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The Development of Hsp90β-Selective Inhibitors to Overcome Detriments Associated with pan-Hsp90 Inhibition
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-01-11 , DOI: 10.1021/acs.jmedchem.0c01700 Sanket J Mishra 1 , Weiya Liu 2 , Kristin Beebe 3 , Monimoy Banerjee 1 , Caitlin N Kent 1 , Vitumbiko Munthali 1 , John Koren 1 , John A Taylor 2 , Leonard M Neckers 3 , Jeffrey Holzbeierlein 2 , Brian S J Blagg 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-01-11 , DOI: 10.1021/acs.jmedchem.0c01700 Sanket J Mishra 1 , Weiya Liu 2 , Kristin Beebe 3 , Monimoy Banerjee 1 , Caitlin N Kent 1 , Vitumbiko Munthali 1 , John Koren 1 , John A Taylor 2 , Leonard M Neckers 3 , Jeffrey Holzbeierlein 2 , Brian S J Blagg 1
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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, which may lead to adverse effects. The development of Hsp90 isoform-selective inhibitors represents an alternative approach toward the treatment of cancer and may limit some of these detriments. Described herein, is a structure-based approach to develop 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 for overcoming the detriments associated with pan-inhibition.
中文翻译：
开发 Hsp90β-选择性抑制剂以克服与泛 Hsp90 抑制相关的损害
90 kD 热休克蛋白 (Hsp90) 是负责选择蛋白质折叠的分子伴侣，其中许多与癌症进展直接相关。因此，Hsp90 蛋白折叠机制的抑制导致对许多致癌途径的组合攻击。17种Hsp90小分子抑制剂已进入治疗癌症的临床试验，均与Hsp90 N端结合并表现出泛-对所有四种 Hsp90 同种型的抑制活性，这可能导致不良反应。Hsp90 异构体选择性抑制剂的开发代表了一种治疗癌症的替代方法，并可能限制其中一些危害。本文所描述的是一种基于结构的方法来开发 Hsp90β 的异构体选择性抑制剂，其诱导选定的 Hsp90 客户的降解，而不会同时诱导 Hsp90 水平。总之，这些初步研究支持开发 Hsp90β 选择性抑制剂作为克服与泛抑制相关的损害的方法。
更新日期：2021-02-11
中文翻译：
开发 Hsp90β-选择性抑制剂以克服与泛 Hsp90 抑制相关的损害
90 kD 热休克蛋白 (Hsp90) 是负责选择蛋白质折叠的分子伴侣，其中许多与癌症进展直接相关。因此，Hsp90 蛋白折叠机制的抑制导致对许多致癌途径的组合攻击。17种Hsp90小分子抑制剂已进入治疗癌症的临床试验，均与Hsp90 N端结合并表现出泛-对所有四种 Hsp90 同种型的抑制活性，这可能导致不良反应。Hsp90 异构体选择性抑制剂的开发代表了一种治疗癌症的替代方法，并可能限制其中一些危害。本文所描述的是一种基于结构的方法来开发 Hsp90β 的异构体选择性抑制剂，其诱导选定的 Hsp90 客户的降解，而不会同时诱导 Hsp90 水平。总之，这些初步研究支持开发 Hsp90β 选择性抑制剂作为克服与泛抑制相关的损害的方法。
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