Lead Optimization of Androgen Receptor-HSP27 Disrupting Agents in Glioblastoma. Academic Article uri icon

Overview

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 IC50s of 35 and 23 nM, respectively, to inhibit cell proliferation and also show significant activity to decrease the tumor growth in vivo.

authors

  • Li, Yaxin
  • Orahoske, Cody
  • Salem, Fatma
  • Johnson, Aidyn
  • Tannous, Christia
  • Devole, Lucas
  • Zhang, Wenjing
  • Lathia, Justin D
  • Wang, Bingcheng
  • Su, Bin

publication date

  • April 6, 2023

Research

keywords

  • Glioblastoma
  • Heat-Shock Proteins

Identity

Scopus Document Identifier

  • 85152125599

Digital Object Identifier (DOI)

  • 10.1021/acs.jmedchem.2c02022

PubMed ID

  • 37023333

Additional Document Info

volume

  • 66

issue

  • 8