CN117835977A - Tead抑制剂的给药方案 - Google Patents
Tead抑制剂的给药方案 Download PDFInfo
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- CN117835977A CN117835977A CN202280057415.5A CN202280057415A CN117835977A CN 117835977 A CN117835977 A CN 117835977A CN 202280057415 A CN202280057415 A CN 202280057415A CN 117835977 A CN117835977 A CN 117835977A
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- tead
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Abstract
本发明涉及用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐,其中在7天治疗周期的前3天的每一天施用所述TEAD抑制剂,并且其中所述治疗包括至少两个治疗周期。
Description
技术领域
本发明涉及TEAD抑制剂或其药学上可接受的盐,用于在癌症的治疗中以及在特定给药方案(例如,在7天治疗周期的前3天的每一天施用TEAD抑制剂)下使用,并且其中所述治疗包括至少两个治疗周期。
背景技术
正常组织的生长以及组织的修复和重塑都需要特异性控制转录活性和调节其平衡。转录输出通过多种关键信号传导模块进行协调,其中一种就是河马途径(Hippopathway)。在果蝇属和哺乳动物中的遗传研究定义了一种保守的核心信号传导盒,其由Mst1/2和Lats1/2激酶组成,可抑制转录共激活因子YAP和TAZ(官方基因名称:WWTR1)。
激活河马途径使YAP和TAZ被磷酸化并且在细胞质中螯合/降解。在河马途径失活后,YAP和TAZ易位至细胞核并与转录因子(即TEAD家族成员(TEAD1-4))结合。YAP/TAZ-TEAD复合物进而促进参与细胞增殖、死亡和分化的下游基因的转录。虽然YAP和TAZ也可以与许多其他因子相互作用,但普遍认为TEAD是YAP和TAZ促进生长和致瘤潜力的关键介质(途径综述于:Yu等人,2015;Holden和Cunningham,2018)。
因此,在几种人类癌症中通常观察到YAP和/或TAZ的过度活化(以及随后的YAP/TAZ-TEAD转录复合物的过度活化)。这通过许多肿瘤(包括乳腺癌、肺癌(例如,非小细胞;NSCLC)、卵巢癌、结直肠癌、胰腺癌、前列腺癌、胃癌、食道癌、肝癌和骨癌(肉瘤))中YAP/TAZ水平和核定位升高而得到证实(Steinhardt等人,2008;Harvey等人,2013;Moroishi等人,2015;广泛综述于Zanconato等人,2016,以及其中的参考文献)。
虽然迄今为止在主要样品中仅以有限的频率检测到核心河马途径部分的遗传改变,但与NF2或Lats1/2中失活突变以及相关的YAP/TEAD过度活化相关联的最突出的癌症恶性肿瘤是恶性胸膜间皮瘤(MPM)(综述于Sekido,2018)。类似地,许多人类肿瘤的特征在于11q22.1基因座处的YAP扩增(例如,肝细胞癌、髓母细胞瘤、食管鳞状细胞癌)、3q25.1基因座处的TAZ(WWTR1)扩增(例如,横纹肌肉瘤、三阴性乳腺癌)、或涉及YAP或TAZ的基因融合(上皮样血管内皮瘤、室管膜肿瘤)(综述于Yu等人,2015,以及其中的参考文献)。与MPM一样,预期此类肿瘤也依赖于其升高的YAP/TAZ-TEAD活性。
破坏YAP/TAZ-TEAD PPI(作为河马途径最远端的效应器节点)有望消除这种复合物的致癌潜力。将本发明的化合物设计和优化为结合TEAD并选择性地破坏它们与YAP和TAZ的相互作用,这被认为可产生能用于治疗上述癌症的药物。特别地,此类癌症的特征在于(但不限于)一些所描述的畸变。
值得注意的是,具有活化的YAP/TAZ-TEAD的肿瘤细胞显示出针对化学治疗药物的抗性,这可能与赋予癌症干细胞样特征的YAP/TAZ有关。此外,YAP/TAZ-TEAD活化还赋予了针对分子靶向疗法(例如,BRAF、MEK或EGFR抑制剂)的抗性,如多种遗传和药理学筛选的结果所报道的(Kapoor等人,2014;Shao等人,2014;Lin等人,2015)。这反过来表明,抑制YAP/TAZ-TEAD活性(与其他癌症治疗并行地或相继地进行)可通过减少对其他治疗有抗性的肿瘤生长而提供有益的治疗效果。
