生物素化的Hsp90β选择性抑制剂。

Biotinylated Hsp90β-selective inhibitors.

作者信息

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

机构信息

Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.

出版信息

Bioorg Med Chem Lett. 2025 Jul 1;128:130323. doi: 10.1016/j.bmcl.2025.130323.

DOI:10.1016/j.bmcl.2025.130323

PMID:40609915

Abstract

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.

摘要

热休克蛋白90（Hsp90）因其在与肿瘤发生相关的客户蛋白折叠和稳定中起关键作用，已成为开发抗癌治疗药物的一个有吸引力的靶点。Hsp90泛抑制剂进入了癌症治疗的临床试验，但显示出有害的副作用。Hsp90α亚型抑制已被归因于诸如心脏和眼部毒性等靶向毒性。为了确定Hsp90β抑制剂与其他细胞蛋白相互作用所引起的脱靶毒性，合成了具有不同连接长度的生物素化Hsp90β选择性抑制剂，并在体外进行了验证，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出毒性降低的Hsp90β选择性抑制剂。