Small molecule inhibitors targeting heat shock protein 90: An updated review

• Published in: European journal of medicinal chemistry 2024-09, Vol.275, p.116562, Article 116562
• Main Authors: Li, Yulong, Dong, Jinyun, Qin, Jiang-Jiang
• Format: Article
• Language: English
• Subjects: Cancer; HSP90; SAR; Small molecule inhibitors
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116562

As a molecular chaperone, heat shock protein 90 (HSP90) plays important roles in the folding, stabilization, activation, and degradation of over 500 client proteins, and is extensively involved in cell signaling, proliferation, and survival. Thus, it has emerged as an important target in a variety of diseases, including cancer, neurodegenerative diseases, and viral infections. Therefore, targeted inhibition of HSP90 provides a valuable and promising therapeutic strategy for the treatment of HSP90-related diseases. This review aims to systematically summarize the progress of research on HSP90 inhibitors in the last five years, focusing on their structural features, design strategies, and biological activities. It will refer to the natural products and their derivatives (including novobiocin derivatives, deguelin derivatives, quinone derivatives, and terpenoid derivatives), and to synthetic small molecules (including resorcinol derivatives, pyrazoles derivatives, triazole derivatives, pyrimidine derivatives, benzamide derivatives, benzothiazole derivatives, and benzofuran derivatives). In addition, the major HSP90 small-molecule inhibitors that have moved into clinical trials to date are also presented here. [Display omitted] •A comprehensive summary of HSP90 inhibitors reported in the past 5 years.•The design strategy, activity, and action mechanism have also been discussed.•The dual or multi-targeting HSP90 inhibitors are also discussed with examples.•It provides an overview of the HSP90 inhibitors in clinical trial or practice applications to date.