用上述LMW化合物进行PPI破坏后,YAP/TAZ-TEAD活性的抑制也可能减弱肿瘤逃避免疫监视。这通过例如关于以下的报道数据而得到证实:YAP促进趋化因子CXCL5表达,这导致募集了抑制T细胞的髓样细胞(Wang等人,2016)。Treg(调节性T细胞)中的YAP也被证明可经由激活素信号传导和Treg功能来支持FOXP3表达。因此,YAP缺乏导致Treg功能失调,从而无法再抑制抗肿瘤免疫力。因此,通过防止Treg功能,选择性抑制YAP/TEAD活性可以有助于增强抗肿瘤免疫力(Ni等人,2018)。最近的文献还显示,YAP上调了PD-L1表达,并通过这种机制直接介导了(例如在对BRAF抑制剂具有抗性的黑色素瘤细胞中)细胞毒性T细胞免疫应答的逃逸(Kim等人,2018)。出于治疗目的,上述YAP/TAZ-TEAD PPI化合物可与癌症免疫疗法药物如免疫检查点抑制剂(例如抗PD-1抗体)组合使用。
TEAD抑制剂4-((2S,4S)-5-氯-6-氟-2-苯基-2-((S)-吡咯烷-2-基)-2,3-二氢苯并呋喃-4-基)-5-氟-6-(2-羟基乙氧基)-N-甲基烟酰胺(化合物A),以及制备所述抑制剂的方法描述于国际专利申请PCT/IB2021/052136中,其通过引用并入。
肾脏毒性,特别是肾小管变性,被认为是与某些TEAD抑制剂相关的安全/毒性风险,特别是在长期治疗的情况下。因此,本领域仍需要导致安全性谱改善的TEAD抑制剂给药方案。
参见例如:
Yu,F-X.,Zhao,B.和Guan,K.-L.(2015).Hippo pathway in organ sizecontrol,tissue homeostasis,and cancer[器官大小控制、组织稳态和癌症中的河马途径].Cell[细胞],163,811-828.
Holden,J.K.和Cunningham,C.N.(2018).Targeting the Hippo pathway andcancer through the TEAD family of transcription factors[通过TEAD转录因子家族靶向河马途径和癌症].Cancers(Basel)[癌症(巴塞尔)],10,E81.
Steinhardt,A.A.,Gayyed,M.F.,Klein,A.P.,Dong,J.,Maitra,A.,Pan,D.,Montgomery,E.A.,Anders,R.A.(2008).Expression of Yes-associated protein incommon solid tumors[Yes相关蛋白在常见实体瘤中的表达].Hum.Pathol.[人类病理学],39,1582-1589.
Harvey,K.F.,Zhang,X.,和Thomas,D.M.(2013).The Hippo pathway and humancancer[河马途径和人类癌症].Nat.Rev.Cancer[自然综述-癌症],13,246-257.
Moroishi,T.,Hansen,C.G.,和Guan,K.-L.(2015).Nat.Rev.Cancer[自然综述-癌症],15,73-79.
Zanconato,F.,Cordenonsi,M.,和Piccolo,S.(2016).YAP/TAZ at the roots ofcancer[癌症的根结处的YAP/TAZ].Cancer Cell[癌细胞],29,783-803.
Sekido,Y.(2018).Cancers(Basel)[癌症(巴塞尔)],10,E90.
Kapoor,A.,Yao,W.,Ying,H.,Hua,S.,Liewen,A.,Wang,Q.,Zhong,Y.,Wu,C.J.,Sadanandam,A.,Hu,B.等人(2014).Yap1 activation enables bypass of oncogenicKras addiction in pancreatic cancer[Yap1激活使得可以绕过胰腺癌中的致癌Kras成瘾].Cell[细胞],158,185-197.
Shao,D.D.,Xue,W.,Krall,E.B.,Bhutkar,A.,Piccioni,F.,Wang,X.,Schinzel,A.C.,Sood,S.,Rosenbluh,J.,Kim,J.W.,等人(2014).KRAS and YAP1 converge toregulate EMT and tumor survival[KRAS和YAP1会聚以调节EMT和肿瘤存活].Cell[细胞],158,171-184.
Lin,L.,Sabnis,A.J.,Chan,E.,Olivas,V.,Cade,L.,Pazarentzos,E.,Asthana,S.,Neel,D.,Yan,J.J.,Lu,X.等人(2015).The Hippo effector YAP promotesresistance to RAF-and MEK-targeted cancer therapies[河马效应器YAP促进对RAF和MEK靶向癌症治疗的抵抗力].Nat.Genet.[自然遗传学],47,250-256.
