New paradigms for Hsp90 inhibition

90 kDa热休克蛋白(Hsp90)负责大约200个客户蛋白的成熟 底物，其中大部分与信号级联有关，调节细胞生长和 扩散。因此，抑制Hsp90为癌症的治疗提供了一种新的途径。 通过抑制依赖于Hsp90的蛋白质折叠可以破坏许多信号级联反应 进程。在这一应用中，我们建议开发hsp90亚型的选择性抑制剂，grp94，hsp90α， 和HSP90β，使用结构引导的方法。此外，我们还将对这些项目进行并排评估 为了验证我们的方法，在体外和体内都有抗PAN抑制剂的化合物。这些方法加在一起， 这将为选择性抑制Hsp90提供新的途径，并将为抗癌提供新的范式 药物开发。

The 90 kDa heat shock proteins (Hsp90) are responsible for the maturation of approximately 200 client protein substrates, most of which are associated with signaling cascades that regulate cellular growth and proliferation. Therefore, Hsp90 inhibition provides a novel approach toward the treatment of cancer as numerous signaling cascades can be derailed through inhibition of the Hsp90-dependent protein folding process. In this application, we propose to develop selective inhibitors of the Hsp90 Isoforms, Grp94, Hsp90α, and Hsp90β, using a structure-guided approach. In addition, we will perform side by side evaluation of these compounds against pan-inhibitors both in vitro and in vivo to validate our approach. Together, these methods will provide a new approach for selective inhibition of Hsp90 and will provide a new paradigm for anti-cancer drug development.