Lead Optimization of Androgen Receptor-HSP27 Disrupting Agents in Glioblastoma

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.