生物素化hsp90 β选择性抑制剂。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-01 DOI:10.1016/j.bmcl.2025.130323

Chaitanya Kondam , Nitin Sharma , Gaya K. Amarasinge , Brian S.J. Blagg

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引用次数: 0

摘要

热休克蛋白90 （Hsp90）由于其在与肿瘤发生相关的客户蛋白的折叠、稳定中起着至关重要的作用，已成为开发抗癌疗法的一个有吸引力的靶点。Hsp90 pan抑制剂进入临床试验治疗癌症显示不利的不良反应。Hsp90α异构体抑制被归因于靶毒性，如心毒性和眼毒性。为了确定Hsp90β抑制剂与其他细胞蛋白相互作用引起的脱靶毒性，合成并在体外验证了具有不同系链长度的生物素化Hsp90β选择性抑制剂，并将用于亲和纯化实验，以鉴定与Hsp90β选择性抑制剂相互作用的蛋白质。这些研究将导致开发具有降低脱靶毒性的hsp90 β选择性抑制剂。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Biotinylated Hsp90β-selective inhibitors

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Biotinylated Hsp90β-selective inhibitors

Heat shock protein 90 (Hsp90) has emerged as an attractive target for the development of therapeutics against cancer due to its crucial role in the folding and stabilization of client proteins associated with oncogenesis. Hsp90 pan inhibitors entered clinical trials for the treatment of cancer and showed detrimental adverse effects. Hsp90α isoform inhibition has been attributed to on-target toxicities such as cardio- and ocular-toxicity. To determine whether off-target toxicities caused by the interaction of Hsp90β inhibitors with other cellular proteins, biotinylated Hsp90β-selective inhibitors with various tether lengths were synthesized and validated in vitro to be used in affinity purification experiments to identify proteins that interact with Hsp90β-selective inhibitors. These studies will lead to the development of Hsp90β-selective inhibitors with reduced toxicities.

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.