Engineering the Next Generation of Safer Hsp90 Inhibitors

总结： 热休克蛋白90是一种分子伴侣，负责构象成熟， 与癌症的所有十个标志相关的信号蛋白，使其成为一个有前途的 作为治疗癌症的靶点，多个信号传导节点可以同时 由于Hsp 90抑制而脱轨。此外，研究人员已经表明， Hsp 90抑制剂以高差异选择性在肿瘤中积累，使Hsp 90成为一种免疫抑制剂。 是癌症治疗的热门目标不幸的是，17个小分子的临床试验 抑制剂导致了多项措施，大大挫伤了人们的热情， 对于Hsp 90抑制剂，由于在临床中观察到Hsp 90水平增加， 剂量递增的毒性以及其他问题。因此，Hsp 90仍然是一种 癌症化疗药物开发的理想目标，但新方法 需要不诱导Hsp 90水平的蛋白质机器来抑制。通过 大量开创性的研究表明，Hsp 90 C-末端的抑制剂 结构域可以将Hsp 90抑制与Hsp 90水平的诱导分离，因此， 在本申请中，我们提出优化这些化合物并进行许多 对最好的分子进行IND前研究，努力将其推向临床 评价

Summary: Hsp90 is a molecular chaperone that is responsible for the conformational maturation of signaling proteins associated with all ten hallmarks of cancer, making it a promising target for the treatment of cancer, as multiple signaling nodes can be simultaneously derailed as a consequence of Hsp90 inhibition. Moreover, researchers have shown that Hsp90 inhibitors accumulate in tumors with high differential selectivity, making Hsp90 a highly sought after target for cancer. Unfortunately, clinical trials with 17 small molecule inhibitors have led to multiple detriments that have significantly dampened enthusiasm for Hsp90 inhibitors, as increased levels of Hsp90 were observed in the clinic, which led to dose-escalating toxicities among other concerns. Consequently, Hsp90 remains a desirable target for the development of cancer chemotherapeutics, but new approaches to inhibit the protein machinery are needed that do not induce Hsp90 levels. Through a number of seminal studies, it has been shown that inhibitors of the Hsp90 C-terminal domain can segregate Hsp90 inhibition from induction of Hsp90 levels, and therefore, we propose in this application to optimize these compounds and to perform a number of pre-IND studies on the best molecules in an effort to move them toward clinical evaluation.