。向残余物添加水(200mL)并在室温下搅拌1小时。将所得混合物过滤,向滤饼添加水(100mL)并搅拌。沉淀固体通过过滤来收集并用水(3×30mL)洗涤。这产生了呈灰白色固体状的4-(6-溴-1-氧代基-3H-异吲哚-2-基)-4-氨甲酰基丁酸叔丁酯(55g,60.46%)。LCMS(ESI)m/z:[M+H]+=397。
步骤3:制备2-[2-[4-(叔丁氧基)-1-氨甲酰基-4-氧代基丁基]-3-氧代基-1H-异吲哚-5-基]-2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯(中间体L)
向搅拌的4-(6-溴-1-氧代基-3H-异吲哚-2-基)-4-氨甲酰基丁酸叔丁酯(10.00g,25.172mmol,1.00当量)和2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐(8.60g,32.723mmol,1.30当量)于二噁烷(200.00mL)中的溶液中添加Cs2CO3(24.60g,75.516mmol,3.00当量)和第3代RuPhos Palladacycle(2.11g,2.517mmol,0.10当量)。在100℃下在氮气气氛下搅拌过夜后,将所得混合物在尚热的时候过滤,并将滤饼用1,4-二噁烷(3×50mL)洗涤。将滤液减压浓缩,得到呈黑色固体状的2-[2-[4-(叔丁氧基)-1-氨甲酰基-4-氧代基丁基]-3-氧代基-1H-异吲哚-5-基]-2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯(21g,粗制物)。LCMS(ESI)m/z:[M+H]+=543。
步骤4:制备2-[2-(2,6-二氧代基哌啶-3-基)-3-氧代基-1H-异吲哚-5-基]-2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯(中间体M)
向搅拌的2-[2-[(1S)-4-(叔丁氧基)-1-氨甲酰基-4-氧代基丁基]-3-氧代基-1H-异吲哚-5-基]-2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯(13.68g,25.208mmol,1.00当量)于THF(100.00mL)中的混合物中添加含t-BuOK的THF(25.00mL,25.000mmol,0.99当量)。将所得混合物在室温下搅拌2小时。将混合物用1M HCl(水溶液)酸化至pH 6,然后用饱和NaHCO3(水溶液)中和至pH 7。将所得混合物用EtOAc(3×200mL)萃取。将合并的有机层减压浓缩。这产生了呈黄色固体状的2-[2-(2,6-二氧代基哌啶-3-基)-3-氧代基-1H-异吲哚-5-基]-2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯(7.8g,59.43%)。LCMS(ESI)m/z:[M+H]+=469。
步骤5:制备3-(6-[2,7-二氮杂螺[3.5]壬烷-2-基]-1-氧代基-3H-异吲哚-2-基)哌啶-2,6-二酮(中间体N)
向搅拌的2-[2-(2,6-二氧代基哌啶-3-基)-3-氧代基-1H-异吲哚-5-基]-2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯(7.80g,16.647mmol,1.00当量)于DCM(10.00mL)中的混合物中添加三氟乙酸(TFA;5.00mL)。在室温下搅拌2小时后,将所得混合物在真空下浓缩。这产生了呈淡黄色固体状的3-(6-[2,7-二氮杂螺[3.5]壬烷-2-基]-1-氧代基-3H-异吲哚-2-基)哌啶-2,6-二酮(6g,92.93%)。LCMS(ESI)m/z:[M+H]+=369。
