Lead Optimization of Androgen Receptor-HSP27 Disrupting Agents in Glioblastoma
Document Type
Article
Publication Date
4-2023
Publication Title
Journal of Medicinal Chemistry
Abstract
Glioblastoma (GBM) is the most common malignant brain tumor with poor prognosis under the current standard treatment. It is critical to develop new approaches to selectively battle the disease. GBM sex differences suggest that an androgen receptor (AR) is a potential therapeutic target to treat AR-overexpressed GBM. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein that stabilizes AR. Inhibition of HSP27 leads to AR degradation, indicating that HSP27 inhibitors could suppress AR activity in GBM. We have identified a lead HSP27 inhibitor that could induce AR degradation. Lead optimization resulted with two new derivatives (compounds 4 and 26) showing potent anti-GBM activity and improved drug distribution in comparison to the lead compound. Compounds 4 and 6 exhibit IC(50)s of 35 and 23 nM, respectively, to inhibit cell proliferation and also show significant activity to decrease the tumor growth in vivo.
Recommended Citation
Li, Yaxin; Orahoske, Cody; Salem, Fatma; Johnson, Aidyn; Tannous, Christia; Devole, Lucas; Zhang, Wenjing; Lathia, Justin D.; Wang, Bingcheng; and Su, Bin Ph.D., "Lead Optimization of Androgen Receptor-HSP27 Disrupting Agents in Glioblastoma" (2023). Chemistry Faculty Publications. 623.
https://engagedscholarship.csuohio.edu/scichem_facpub/623
DOI
10.1021/acs.jmedchem.2c02022
Volume
66
Issue
8
Comments
This research is supported by grant 1R15NS116766-01A1 (B.S.) , National Science Foundation Major Research Instrumentation Grants (CHE-0923398 and CHE-1126384) , Faculty Research Development (FRD) , and Center for Gene Regulation in Health and Disease of Cleveland State University.