Novel matrinic acid derivatives bearing 2-anilinothiazole structure for non-small cell lung cancer treatment with improved Hsp90 targeting effect

Abstract

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 (IC₅₀ < 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.

Keywords: Hsp90; anticancer activities; matrinic 2-anilinothiazole scaffold.