Wang,G.,Lu,X.,Dey,P.,Deng,P.,Wu,C.C.,Jiang,S.,Fang,Z.,Zhao,K.,Konaprathi,R.,Hua,S.,等人(2016).Cancer Discov.[癌症发现],6,80-95.
Ni,X.,Tao,J.,Barbi,J.,Chen,Q.,Park B.V.,Li,Z.,Zhang,N.,Lebid,A.,Ramaswamy,A.,Wei,P.,等人(2018).YAP is essential for Treg-mediated suppressionof antitumor immunity[YAP对于Treg介导的抗肿瘤免疫抑制至关重要].Cancer Discov.[癌症发现],8,1026-1043.
Kim,M.H.,Kim,C.G.,Kim,S.K.,Shin,S.J.,Choe,E.A.,Park,S.H.,Shin,E.C.,和Kim,J.(2018).Cancer Immunol Res.[癌症免疫研究],6,255-266.
发明内容
开发TEAD抑制剂的目标之一是找到一种确保功效但同时与不良副作用(例如肾毒性)减少相关的给药方案。
已经出人意料地发现,与连续的每日给药方案相比,本发明的给药方案与降低的肾毒性有关。
具体地,本发明单独或组合地提供以下方面、有利特征和具体实施例,如以下编号的实施例中所列。
实施例1.一种用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐,其中在7天治疗周期的前3天的每一天施用所述TEAD抑制剂或其药学上可接受的盐,并且其中所述治疗包括至少两个治疗周期。
实施例2.一种在有需要的受试者中治疗癌症的方法,其中所述方法包括在7天治疗周期的前3天的每一天向所述受试者施用治疗有效量的TEAD抑制剂或其药学上可接受的盐,并且其中所述治疗包括至少两个治疗周期。
实施例3.一种降低接受TEAD抑制剂或其药学上可接受的盐治疗的受试者的蛋白尿和/或肾毒性的方法,其中所述方法包括在7天治疗周期的前3天的每一天向所述受试者施用治疗有效量的所述TEAD抑制剂或其药学上可接受的盐,并且其中所述治疗包括至少两个治疗周期。
实施例4.根据实施例1所述的用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐,或根据实施例2或实施例3所述的方法,其中所述TEAD抑制剂是YAP/TAZ-TEAD蛋白/蛋白相互作用抑制剂,或其药学上可接受的盐。
实施例5.根据实施例1或实施例4所述的用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐,或根据实施例2至4中任一项所述的方法,其中所述TEAD抑制剂或其盐是4-((2S,4S)-5-氯-6-氟-2-苯基-2-((S)-吡咯烷-2-基)-2,3-二氢苯并呋喃-4-基)-5-氟-6-(2-羟基乙氧基)-N-甲基烟酰胺或其药学上可接受的盐。
实施例6.根据实施例1、4和5中任一项所述的用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐,或根据实施例2至5中任一项所述的方法,其中每个施用日的日剂量是15mg至100mg。
实施例6a.根据实施例1、4和5中任一项所述的用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐,或根据实施例2至5中任一项所述的方法,其中每个施用日的日剂量是15mg至500mg,例如60mg至300mg,例如60mg至240mg。
实施例7.根据实施例6所述的用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐,或根据实施例6所述的方法,其中每个施用日的日剂量是15mg、30mg、45mg、60mg、75mg、90mg或100mg。
实施例8.根据实施例1和4至7中任一项所述的用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐,或根据实施例2至7中任一项所述的方法,其中所述癌症是TEAD依赖性癌症(例如其中所述癌症具有河马途径失调)或者是具有NF2/LATS1/LATS2突变的实体瘤。