步骤6:制备4-([2-[2-(2,6-二氧代基哌啶-3-基)-3-氧代基-1H-异吲哚-5-基]-2,7-二氮杂螺[3.5]壬烷-7-基]甲基)哌啶-1-甲酸叔丁酯(中间体O)
在室温下向搅拌的3-(6-[2,7-二氮杂螺[3.5]壬烷-2-基]-1-氧代基-3H-异吲哚-2-基)哌啶-2,6-二酮(4.00g,8.685mmol,1.00当量,80%)和4-甲酰基哌啶-1-甲酸叔丁酯(1.48g,6.939mmol,0.80当量)于DMF(20.00mL)中的溶液中添加NaBH(OAc)3(3.68g,17.363mmol,2.00当量)。将所得混合物在室温下搅拌2小时。在室温下将反应用水淬灭。所得混合物通过逆相快速色谱法利用以下条件(柱,C18硅胶;流动相,含CH3CN的水(0.1%FA),40分钟内0至100%梯度;检测器,UV 254nm)来纯化。这产生了呈深黄色固体状的4-([2-[2-(2,6-二氧代基哌啶-3-基)-3-氧代基-1H-异吲哚-5-基]-2,7-二氮杂螺[3.5]壬烷-7-基]甲基)哌啶-1-甲酸叔丁酯(2.8g,51.29%)。LCMS(ESI)m/z:[M+H]+=566。
步骤7:制备3-[1-氧代基-6-[7-(哌啶-4-基甲基)-2,7-二氮杂螺[3.5]壬烷-2-基]-3H-异吲哚-2-基]哌啶-2,6-二酮(中间体P)
向搅拌的4-([2-[2-(2,6-二氧代基哌啶-3-基)-3-氧代基-1H-异吲哚-5-基]-2,7-二氮杂螺[3.5]壬烷-7-基]甲基)哌啶-1-甲酸叔丁酯(2.80g,4.949mmol,1.00当量)于DCM(5.00mL)中的混合物中添加TFA(2.00mL)。将混合物在室温下搅拌2小时。将所得混合物减压浓缩,得到呈黄色固体状的3-[1-氧代基-6-[7-(哌啶-4-基甲基)-2,7-二氮杂螺[3.5]壬烷-2-基]-3H-异吲哚-2-基]哌啶-2,6-二酮(3.9g,粗制物)。LCMS(ESI)m/z:[M+H]+=466。
实施例8-制备3-[6-(7-[[1-([4-[6-(氮杂环丁烷-1-基)-2-甲基-1-氧代基-2,7-萘啶-4-基]-2,6-二甲氧基苯基]甲基)哌啶-4-基]甲基]-2,7-二氮杂螺[3.5]壬烷-2-基)-1-氧代基-3H-异吲哚-2-基]哌啶-2,6-二酮TFA盐(化合物D1 TFA盐)
将3-[1-氧代基-6-[7-(哌啶-4-基甲基)-2,7-二氮杂螺[3.5]壬烷-2-基]-3H-异吲哚-2-基]哌啶-2,6-二酮(4.5g,10.52mmol,1.00当量)和4-[6-(氮杂环丁烷-1-基)-2-甲基-1-氧代基-2,7-萘啶-4-基]-2,6-二甲氧基苯甲醛(4.0g,10.52mmol,1.00当量)和异丙氧基钛(IV)(3.0g,10.52mmol,1.00当量)于DMSO(100mL)中的溶液在室温下搅拌3小时。然后分批添加NaBH(OAc)3(8.92g,42.08mmol,4.00当量)到以上所得溶液中,并将所得混合物在室温下搅拌过夜。反应通过添加水(30mL)淬灭,然后过滤溶液。将滤饼用水和乙腈洗涤。然后滤液真空浓缩。粗产物通过逆相快速色谱法利用以下条件(柱:AQ C18柱,50×250mm10μm;流动相A:水(TFA 0.1%),流动相B:CAN;流速:100毫升/分钟;梯度:35分钟内5B至25B;254/220nm)来纯化。