Structure-Activity Relationships of Benzothiazole-Based Hsp90 C-Terminal-Domain Inhibitors

Pharmaceutics

Jaka Dernovšek¹  Nace Zidar¹  Tihomir Tomašič¹  Martina Gobec¹  Živa Zajec¹  Martina Durcik¹  Lucija Peterlin Mašič¹ 

[1] Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, 1000 Ljubljana, Slovenia;

关键词: allosteric;    Hsp90;    benzothiazole;    cancer;    inhibitor;    cancer therapy;   

DOI  :  10.3390/pharmaceutics13081283

来源: DOAJ

【 摘 要 】

Heat shock protein 90 (Hsp90) is a chaperone responsible for the maturation of many cancer-related proteins, and is therefore an important target for the design of new anticancer agents. Several Hsp90 N-terminal domain inhibitors have been evaluated in clinical trials, but none have been approved as cancer therapies. This is partly due to induction of the heat shock response, which can be avoided using Hsp90 C-terminal-domain (CTD) inhibition. Several structural features have been shown to be useful in the design of Hsp90 CTD inhibitors, including an aromatic ring, a cationic center and the benzothiazole moiety. This study established a previously unknown link between these structural motifs. Using ligand-based design methodologies and structure-based pharmacophore models, a library of 29 benzothiazole-based Hsp90 CTD inhibitors was prepared, and their antiproliferative activities were evaluated in MCF-7 breast cancer cells. Several showed low-micromolar IC₅₀, with the most potent being compounds 5g and 9i (IC₅₀, 2.8 ± 0.1, 3.9 ± 0.1 μM, respectively). Based on these results, a ligand-based structure–activity relationship model was built, and molecular dynamics simulation was performed to elaborate the binding mode of compound 9i. Moreover, compound 9i showed degradation of Hsp90 client proteins and no induction of the heat shock response.

【 授权许可】

Unknown