实施例9.根据实施例1和4至8中任一项所述的用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐,或根据实施例2至8中任一项所述的方法,其中所述癌症选自乳腺癌、肺癌、卵巢癌、肾癌、子宫癌、结直肠癌、间皮瘤例如恶性胸膜间皮瘤、胰腺癌、前列腺癌、胃癌、食道癌、肝癌、成神经管细胞瘤、头颈癌、肉瘤、上皮样血管内皮瘤、室管膜瘤和骨癌,例如其中所述癌症是间皮瘤,例如其中所述癌症是恶性胸膜间皮瘤。
如附图和实例所示,本发明的给药方案提供降低的肾毒性。
附图说明
在下文中,参照附图详细描述本发明,在附图中:
图1显示了化合物A在MSTO-211H s.c.异种移植大鼠模型中使用每周剂量420mg/kg p.o.遵循四种不同化合物A给药方案之一或媒剂对照的(A)抗肿瘤活性、(B)存活和(C-E)尿肾损伤标志物评估。
图2显示了化合物A在携带(A)MSTO-211H和(B)NCI-H226间皮瘤肿瘤的裸鼠中每日或间歇方案时的比较性抗肿瘤功效和耐受性。值为平均值±SEM;样品量:n=5。*p<0.05,与媒剂对照组相比具有显著抑制作用(单向ANOVA,连同对耐受性数据的Dunnett多重比较检验)。(C)化合物A的尿肾损伤标志物评估,来自MSTO-211H和NCI-H226 s.c.异种移植大鼠模型的两个实验的结果相组合,值是平均值±SEM;样品量:n=4-6。*p<0.05,**p<0.01,***p<0.001,与媒剂对照组相比具有显著抑制作用(单向ANOVA,连同Dunnett多重比较检验)。
具体实施方式
如上所述,开发TEAD抑制剂的目标之一是找到一种确保功效但同时与不良副作用(例如肾毒性)减少相关的给药方案。
因此,本发明提供了用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐,其中在7天治疗周期的前3天的每一天施用TEAD抑制剂或其药学上可接受的盐,并且其中治疗由至少两个治疗周期构成。如实例和附图中所解释的,已发现这在功效方面等同于QD给药,但同时导致存活改善和肾毒性降低,从而导致更大的治疗窗口。
应理解“在7天治疗周期的前3天的每一天施用”是指TEAD抑制剂或其药学上可接受的盐在7天治疗周期的前3天的每一天施用,并且在7天治疗周期的随后4天不施用。
优选地,所述至少两个治疗周期是连续的,即第二治疗周期紧接在第一治疗周期之后。例如,本发明因此包括以下:
第1-3天:每天施用TEAD抑制剂;
第4-7天:不施用TEAD抑制剂;
第8-10天:每天施用TEAD抑制剂;和
第11-14天:不施用TEAD抑制剂。
在此实例中,第1-3天和第8-10天是施用天数。因此,“施用日”是指对患者施用TEAD抑制剂的任何一天。
当存在时,第三(第四等)治疗周期优选地紧接在前一个治疗周期之后。因此,在具有三个治疗周期的实施例中,本发明包括以下:
第1-3天:每天施用TEAD抑制剂;
第4-7天:不施用TEAD抑制剂;
第8-10天:每天施用TEAD抑制剂;
第11-14天:不施用TEAD抑制剂;
第15-17天:每天施用TEAD抑制剂;和
第18-21天:不施用TEAD抑制剂。
在实施例中,存在三个或更多个治疗周期,例如四个或更多治疗周期,例如五个或更多治疗周期,例如六个或更多治疗周期,例如八个或更多治疗周期,例如十个或更多治疗周期。
TEAD抑制剂可以作为游离分子或其药学上可接受的盐存在。优选地,TEAD抑制剂以游离形式存在(即不是盐),并且任选地被溶剂化。
术语“TEAD抑制剂”表示通过时间分辨荧光能量转移(TR-FRET)测定以IC50小于10μM,优选小于1μM,更优选小于0.1μM,甚至更优选小于0.01μM抑制TEAD蛋白的任何化合物。
如本文所用,术语“YAP/TAZ-TEAD PPII”或“YAP/TAZ-TEAD蛋白质-蛋白质相互作用抑制剂”或“YAP/TAZ-TEAD PPI抑制剂”是指能够抑制i)TEAD和ii)YAP和/或TAZ之间相互作用的化合物,例如通过与TEAD结合,从而选择性地破坏TEAD与YAP和/或TAZ的相互作用。在实施例中,通过时间分辨荧光能量转移(TR-FRET)测定,IC50小于10μM,优选小于1μM,更优选小于0.1μM,甚至更优选小于0.01μM。
如本文所用,术语“日剂量”是指在一天24小时内施用给个体的总剂量。
当提及本文中的TEAD抑制剂的剂量时,例如以mg(毫克)表示,它是指游离形式的TEAD抑制剂的(当量)量(即不包括例如盐或共晶伴侣以及任何存在的溶剂)。
