Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States.
Curr Drug Targets. 2017;18(13):1572-1585. doi: 10.2174/1389450117666160527125522.
BACKGROUND & OBJECTIVE: The Hsp90 chaperone protein regulates the folding, maturation and stability of a wide variety of oncoproteins. In recent years, many Hsp90 inhibitors have entered into the clinical trials while all of them target ATPase showing similar binding capacity and kinds of side-effects so that none have reached to the market. During the regulation progress, numerous protein- protein interactions (PPI) such as Hsp90 and client proteins or cochaperones are involved. With the Hsp90-cochaperones PPI networks being more and more clear, many cancerous proteins have been reported to be tightly correlated to Hsp90-cochaperones PPI. Among them, Hsp90-Cdc37 PPI has been widely reported to associate with numerous protein kinases, making it a novel target for the treatment of cancers.
In this paper, we briefly review the strategies and modulators targeting Hsp90-Cdc37 complex including direct and indirect regulation mechanism. Through these discussions we expect to present inspirations for new insights into an alternative way to inhibit Hsp90 chaperone function.
Hsp90 伴侣蛋白调节多种癌蛋白的折叠、成熟和稳定性。近年来，许多 Hsp90 抑制剂已进入临床试验，但它们都针对 ATP 酶，具有相似的结合能力和各种副作用，因此没有一种药物进入市场。在调控过程中，涉及到许多蛋白质-蛋白质相互作用（PPI），如 Hsp90 和客户蛋白或共伴侣。随着 Hsp90-共伴侣 PPI 网络越来越清晰，许多致癌蛋白与 Hsp90-共伴侣 PPI 紧密相关。其中，Hsp90-Cdc37 PPI 已被广泛报道与许多蛋白激酶相关，使其成为治疗癌症的新靶点。
本文简要综述了针对 Hsp90-Cdc37 复合物的策略和调节剂，包括直接和间接调控机制。通过这些讨论，我们期望为抑制 Hsp90 伴侣蛋白功能提供新的见解和替代方法。