纯溶离份蒸发至干,得到呈白色固体状的3-[6-(7-[[1-([4-[6-(氮杂环丁烷-1-基)-2-甲基-1-氧代基-2,7-萘啶-4-基]-2,6-二甲氧基苯基]甲基)哌啶-4-基]甲基]-2,7-二氮杂螺[3.5]壬烷-2-基)-1-氧代基-3H-异吲哚-2-基]哌啶-2,6-二酮TFA盐(3.2g,32.3%)。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),9.01(s,1H),7.59(s,1H),7.36(d,J=8.0Hz,1H),6.72(s,2H),6.68(d,J=8.1Hz,2H),6.20(s,1H),5.07(dd,J=13.3,5.1Hz,1H),4.35-4.13(m,2H),4.06-3.95(m,4H),3.80(s,6H),3.57(s,4H),3.47(s,5H),2.97-2.75(m,3H),2.70-2.55(m,1H),2.44-2.16(m,7H),2.13-1.88(m,5H),1.80-1.67(m,4H),1.61(d,J=12.4Hz,2H),1.53-1.33(m,1H),1.13-0.94(m,2H)。LCMS(ESI)m/z:[M+H]+=829.55。
通过超临界流体色谱法在手性载体上来分离化合物D1的对映异构物以产生化合物S-D1和化合物R-D1。
实施例9-制备化合物D2
与上述实施例中所述的程序类似,使用适当起始物质制备化合物D2。
化合物D2:1H NMR(300MHz,DMSO-d6)δ10.98(s,1H),9.02(d,J=0.7Hz,1H),7.63(d,J=2.3Hz,1H),7.41(d,J=8.8Hz,1H),6.88(s,2H),6.70(h,J=2.4Hz,2H),6.24(d,J=6.0Hz,1H),5.08(dd,J=13.2,5.1Hz,1H),4.41-4.14(m,4H),4.04(t,J=7.4Hz,4H),3.91(s,1H),3.70(d,J=22.5Hz,4H),3.50(s,3H),3.45(s,1H),3.22(s,1H),3.14-2.82(m,6H),2.60(d,J=16.2Hz,1H),2.55(s,2H),2.44-2.28(m,3H),2.18-2.05(m,3H),1.97(t,J=13.9Hz,5H),1.51(q,J=12.2,11.1Hz,2H)。LCMS(ESI)m/z:[M+H]+=835.45。
实施例10-SYO1 BRD9 NanoLuc降解测定
本实施例在基于细胞的降解测定中证明了本公开的化合物降解纳米荧光素酶(Nanoluciferase)-BRD9融合蛋白的能力。
程序:产生表达3xFLAG-NLuc-BRD9的稳定SYO-1细胞系。第0天,将细胞于30μL培养基中接种于384孔细胞培养板的每个孔中。接种密度为8000个细胞/孔。第1天,将细胞用30nL DMSO或30nL3倍连续DMSO稀释的化合物处理(10个点,一式两份,1μM为最终最高剂量)。随后将平板在标准组织培养孵育器中孵育6小时并在室温下平衡15分钟。通过添加15μL新鲜制备的Nano-Glo荧光素酶测定试剂(Promega N1130),震荡平板10分钟并使用EnVision读数器读取生物发光来测量纳米荧光素酶活性。
结果:使用下式计算抑制%:抑制%=100×(LumHC-Lum样品)/(LumHC-LumLC)。DMSO处理的细胞用作高对照物(HC),1μM已知的BRD9降解剂标准处理的细胞用作低对照物(LC)。数据拟合成四参数非线性曲线拟合,以计算IC50(μM)值,如表2所示。如表2中的结果所示,许多本公开的化合物展现降解BRD9的IC50值<1μM,这表明了它们用作降低BRD9的水平和/或活性的化合物和它们治疗BRD9相关病症的潜能。
