Medical College, Guangxi University, Nanning, China.
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA.
Drug Dev Res. 2022 Sep;83(6):1434-1454. doi: 10.1002/ddr.21974. Epub 2022 Jul 15.
Involved in mediating the folding and maturation of more than 300 client proteins, many of which are oncoproteins, Hsp90 has emerged as a promising drug target for cancer therapy. In particular, inhibiting Hsp90 plays a vital role in the treatment of non-small cell lung cancer. Owing to undesirable outcomes of Hsp90 inhibitors in clinical trials, a series of matrinic acid compounds bearing 2-anilinothiazole moiety were designed based on the structural features allocation shared among Hsp90 inhibitors within the ATP-binding pocket. Most of the compounds showed potent anticancer activities validated by MTT assay. Among them, the most potent compound C4 (IC < 10 μM against four cell lines) was chosen for further mechanism study. Notably, C4 showed a better safety profile than 17AAG with a higher SI value. Thermal shift assay data indicated C4 exhibited a strong binding affinity with Hsp90 (-18.85 ± 0.56°C) comparable to radicicol. Mechanism studies verified that C4 significantly inhibited proliferation and migration activities of A549 cells. Besides, C4 can induce a prolonged G1-phase and cell apoptosis. Western blot analysis results indicated C4 could moderately suppress Hsp90 and upregulate Hsp70 expression. Furthermore, the downregulated trend of the client proteins of Hsp90, such as β-Catenin and Bcl-2, were consistent with the cellular effect of C4, suggesting that C4 could exert anticancer activity via targeting Hsp90. In the xenograft model in vivo, C4 effectively inhibited lung cancer growth without obvious side effects. Collectively, C4 could be a promising therapeutic agent for lung cancer and the novel scaffold provided new insights into the design of Hsp90 inhibitors.
涉及介导 300 多种客户蛋白的折叠和成熟，其中许多是癌蛋白，Hsp90 已成为癌症治疗的有前途的药物靶点。特别是，抑制 Hsp90 在非小细胞肺癌的治疗中起着至关重要的作用。由于 Hsp90 抑制剂在临床试验中的不良结果，根据 ATP 结合口袋中 Hsp90 抑制剂的结构特征分配，设计了一系列带有 2-苯胺噻唑部分的马替林酸化合物。大多数化合物通过 MTT 测定验证了具有强大的抗癌活性。其中，最有效的化合物 C4（对四种细胞系的 IC < 10μM）被选为进一步的机制研究。值得注意的是，C4 与 17AAG 相比具有更高的安全性，具有更高的 SI 值。热位移测定数据表明 C4 与 Hsp90 具有很强的结合亲和力（-18.85 ± 0.56°C），与雷迪霉素相当。机制研究证实 C4 可显著抑制 A549 细胞的增殖和迁移活性。此外，C4 可以诱导细胞 G1 期延长和细胞凋亡。Western blot 分析结果表明，C4 可以适度抑制 Hsp90 并上调 Hsp70 表达。此外，Hsp90 的客户蛋白，如 β-Catenin 和 Bcl-2 的下调趋势与 C4 的细胞作用一致，表明 C4 可以通过靶向 Hsp90 发挥抗癌活性。在体内异种移植模型中，C4 有效抑制肺癌生长，无明显副作用。总之，C4 可能是一种有前途的肺癌治疗药物，新型支架为 Hsp90 抑制剂的设计提供了新的思路。
