Selective and dual-acting Hsp90 and TRAP1 inhibitors

描述(申请人提供)：尽管现有的治疗癌症的药物已经显示出有希望的结果，但癌细胞固有的遗传可塑性继续破坏这些治疗的有效性。解决这一问题的可能解决方案之一是攻击帮助癌细胞和肿瘤在压力下成功适应的基本机制。热休克蛋白90(Hsp90)是一种主要的分子伴侣蛋白，通过协助蛋白质的一般折叠和防止非特异性聚集来帮助其客户蛋白克服这种应激。因此，通过直接靶向Hsp90，人们可以关闭与癌症相关的活动，同时绕过多个信号通路。临床研究中细胞质HSP90的抑制剂表明，虽然每周给药一次是可以耐受的，但每天给药几天后就会出现肝毒性。如果这些现有化合物的剂量限制毒性是与结构有关的，那么就需要更好的化合物，这些化合物的结构多样化，可以克服所观察到的毒性。最近的研究表明，线粒体中存在一种与胞浆Hsp90密切相关的类似物，称为肿瘤坏死因子受体相关蛋白1(TRAP1)。已有报道表明TRAP1在保护细胞免受氧化应激引起的线粒体诱导的细胞凋亡中起作用。以新型的TRAP1 ATPase拮抗剂为基础的抑制TRAP1的策略，可诱导线粒体功能突然崩溃和细胞凋亡，从而提高抗癌治疗的疗效。因此，从这个角度来看，同时靶向TRAP1/Hsp90伴侣蛋白可能代表了一种新的双管齐下的分子机制，以克服现有癌症治疗方法的局限性，包括耐药性。因此，在目前的方案中，我们想要采用组合的方法来选择性地鉴定Hsp90和TRAP1的亚细胞特异性抑制剂和/或同时靶向胞浆Hsp90和线粒体TRAP1的N-末端结构域的双重活性的抑制剂。我们将使用我们专有的基于差异片段的筛选结合基于“拨入拨出”结构的方法来产生具有新作用机制的有效抗癌药物。鉴于Hsp90和TRAP1(图3)N-末端结构域之间的高度序列同源性(~70%)，我们希望使用这种方法来发现选择性和双活性抑制剂，并将它们开发成有效的抗癌药物。 公共卫生相关性：这项建议中使用的基于差异片段的筛选技术与生化和药物化学方法相结合，将加快发现和开发针对两个关键蛋白Hsp90和TRAP1的具有新作用机制的新型、安全和有效的抗癌和神经退行性药物候选药物。

DESCRIPTION (provided by applicant): Although the existing agents for treating cancer have shown promising results, the inherent genetic plasticity of the cancer cells continues to undermine the efficacy of these treatments. One of the possible solutions to address this problem is to attack the basic machinery that helps the cancer cells and tumors to adapt successfully under stress. Heat shock protein 90 (Hsp90) is the major molecular chaperone that helps its client proteins to overcome this stress by assisting general protein folding and preventing non-specific aggregation. By directly targeting Hsp90 one can, therefore, shut down the activities associated with cancer, at the same time stepping around the multiple signaling pathways. Inhibitors of the cytosolic Hsp90 in clinical studies have revealed that while once-a-week administration is tolerated, hepato-toxicity develops after several days of daily administration. If dose-limiting toxicity of these existing compounds is structure-related, there is a need for better compounds that are structurally diverse and can overcome the observed toxicity. Recent studies have shown that a close analog of cytosolic Hsp90 is present in the mitochondria, known as TNF Receptor-Associated Protein 1 (TRAP1). Reports have implicated TRAP1 in protecting cells from mitochondria-mediated apoptosis by oxidative stress. Strategies aimed at inhibiting TRAP1, based on novel TRAP1 ATPase antagonists, induce sudden collapse of mitochondrion function and apoptosis, thereby improving the efficacy of anticancer treatments. Therefore, from this perspective, targeting the TRAP1/Hsp90 chaperones together may represent a novel double-pronged molecular mechanism to overcome the limitations of the existing cancer therapies including drug resistance. Therefore, in the current proposal, we would like to take a combinatorial approach to selectively identify inhibitors of Hsp90 and TRAP1 that are sub-cellular specific and/or inhibitors with dual activity simultaneously targeting the N-terminal domains of cytosolic Hsp90 and mitochondria TRAP1. We will use our proprietary differential fragment-based screening combined with "dial in-dial out" structure based approach to generate effective anticancer drugs with a novel mechanism of action. Given the high degree of sequence homology (~70%) between the N-terminal domains of Hsp90 and TRAP1 (Fig. 3), we would like to employ this approach to discover selective and dual- active inhibitors and develop them into effective anticancer drugs. PUBLIC HEALTH RELEVANCE: The differential fragment-based screening technology combined with biochemical and medicinal chemistry approaches being used in this proposal will expedite the discovery and development of novel, safe and potent anti-cancer and neurodegenerative drug candidates with novel mechanism of action targeting two key proteins Hsp90 and TRAP1.