表2.SYO1 BRD9-NanoLuc降解
实施例11-BRD9的降解抑制滑膜肉瘤肿瘤在体内的生长
方法:将NOD SCID小鼠(Beijing Anikeeper Biotech,Beijing)在右侧腰窝中皮下接种SYO-1人双相滑膜肉瘤肿瘤细胞(5×106)于100μL具有10%胎牛血清(FBS)的达尔伯克改良伊格尔培养基(Dulbecco'sModified Eagle Medium,DMEM)中的单细胞悬浮液。当平均肿瘤尺寸达到约117mm3时,将小鼠随机化到对照组[10%二甲亚砜(DMSO)、40%聚乙二醇(PEG400)和50%水]或处理组D1。每日通过腹膜内(i.p.)途径在3周过程中向小鼠给药。所有剂量体积均根据mg/kg随体重而调整。
结果:如图14所示,用1mg/kg化合物D1处理引起肿瘤生长抑制。基于观察到的体重变化%,所有处理均耐受性良好。
实施例12-化合物D1引起BRD9在体内在滑膜肉瘤肿瘤中的降解
方法:将小鼠用1mg/kg D1 i.p.处理4周。然后对小鼠施以安乐死,并在最后一剂后8小时、72小时和168小时收集肿瘤。用具有蛋白酶和磷酸酶蛋白质抑制剂(RocheApplied Science#04906837001和05892791001)的1x RIPA溶解缓冲液(BostonBioProducts,BP-115D)使肿瘤溶解。将同等量的溶解产物(30μg)装载于1X MOPS缓冲液中的4-12%Bis-Tris Midi蛋白质凝胶中;样品在120V下跑动120分钟。在250mA下将蛋白质转移至具有TransBlot的膜,历时150分钟,然后在室温下用Odyssey封闭缓冲液封闭膜1小时。膜在冷室中与一级抗体杂交过夜。使用Li-COR成像系统(Li-COR Biotechnology,Lincoln,Nebraska)获得图像。
表3展示了检测抗体信息。
表3.
抗体 | 供货商 | 目录号 | 物种 | 稀释 |
BRD9 | Bethyl,(Montgomery,TX) | A303-781A | 兔 | 1:1000 |
GAPDH | CST,(Danvers,MA) | 97166 | 小鼠 | 1:2000 |
结果:如图15所示,用1mg/kg化合物D1处理引起BRD9靶完全降解,直至在给药之后168小时。
实施例13-化合物S-D1和R-D1对滑膜肉瘤细胞的作用
方法.将滑膜肉瘤细胞以500-100k个细胞/孔涂铺于6孔板中,次日,在两个时间点在37℃下用连续浓度的BRD9降解剂(10nM最高浓度,1:3稀释)处理。然后收获细胞,用冷PBS洗涤,并在-80℃下冷冻成细胞团粒。通过使解冻的团块再悬浮于1x RIPA溶解和提取缓冲液(Thermo Fisher,目录号89900)中来制备溶解产物,该缓冲液具有无EDTA的1x HaltTM蛋白酶和磷酸酶抑制剂混合物(Thermo Fisher,目录号78441)和1:1000稀释的PierceTM细胞溶解通用核酸酶25ku(Thermo Fisher,目录号88700)。将溶解产物在冰上孵育10分钟,然后在4℃下以最大速度(15,000rpm)离心10分钟。然后使用BCA蛋白质定量测定,对样品的总蛋白进行分析,并用溶解缓冲液和1xNuPAGETM LDS样品缓冲液(4X)(Thermo Fisher,目录号NP0007)和来自30X原液的1x DTT(Cell Signaling Technologies,目录号14265S)稀释至1μg/μL。将具有20-25ug总蛋白的样品装载到具有1x MES电泳缓冲液的4-12%Bis-TrisMini-Gel中并在150V下跑动45分钟。