Selective and dual-acting Hsp90 and TRAP1 inhibitors

选择性双作用 Hsp90 和 TRAP1 抑制剂

• 批准号: 8001042
• 负责人: Sridhar G Prasad
• 金额: $ 27.91万
• 依托单位: PLEX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2012-09-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8001042
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; ATP phosphohydrolase; Active Sites; Address; Adverse effects; Affinity; Alabama; Antineoplastic Agents; Apoptosis; Apoptotic; Binding; Biochemical; Biological Assay; Biological Models; Biology; Cancer Cell Growth; Cell Culture Techniques; Cells; Central Nervous System Degenerative Diseases; Cessation of life; Client; Clinical Research; Collaborations; Crystallization; Crystallography; Data; Degenerative Disorder; Development; Dose-Limiting; Drug Design; Drug Formulations; Drug Kinetics; Drug resistance; Enzymes; Evaluation; Evolution; Figs - dietary; Genetic; Growth; HSP 90 inhibition; Heat-Shock Proteins 90; In Vitro; Lead; Length; Libraries; Malignant Neoplasms; Mediating; Methods; Mitochondria; Molecular; Molecular Chaperones; Mutate; N-terminal; Nerve Degeneration; Oxidative Stress; Pharmaceutical Chemistry; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Play; Pre-Clinical Model; Property; Proteins; Recombinants; Reporting; Research; Research Design; Role; Screening procedure; Sequence Homology; Signal Pathway; Signaling Protein; Solubility; Solutions; Staging; Stress; Structural Biologist; Structure; TNF receptor-associated factor 1; Technology; Testing; Time; Toxic effect; Treatment Efficacy; Universities; analog; anticancer treatment; base; cancer cell; cancer therapy; combinatorial; design; drug candidate; expression cloning; improved; inhibitor/antagonist; lead series; neoplastic cell; novel; prevent; programs; protein folding; public health relevance; small molecule; tool; tumor

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.

描述（由申请人提供）：虽然现有的治疗癌症的药物已经显示出良好的效果，但癌细胞固有的遗传可塑性继续破坏这些治疗的效果。解决这个问题的一个可能的解决方案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，通过协助一般蛋白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，可以关闭与癌症相关的活动，同时绕过多种信号通路。临床研究表明，虽然每周一次给药是耐受的，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性毒性与结构有关，则需要更好的结构多样化并能够克服所观察到的毒性的化合物。最近的研究表明，线粒体中存在一种与细胞质Hsp90相似的类似物，称为TNF受体相关蛋白1 （TRAP1）。有报道暗示TRAP1在氧化应激下保护细胞免受线粒体介导的凋亡。以新型TRAP1 atp酶拮抗剂为基础，旨在抑制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效果。因此，从这个角度来看，共同靶向TRAP1/Hsp90伴侣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。因此，在目前的建议中，我们希望采用组合方法选择性地鉴定亚细胞特异性的Hsp90和TRAP1抑制剂和/或同时针对细胞质Hsp90和线粒体TRAP1的n端结构域具有双重活性的抑制剂。我们将使用我们专有的基于差异片段的筛选结合“拨入拨出”结构的方法来产生具有新型作用机制的有效抗癌药物。鉴于Hsp90的n端结构域与TRAP1之间的序列高度同源（~70%）（图3），我们希望利用这种方法发现选择性和双活性抑制剂，并将其开发成有效的抗癌药物。