HSP90 Inhibitors

描述（由申请人提供）：90 kDa热休克蛋白（Hsp 90）负责约200种客户蛋白底物的成熟，其中大多数与调节细胞生长和增殖的信号级联相关。因此，Hsp 90抑制提供了一种治疗癌症的新方法，因为许多信号级联可以通过抑制Hsp 90依赖性蛋白质折叠过程而脱轨。有四种Hsp 90亚型。然而，选择性抑制这些中的每一个的能力尚未实现。通过合作研究，我们建议通过合理设计的类似物开发Hsp 90亚型的选择性抑制剂，这些类似物结合到N-末端ATP结合位点，选择性地破坏Hsp 90/共分子伴侣相互作用，并通过修饰天然产物格尔德霉素。这样的方法可能提供表现出更大的选择性、降低的毒性并鉴定异构体依赖性客户蛋白底物的化合物。这些数据的最终结果将提供一个平台，在此平台上可以进一步寻求亚型选择性抑制剂，用于开发新的癌症化疗药物。 公共卫生相关性：显示出最小毒性的癌症化疗药物的开发代表了药物化学/药物设计中的新兴范例。利用本申请中描述的技术，将合理地开发Hsp 90蛋白折叠过程的抑制剂，目的是增加选择性和最小化毒性，希望能够开发更有效的化合物用于治疗癌症。

DESCRIPTION (provided by applicant): 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. There are four Hsp90 isoforms. However, the ability to selectively inhibit each of these has not been realized. Through collaborative studies, we propose to develop selective inhibitors of Hsp90 isoforms through rationally designed analogues that bind to the N-terminal ATP-binding site, that selectively disrupt Hsp90/co- chaperone interactions, and through modification of the natural product, geldanamycin. Such approaches are likely to afford compounds that exhibit greater selectivity, reduced toxicity, and identify isoform-dependent client protein substrates. Culmination of such data will provide a platform on which further isoform-selective inhibitors can be pursued for the development of new cancer chemotherapeutics. PUBLIC HEALTH RELEVANCE: The development of cancer chemotherapeutics that exhibit minimal toxicity represents an emerging paradigm in medicinal chemistry/drug design. Utilizing the techniques described in this application, inhibitors of the Hsp90 protein folding process will be rationally developed with the aim of increasing selectivity and minimizing toxicity in the hopes that more efficacious compounds can be developed for the treatment of cancer.