Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott Hall 4048, Lawrence, KS, 66045, USA.
Department of Chemistry and Biochemistry, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN, 46556, USA.
Nat Commun. 2018 Jan 30;9(1):425. doi: 10.1038/s41467-017-02013-1.
The 90 kDa heat shock protein (Hsp90) is a molecular chaperone responsible for folding proteins that 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, 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 that may limit some of the detriments. Described herein is a structure-based approach to design isoform-selective inhibitors of Hsp90β, which induces the degradation of select Hsp90 clients without concomitant induction of Hsp90 levels. Together, these initial studies support the development of Hsp90β-selective inhibitors as a method to overcome the detriments associated with pan-inhibition.
90kDa 热休克蛋白（Hsp90）是一种分子伴侣，负责折叠与癌症进展直接相关的蛋白质。因此，抑制 Hsp90 蛋白折叠机制会导致对众多致癌途径的组合攻击。已有 17 种 Hsp90 的小分子抑制剂进入临床试验，它们都与 Hsp90 N 端结合，对所有四种 Hsp90 同工型均具有泛抑制活性。Hsp90 的泛抑制似乎是有害的，因为已经报道了与诱导生存热休克反应相关的毒性。开发 Hsp90 同工型选择性抑制剂是治疗癌症的一种替代方法，它可能会限制一些副作用。本文描述了一种基于结构的方法来设计 Hsp90β 的同工型选择性抑制剂，它诱导选择性 Hsp90 客户的降解，而不会同时诱导 Hsp90 水平。这些初步研究共同支持开发 Hsp90β 选择性抑制剂作为克服泛抑制相关副作用的一种方法。