如本文所用,术语“盐”或“多种盐”是指本发明缀合物的酸加成盐或碱加成盐。“盐”特别包括“药学上可接受的盐”。术语“药学上可接受的盐”是指保留本发明缀合物的生物有效性和特性,并且通常地不是生物学上或其他方面不希望的盐。在许多情况下,由于氨基和/或羧基基团或与其类似的基团的存在,本发明的缀合物能够形成酸盐和/或碱盐。当在同一分子中存在碱性基团和酸性基团两者时,本发明缀合物还可以形成内盐,例如两性离子型分子。
可以用无机酸和有机酸形成药学上可接受的酸加成盐。
可以衍生出盐的无机酸包括,例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以衍生出盐的有机酸包括例如乙酸、丙酸、乙醇酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、甲苯磺酸、磺基水杨酸等。
可以用无机碱和有机碱形成药学上可接受的碱加成盐。
可以衍生成盐的无机碱包括例如铵盐和元素周期表中I-XII栏的金属。在某些实施例中,盐衍生自钠、钾、铵、钙、镁、铁、银、锌和铜;特别合适的盐包括铵盐、钾盐、钠盐、钙盐和镁盐。
可以衍生出盐的有机碱包括例如伯胺、仲胺和叔胺,经取代的胺(包括天然存在的经取代的胺),环胺,碱性离子交换树脂等。某些有机胺包括异丙胺、苄星、胆碱盐、二乙醇胺、二乙胺、赖氨酸、葡甲胺、哌嗪和氨丁三醇。
在另一个方面,本发明提供了呈以下形式的本发明的缀合物:乙酸盐、抗坏血酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、癸酸盐、氯化物/盐酸盐、氯茶碱盐(chlortheophyllonate)、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、谷氨酸盐、戊二酸盐、乙醇酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、十二烷基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、粘酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八烷酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖醛酸盐、丙酸盐、癸二酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐、三苯乙酸盐(trifenatate)、三氟乙酸盐或昔萘酸盐形式。
优选地,药物施用是通过口服递送,即口服施用,经口服(p.o.)进行。
将药物优选地以口服剂型的形式、更优选地以固体口服剂型(例如胶囊或片剂)的形式提供。
优选地,将药物与一杯水一起服用但不咀嚼胶囊或片剂。
如果将患者分配为需要服用多个胶囊/片剂的剂量水平,则应在尽可能短的时间间隔内(例如5分钟内)连续服用胶囊/片剂。
优选地,药物在每个施用日大致相同的时间施用。优选地,药物在每个施用日每天施用一次。更优选地,将药物在早上施用。
优选地,将药物在空腹状态下,即餐前至少1小时或餐后至少2小时施用。
如本文所用,术语“药物”是指TEAD抑制剂或其药学上可接受的盐。
TEAD抑制剂可以药物组合物的形式递送至受试者。
使用的口服剂型例如是片剂、胶囊、小袋、微丸、颗粒等。除了Mdm2i之外,口服剂型还可以包含用于药物的其他常规载剂或赋形剂。此类载剂或赋形剂的实例包括但不限于崩解剂、粘结剂、润滑剂、助流剂、稳定剂和填充剂、稀释剂、着色剂、风味剂和防腐剂。本领域普通技术人员可以通过常规实验且无需任何不当负担关于剂型的特定所需特性来选择前述载体中的一种或多种。所使用的每种载体的量可以在本领域的常规范围内变化。以下参考文献披露了用于配制口服剂型的技术和赋形剂。参见The Handbook of PharmaceuticalExcipients[药用辅料手册],第4版,Rowe等人编辑,American PharmaceuticalsAssociation[美国药师协会](2003);以及Remington:the Science and Practice ofPharmacy[雷明顿:药学的科学与实践],第20版,Gennaro编辑,Lippincott Williams&Wilkins[威尔金斯出版公司](2003)。例如通过混合、制粒、压制、压实、填充、筛分、混合和/或压片来制备剂型。