使用TurboTM转移系统(半干)在25V下10分钟(高MW设置)将凝胶转移在硝化纤维素印迹上。将印迹在含5%牛奶的TBST中封闭1小时并用BRD9抗体(SYO1,Bethyl Labs,目录号A303-781A,1:750;和ASKA,Cell SignalingTechnologies,目录号71232S)和β-肌动蛋白抗体(Cell Signaling Technologies,目录号3700,1:2000)在4℃下探测过夜。次日,将印迹在TBST中洗涤3次并在室温下在LiCOR封闭缓冲液(TBS)中用1:5000680LT山羊抗兔IgG二级抗体(LiCOR,目录号926-68021)和1:10000800CW山羊抗小鼠IgG二级抗体(LiCOR,目录号926-32210)探测1小时。将印迹在TBST中洗涤3次并使用LiCORCLx成像系统在700nM和800nM波长下扫描。使用同一机器中包括的同一分析程序定量蛋白质印迹信号。通过相对于β-肌动蛋白信号归一化来定量BRD9信号传导,并将所有样品均相对于设为100%信号的DMSO归一化。
为评定细胞培养基中对映异构物1与对映异构物2之间的相互转化,执行以下测试。将对映异构物1和对映异构物2(各为DMSO中40μM)以0.2μM的最终浓度外加到细胞培养基(DMEM+Glutamax+10%FBS)中并在37℃和5%CO2下一式两份孵育。在指定时间点,获取等分试样(50μL)并通过添加150μL含有0.1%甲酸的乙腈和内标准品来处理,以进行LC/MS-MS分析。使用手性特定分析法测定每个样品的对映异构物1和对映异构物2的峰面积。结果概述于下5表中。
结果.为了评估两种对映异构物的BRD9降解活性,使用两种滑膜肉瘤细胞系(SYO-1和ASKA)进行降解剂处理和后续蛋白质印迹实验。在对映异构物2下观察到显著更有效的BRD9降解活性,其中与对映异构物1在SYO-1中处理1小时时间下的2.8nM相比,拟合的DC50值为0.092nM(图16、17和18和表4)。对于对映异构物2,在30分钟时,显而易见ASKA细胞的更显著差异,DC50为0.34nM,但对于对映异构物1,在相同时间点,直至10μM,活性都不可辩别(图20、21和22和表4)。在ASKA中在2小时差异减少到约32倍,其中对映异构物1和对映异构物2的拟合的DC50值分别为0.38nM和0.012nM(表4)。在SYO1中,到6小时,差异进一步减少到大约3倍。在降解BRD9上,对映异构物2稍微比其外消旋母体化合物D1更佳,但在相同的研究条件下总体相当(图16和17)。对于所有三种化合物,在24小时,BRD9降解活性变得高度相似(图19)。总之,在两种滑膜肉瘤细胞系中在早期时间点,对映异构物2降解内源BRD9蛋白更有效,而对映异构物1基本上无活性或具有大量降低的降解效力。然而,效力差异随着时间推移而减小,到24小时,基本上消失。
表4.
报告了沙利度胺或其它IMiD药物和它们的衍生物中手性中心的差向异构作用。在物理或中性pH条件下手性中心中的酸性氢可能被会扰乱。为了研究这些降解剂在细胞测定条件下的手性稳定性,在细胞培养基中在37℃下对对映异构物1和对映异构物2执行时程研究。在时间0或0.5小时,在对映异构物1样品中未检测到对映异构物2。但在随后时间点,检测到大量对映异构物2,在2小时和6小时分别占总数12%和30%(表5)。类似地,对映异构物2随着时间推移转化成对映异构物1,并在6小时,其有效浓度降低至63%(表5)。这些数据指示在细胞分析条件下差向异构速率相对较快,表明对映异构物1的时间依赖性BRD9降解活性可能由转化的对映异构物2引起。总体上,这些数据指示对映异构物2是降解细胞中的BRD9的活性对映异构物。
表5.
