Amatya Eva, Subramanian Chitra, Cohen Mark S, Blagg Brian S J
Department of Chemistry and Biochemistry, Warren Center for Drug Discovery, University of Notre Dame Notre Dame Indiana 46556 USA
Cancer Center at Illinois, University of Illinois Urbana-Champaign Urbana Illinois 61801 USA.
RSC Med Chem. 2024 Jan 18;15(3):888-894. doi: 10.1039/d3md00529a. eCollection 2024 Mar 20.
Inhibition of the Hsp90 C-terminal domain offers a promising opportunity to treat numerous diseases/indications. Furthermore, the development of Hsp90 C-terminal inhibitors (CTIs) is advantageous over N-terminal inhibitors because it avoids the detriments associated with induction of the heat shock response (HSR). However, the lack of co-crystal structures of small molecules bound to the C-terminus have hindered their development. Therefore, structure-activity relationship (SAR) studies have been pursued to optimize such inhibitors. Noviose sugar surrogates, also known as noviomimetics have been prepared to investigate the size and nature of the C-terminal domain binding pocket. Herein, we report the synthesis and anti-proliferative activity manifested by this new series of Hsp90 C-terminal inhibitors.
抑制热休克蛋白90（Hsp90）的C末端结构域为治疗多种疾病/适应症提供了一个有前景的机会。此外，Hsp90 C末端抑制剂（CTIs）的开发比N末端抑制剂更具优势，因为它避免了与诱导热休克反应（HSR）相关的不利影响。然而，缺乏与C末端结合的小分子的共晶体结构阻碍了它们的开发。因此，人们开展了构效关系（SAR）研究以优化此类抑制剂。已制备了新霉素糖替代物，也称为新霉素模拟物，以研究C末端结构域结合口袋的大小和性质。在此，我们报告了这一系列新型Hsp90 C末端抑制剂的合成及其抗增殖活性。