如本文所用,术语“受试者”是指动物。优选地,所述动物是哺乳动物。受试者指例如灵长类动物(例如人)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。在一个优选的实施例中,所述受试者是人。
如本文所用,术语“TEAD依赖性癌症”是指已知其中TEAD(即TEAD1、TEAD2、TEAD3和/或TEAD4)或其突变体或变体是相关的任何癌症,例如在其中河马通路是遗传改变的癌症中。
如本文所用,术语“抑制(inhibit、inhibition或inhibiting)”是指减少或抑制给定的病症、症状或障碍、或疾病,或在生物活性或过程的基线活性方面的显著降低。
如本文所用,术语任何疾病或障碍的“治疗(treat、treating或treatment)”是指减轻或改善疾病或障碍(即,减慢或阻止疾病或其临床症状中的至少一种的发展);或者减轻或改善与所述疾病或障碍相关联的至少一种物理参数或生物标志物,包括针对患者可能无法辨别的那些物理参数或生物标志物。
如本文所使用的,术语任何疾病或障碍的“预防”是指疾病或障碍的预防性治疗;或延迟疾病或障碍的发作或进展。
如本文所用,如果受试者将在生物学上、在医学上或在生活质量上从治疗中获益,则这样的受试者是“需要”这种治疗的。
如本文所用,术语“降低肾毒性”尤其包括减少尿肾损伤生物标志物NGAL和/或KIM-1。
本披露化合物的术语“治疗有效量”是指将引起受试者的生物学或医学反应(例如酶或蛋白质活性的降低或抑制)或改善症状,减轻病症,减慢或延迟疾病进展,或预防疾病等的本披露化合物的量。在一个非限制性实施例中,术语“治疗有效量”是指本披露的化合物的量,当施用于受试者时,其有效地(1)至少部分地缓解、抑制、预防和/或改善与(i)YAP/TAZ-TEAD复合物过度活化(ii)由YAP过表达和/或YAP扩增介导或(iii)与YAP活性相关,或(iv)以YAP的活性(正常或异常)为特征相关的病症、障碍或疾病;或(2)减少或抑制YAP和/或TAZ与TEAD的相互作用。在另一个非限制性实施例中,术语“治疗有效量”是指本披露化合物的如下量:当施用至细胞、或组织、或非细胞生物材料、或介质时,该量有效地至少部分地降低或抑制YAP和/或TAZ与TEAD的相互作用。
如本文所使用的,术语“一个/种”、“该/所述”以及在本发明的上下文中使用的类似术语(尤其是在权利要求的上下文中)应被解释为涵盖单数和复数两者,除非本文另外说明或与上下文明显矛盾。
术语“包含”涵盖“包括”以及“由……组成”;例如,包含X的组合物可以仅由X组成,或者可以包括另外的,例如X和Y。
在实施例中,TEAD抑制剂是YAP/TAZ-TEAD蛋白/蛋白相互作用抑制剂,或其药学上可接受的盐。YAP/TAZ-TEAD蛋白质/蛋白质相互作用抑制剂通过破坏YAP1/WWTR1和所有四种TEAD同种型之间的蛋白质-蛋白质相互作用发挥作用,从而消除调节参与增殖和存活的关键基因的复合物的转录活性,如以下中所述:
Dupont S,Morsut L,Aragona M,Enzo E,Giulitti S,Cordenonsi M,ZanconatoF,Le Digabel J,Forcato M,Bicciato S,等人(2011).Role of YAP/TAZ inmechanotransduction[YAP/TAZ在机械转导中的作用].Nature[自然]474,179-183,
Lai D,Ho KC,Hao Y,和Yang X(2011).Taxol resistance in breast cancercells is mediated by the hippo pathway component TAZ and its downstreamtranscriptional targets Cyr61 and CTGF[乳腺癌细胞中的紫杉醇抗性由河马通路组分TAZ及其下游转录靶标Cyr61和CTGF介导].Cancer Res.[癌症研究]71,2728-2738,和
Zhao B,Ye X,Yu J,Li L,Li W,Li S,等人(2008)TEAD mediates YAP-dependentgene induction and growth control[TEAD介导YAP依赖性基因诱导和生长控制].GenesDev.[基因与发育];22(14):1962-71。
在实施例中,TEAD抑制剂是4-((2S,4S)-5-氯-6-氟-2-苯基-2-((S)-吡咯烷-2-基)-2,3-二氢苯并呋喃-4-基)-5-氟-6-(2-羟基乙氧基)-N-甲基烟酰胺或其药学上可接受的盐。