实施例14-化合物S-D1和R-D1对滑膜肉瘤细胞的作用
方法.SYO-1肿瘤细胞在体外呈粘附细胞维持在补充有10%胎牛血清的达尔伯克改良的伊格尔培养基(DMEM)中37℃下含5%CO2的空气的气氛中。收获在指数生长期生长的细胞并计数,以用于肿瘤接种。将BALB/c裸小鼠(Shanghai Lingchang biologicalscience)在右侧腰窝上皮下接种于0.1mL磷酸盐缓冲盐水(PBS)中(5×106)。当平均肿瘤尺寸达到499mm3时,在肿瘤接种之后第19天开始处理(下表中所述)。
处理信息:
抗体 | 小鼠数目 |
媒介物对照物,磺丁基醚-β-环糊精(SBECD),单剂量,10ul/g | 3 |
外消旋D1,0.5mg/kg i.v.,单剂量,10ul/g(20%SBECD) | 12 |
对映异构物1,0.25mg/kg i.v.,单剂量,10ul/g(20%SBECD) | 18 |
对映异构物2,0.25mg/kg i.v.,单剂量,10ul/g(20%SBECD) | 18 |
对映异构物2,1mg/kg i.v.,单剂量,10ul/g(20%SBECD) | 18 |
将小鼠用1mg/kg外消旋D1 i.p.处理4周,对小鼠施以安乐死,并在最后一剂后1小时、4小时、8小时、24小时、48小时和72小时收集肿瘤。用具有蛋白酶和磷酸酶蛋白质抑制剂(Roche Applied Science#04906837001和05892791001)的1x RIPA溶解缓冲液(BostonBioProducts,BP-115D)使肿瘤溶解。将同等量的溶解产物(30μg)装载于1X MOPS缓冲液中的4-12%Bis-Tris Midi蛋白质凝胶中;样品在120V下跑动120分钟。在250mA下将蛋白质转移至具有TransBlot的膜(NC),历时150分钟,然后在室温下用Odyssey封闭缓冲液封闭膜1小时。膜在冷室中与一级抗体杂交过夜。使用Li-COR成像系统(Li-COR Biotechnology,Lincoln,Nebraska)获得图像
检测抗体信息:
抗体 | 供货商 | 目录号 | 物种 | 稀释 |
BRD9 | Bethyl,(Montgomery,TX) | A303-781A | 兔 | 1:1000 |
GAPDH | CST,(Danvers,MA) | 97166 | 小鼠 | 1:2000 |
结果.在SYO-1异种移植模型中评估对映异构物1、对映异构物2和外消旋化合物D1的药效活性。对映异构物2证明显著活性,通过BRD9蛋白水平使用蛋白质印迹测定评定,图23。对映异构物2在单一剂量之后直到72小时均降解BRD9。对映异构物1无活性,且不降解BRD9蛋白。这些结果表明对映异构物2与外消旋化合物D1同等效力。
其它实施方案
本说明书中所提及的所有公布、专利和专利申请均以引用的方式整体并入本文中,其引用程度如同特别且个别地指示每篇个别的公布、专利或专利申请以引用的方式整体并入一般。在发现本申请中的术语在以引用的方式并入本文中的文献中的定义不同的情况下,本文提供的定义将充当该术语的定义。
在本发明已结合其特定实施方案来描述的情况下,应了解本发明能够进行进一步修改并且本申请意图涵盖本发明的任何变化形式、用途或改变,这些变化形式、用途或改变一般遵循本发明的原理并且包括在本发明本领域内的已知或惯常实践内的与本公开的偏离,并且可应用于以上阐述的基本特征,并在权利要求书的范围内。
其它实施方案在权利要求书内。
Claims (34)
9.一种抑制细胞中的BRD9水平的方法,所述方法包括使所述细胞与有效量的如权利要求1至4中任一项所述的化合物或其药学上可接受的盐或如权利要求5至8中任一项所述的药物组合物接触。
10.一种抑制细胞中的BRD9活性的方法,所述方法包括使所述细胞与有效量的如权利要求1至4中任一项所述的化合物或其药学上可接受的盐或如权利要求5至8中任一项所述的药物组合物接触。
