Development of Hsp90 beta-selective inhibitors as safer anti-cancer agents

摘要 90kD热休克蛋白(Hsp90)是负责SELECT折叠的分子伴侣 蛋白质，其中许多与癌症进展直接相关。因此，对Hsp90的抑制 蛋白质折叠机制导致对许多致癌途径的组合攻击。十七个小的 Hsp90的分子抑制剂已进入治疗癌症的临床试验，所有这些药物都与Hsp90结合 N-末端，表现出对所有四种Hsp90亚型的泛抑制活性。热休克蛋白90出现泛抑制作用 是有害的，因为有报道称，在诱导有利于生存的热休克反应的同时，还有毒性反应。 Hsp90异构体选择性抑制剂的开发代表了一种替代方法 治疗癌症，并可能减少用PAN-Hsp90抑制观察到的副作用。此应用程序 提出了一类新型的诱导SELECT降解的热休克蛋白90β选择性抑制剂的优化 HSP90客户端，无需同时诱导HSP90水平。涉及热休克蛋白90β-选择性的初步工作 圣母大学的化合物已经证实，抑制热休克蛋白90β提供了一种有针对性的、更安全的 治疗癌症的方法。在这个第一阶段，PrevAllants(d/b/a Grannus Treeutics)将 用合理的结构优化新型β选择性抑制剂的疗效和类药物性能. 基于药物设计的方法来获得先导化合物。目标1.优化电流引线HSP90-β-选择性 通过合成合理设计的新类似物来提高亲和力、药代动力学特性 以及已发现的热休克蛋白90β选择性抑制剂系列的代谢稳定性。工作假说是 官能团的引入将增加我们目前先导化合物的药物相似性。目标2.评估 在AIM 1中利用药代动力学分析和体外细胞研究开发的HSP90HSP90β选择性抑制剂， 以及体内研究，以帮助识别候选药物。根据该团队的初步细胞 涉及多个癌细胞系的研究表明，对Hsp90β依赖性增加的癌症 这些已识别的癌症的动物模型将得到治疗。在完成拟议的工作后， Grannus Treateutics将识别出具有改进的类药物特性的先导化合物，以进入 研究性新药(IND)-使研究成为可能。第二阶段的结果将导致IND申请和 随后启动临床试验，以治疗仍存在未得到满足的医疗需求的已确定癌症。 好了！

Abstract The 90 kD heat shock proteins (Hsp90) are molecular chaperones that are responsible for the folding of select proteins, many of which are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. Seventeen small molecule inhibitors of Hsp90 have entered clinical trials for the treatment of cancer, all of which bind the Hsp90 N-terminus and exhibit pan-inhibitory activity against all four Hsp90 isoforms. Pan-Inhibition of Hsp90 appears to be detrimental as toxicities have been reported alongside induction of the pro-survival heat shock response. The development of Hsp90 isoform-selective inhibitors represents an alternative approach towards the treatment of cancer and may reduce side effects observed with pan-Hsp90 inhibition. This application proposes optimization of a novel class of Hsp90β-selective inhibitors that induces the degradation of select Hsp90 clients without simultaneous induction of Hsp90 levels. Preliminary work involving Hsp90β-selective compounds at University of Notre Dame has established that Hsp90β inhibition offers a targeted and safer therapeutic approach for the treatment of cancer. In this Phase I, PrevAllergy (d/b/a Grannus Therapeutics) will optimize the efficacy and drug like properties of the novel Hsp90β-selective inhibitor using a rational, structure- based drug design approach to obtain a lead compound. Aim 1. Optimize the current lead Hsp90β-selective compounds by synthesizing rationally designed new analogs to improve affinity, pharmacokinetic properties and metabolic stability of the discovered series of Hsp90β-selective inhibitors. The working hypothesis is that introduction of functional groups will increase drug-likeness of our current lead compounds. Aim 2. Evaluate Hsp90β-selective inhibitors developed in Aim 1 utilizing pharmacokinetic assays and in vitro cellular studies, and in vivo studies to assist in the identification of a drug candidate. Based on the team's preliminary cellular studies involving multiple cancer cell lines, cancers with increased dependency upon Hsp90β have been identified, animal models of these identified cancer will be treated. Upon completion of the proposed work, Grannus Therapeutics will have identified lead compounds with improved drug-like properties to progress into Investigational New Drug (IND)-enabling studies. The result from Phase II will lead to an IND application and subsequent initiation of clinical trials to treat the identified cancers that still represent an unmet medical need. !