在实施例中,TEAD抑制剂(例如4-((2S,4S)-5-氯-6-氟-2-苯基-2-((S)-吡咯烷-2-基)-2,3-二氢苯并呋喃-4-基)-5-氟-6-(2-羟基乙氧基)-N-甲基烟酰胺)的日剂量为15mg至100mg,例如从15mg到75mg,例如15mg、30mg、45mg、60mg、75mg、90mg或100mg(以游离药物表示)。
在一个替代实施例中,TEAD抑制剂是该抑制剂披露于WO 2022/159986和WO 2020/243415。
在实施例中,癌症是TEAD依赖性癌症,或选自以下的癌症:乳腺癌(例如三阴性乳腺癌)、肺癌、卵巢癌、肾癌、子宫癌、结直肠癌、恶性胸膜间皮瘤、胰腺癌、前列腺癌、胃癌、食道癌、肝癌、成神经管细胞瘤、头颈癌、肉瘤、上皮样血管内皮瘤、室管膜瘤和骨癌。
在实施例中,TEAD抑制剂与另外的药学活性药物(组合伴侣)一起施用。如果存在组合伴侣,则优选给TEAD抑制剂提供用于组合使用的说明。组合中的化合物可以完全分开施用。化合物可以是完全独立的药物剂型。组合伴侣可以是彼此独立销售的药物组合物,并且在包装设备中仅提供它们组合使用的说明,例如传单等,或在例如提供给医生和医务人员(例如口头交流、书面交流等)的其他信息中,用于针对联合活性的同时或顺序使用。TEAD抑制剂和其他药物活性药物可以作为活性成分的固定或非固定组合提供。术语“固定组合”意指活性成分以单个实体或剂量的形式同时都施用于患者。换句话说:活性成分存在于一种剂型中,例如在一个片剂或一个胶囊中。术语“非固定组合”意指将活性成分以不同的实体同时、并行或无特定时间限制地施用于患者,其中此类施用在患者体内提供了这两种化合物的治疗有效的水平。
化合物A(4-((2S,4S)-5-氯-6-氟-2-苯基-2-((S)-吡咯烷-2-基)-2,3-二氢苯并呋喃-4-基)-5-氟-6-(2-羟基乙氧基)-N-甲基烟酰胺)的合成最初描述于PCT/IB2021/052136(WO 2021/186324),其内容通过引用并入。
实例
以下实例说明(但不旨在限制)本发明:
实例1
化合物A在MSTO-211H s.c.异种移植大鼠模型中的抗肿瘤活性、存活和尿肾损伤标志物评估
用化合物A或媒剂对照治疗携带MSTO-211H皮下异种移植物的雌性裸鼠总共4周的时间。用化合物A治疗的所有大鼠口服给予每周总剂量420mg/kg化合物A,尽管是以四个不同的队列:
i)60mg/kg QD
ii)84mg/kg,用5天/停2天
iii)120mg/kg,用1天/停1天
iv)140mg/kg,用3天/停4天
从大鼠样品中收集与抗肿瘤活性(图1A)、存活(图1B)和尿肾损伤标志物评估相关的数据,即NGAL(图1C)、KIM-1(图1D)和白蛋白(图1E)。
A)化合物A的抗肿瘤活性:当大鼠免疫系统从亚致死辐射中恢复时,媒剂肿瘤中的一些会自发消退。值为平均值±SEM;样品量,(n=3-4只大鼠/组)。化合物A给药方案在减少肿瘤体积方面相似地有效。
B)动物存活*:p<0.05,与媒剂对照组相比有显著抑制作用(对数秩Mantel Cox检验)。化合物A的毒性被证明是时间表依赖性的,这一发现表明,当以60mg/kg QD方案按给予时,每周剂量420mg/kg/周是致命的,但当在用3天/停4天的方案中在长时间中断给药的情况下施用相同的每周剂量时,所有大鼠都存活,并且NGAL和KIM-1肾尿生物标志物水平较低,表明肾小管损伤较少。
尿液分析物。C)NGAL、D)KIM-1和E)白蛋白从在指定日期收集的大鼠样品中进行定量。样品量n=1-4/组,表示平均值±SEM。定量上限(LOQ)用于尿白蛋白水平。在60mg/kd QD队列中观察到尿肾标志物升高,这导致动物在连续治疗14至18天后被处死。对NGAL、KIM-1和白蛋白的尿液定量分析表明,肾小管损伤和蛋白丢失性肾病在裸鼠中构成剂量限制性毒性。
实例2
在携带MSTO-211H和NCI-H226间皮瘤肿瘤的裸鼠中每日或间歇方案情况下化合物A的比较性抗肿瘤活性。
在MSTO-211H和NCI-H226大鼠模型中,使用105或210mg/kg的每周剂量进行QD(平直线)或用3天/停4天间歇方案(虚线)情况下化合物A口服施用3或4周治疗的功效研究。携带MSTO-211H或NCI-H226 s.c.异种移植物的雌性裸鼠用媒剂对照或化合物A治疗。用化合物A治疗的大鼠被分成四个独立队列:
i)15mg/kg qd
ii)35mg/kg,用3天/停4天
iii)30mg/kg qd;和
iv)70mg/kg,用3天/停4天
收集了功效(图2A、B,左侧)和耐受性(图2A、B,右侧)数据。与QD给药相比,间歇给药的使用对MSTO-211H或NCI-H226间皮瘤肿瘤模型中的抗肿瘤功效没有影响。210mg/kg的每周总剂量是非致命的,并且在所有方案情况下(包括30mg/kg QD(与实例1中测试的60mg/kd QD给药方案不同))都具有良好的耐受性。然而,如图2C所示,与30mg/kg QD方案时处于或接近基线水平相比,70mg/kg用3天/停4天间歇给药方案仍然减少了蛋白尿和尿肾损伤标志物NGAL和KIM-1,表明即使在耐受性给药水平下,与每日给药相比,用3天/停4天方案可能会降低对肾脏的毒性。
实例3
将进行一项研究,表征化合物A在患有河马途径失调的间皮瘤和其他实体瘤患者中的安全性和耐受性,以评估化合物A的安全性、耐受性、PK和PD。在该研究中,将在7天治疗周期的前3天的每一天施用化合物A,并且治疗将包括至少两个治疗周期。
Claims (10)
1.一种用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐,其中在7天治疗周期的前3天的每一天施用所述TEAD抑制剂或其药学上可接受的盐,并且其中所述治疗包括至少两个治疗周期。
2.一种在有需要的受试者中治疗癌症的方法,其中所述方法包括在7天治疗周期的前3天的每一天向所述受试者施用治疗有效量的TEAD抑制剂或其药学上可接受的盐,并且其中所述治疗包括至少两个治疗周期。
3.一种降低接受TEAD抑制剂或其药学上可接受的盐治疗的受试者的蛋白尿和/或肾毒性的方法,其中所述方法包括在7天治疗周期的前3天的每一天向所述受试者施用治疗有效量的所述TEAD抑制剂或其药学上可接受的盐,并且其中所述治疗包括至少两个治疗周期。
4.根据权利要求1所述的用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐、或根据权利要求2或权利要求3所述的方法,其中所述TEAD抑制剂是YAP/TAZ-TEAD蛋白/蛋白相互作用抑制剂,或其药学上可接受的盐。
5.根据权利要求1或权利要求4所述的用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐、或根据权利要求2至4中任一项所述的方法,其中所述TEAD抑制剂或其盐是4-((2S,4S)-5-氯-6-氟-2-苯基-2-((S)-吡咯烷-2-基)-2,3-二氢苯并呋喃-4-基)-5-氟-6-(2-羟基乙氧基)-N-甲基烟酰胺或其药学上可接受的盐。
6.根据权利要求1、4和5中任一项所述的用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐、或根据权利要求2至5中任一项所述的方法,其中每个施用日的日剂量是15mg至500mg。
7.根据权利要求6所述的用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐、或根据权利要求6所述的方法,其中每个施用日的日剂量是15mg至100mg。
8.根据权利要求6所述的用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐、或根据权利要求6所述的方法,其中每个施用日的日剂量是15mg、30mg、45mg、60mg、75mg、90mg或100mg。
9.根据权利要求1和4至8中任一项所述的用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐、或根据权利要求2至8中任一项所述的方法,其中所述癌症是TEAD依赖性癌症或者是具有NF2/LATS1/LATS2突变的实体瘤。
10.根据权利要求1和4至9中任一项所述的用于在癌症的治疗中使用的TEAD抑制剂或其药学上可接受的盐、或根据权利要求2至9中任一项所述的方法,其中所述癌症选自乳腺癌、肺癌、卵巢癌、肾癌、子宫癌、结直肠癌、间皮瘤例如恶性胸膜间皮瘤、胰腺癌、前列腺癌、胃癌、食道癌、肝癌、成神经管细胞瘤、头颈癌、肉瘤、上皮样血管内皮瘤、室管膜瘤和骨癌,例如其中所述癌症是间皮瘤,例如其中所述癌症是恶性胸膜间皮瘤。
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