11.如权利要求9或10所述的方法,其中所述细胞为癌细胞。
12.如权利要求11所述的方法,其中所述癌症为恶性横纹肌样瘤、CD8+T细胞淋巴瘤、子宫内膜癌、卵巢癌、膀胱癌、胃癌、胰腺癌、食道癌、前列腺癌、肾细胞癌、黑色素瘤、结肠直肠癌、肉瘤、非小细胞肺癌、胃癌或乳腺癌。
13.如权利要求12所述的方法,其中所述癌症为肉瘤。
14.如权利要求13所述的方法,其中所述肉瘤为软组织肉瘤、滑膜肉瘤、尤文氏肉瘤、骨肉瘤、横纹肌肉瘤、成人纤维肉瘤、腺泡状软组织肉瘤、血管肉瘤、透明细胞肉瘤、促纤维组织增生性小圆细胞肿瘤、上皮样肉瘤、纤维粘液样肉瘤、胃肠道基质瘤、卡波西肉瘤、脂肪肉瘤、平滑肌肉瘤、恶性间叶瘤恶性外周神经鞘膜瘤、粘液纤维肉瘤或低级别横纹肌肉瘤。
15.如权利要求14所述的方法,其中所述肉瘤为滑膜肉瘤。
16.如权利要求14所述的方法,其中所述肉瘤为横纹肌肉瘤。
17.一种治疗有需要的受试者的BAF复合物相关病症的方法,所述方法包括向所述受试者施用有效量的如权利要求1至4中任一项所述的化合物或其药学上可接受的盐或如权利要求5至8中任一项所述的药物组合物。
18.一种治疗有需要的受试者的SS18-SSX融合蛋白相关病症的方法,所述方法包括向所述受试者施用有效量的如权利要求1至4中任一项所述的化合物或其药学上可接受的盐或如权利要求5至8中任一项所述的药物组合物。
19.一种治疗有需要的受试者的BRD9相关病症的方法,所述方法包括向所述受试者施用有效量的如权利要求1至4中任一项所述的化合物或其药学上可接受的盐或如权利要求5至8中任一项所述的药物组合物。
20.如权利要求17至19中任一项所述的方法,其中所述病症为癌症。
21.一种治疗有需要的受试者的癌症的方法,所述方法包括向所述受试者施用有效量的如权利要求1至4中任一项所述的化合物或其药学上可接受的盐或如权利要求5至8中任一项所述的药物组合物。
22.如权利要求20或21所述的方法,其中所述癌症为恶性横纹肌样瘤、CD8+T细胞淋巴瘤、子宫内膜癌、卵巢癌、膀胱癌、胃癌、胰腺癌、食道癌、前列腺癌、肾细胞癌、黑色素瘤、结肠直肠癌、肉瘤、非小细胞肺癌、胃癌或乳腺癌。
23.如权利要求22所述的方法,其中所述癌症为肉瘤。
24.如权利要求23所述的方法,其中所述肉瘤为软组织肉瘤、滑膜肉瘤、尤文氏肉瘤、骨肉瘤、横纹肌肉瘤、成人纤维肉瘤、腺泡状软组织肉瘤、血管肉瘤、透明细胞肉瘤、促纤维组织增生性小圆细胞肿瘤、上皮样肉瘤、纤维粘液样肉瘤、胃肠道基质瘤、卡波西肉瘤、脂肪肉瘤、平滑肌肉瘤、恶性间叶瘤恶性外周神经鞘膜瘤、粘液纤维肉瘤或低级别横纹肌肉瘤。
25.如权利要求24所述的方法,其中所述肉瘤为滑膜肉瘤。
26.如权利要求24所述的方法,其中所述肉瘤为横纹肌肉瘤。
27.如权利要求12或22所述的方法,其中所述癌症为前列腺癌。
28.如权利要求11、20或21所述的方法,其中所述癌症为急性髓系白血病。
29.如权利要求11、20或21所述的方法,其中所述癌症为BRCA突变癌症。
30.如权利要求17至19中任一项所述的方法,其中所述病症为感染。
31.一种治疗有需要的受试者的感染的方法,所述方法包括向所述受试者施用有效量的如权利要求1至4中任一项所述的化合物或其药学上可接受的盐或如权利要求5至8中任一项所述的药物组合物。
32.如权利要求30或31所述的方法,其中所述感染为病毒感染。
33.如权利要求32所述的方法,其中所述病毒感染为逆转录病毒科、肝脱氧核糖核酸病毒科、黄病毒科、腺病毒科、疱疹病毒科、乳头瘤病毒科、细小病毒科、多瘤病毒科、副粘病毒科或披膜病毒科病毒的感染。
34.如权利要求32或33所述的方法,其中所述病毒感染为科芬西里斯病、神经纤维瘤或多发性脑膜瘤。
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