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 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.

Automated summary

Glioblastoma (GBM), the most common malignant brain tumor, has a poor prognosis under standard treatment. The androgen receptor (AR) is a potential therapeutic target for AR-overexpressed GBM, and inhibiting the chaperone protein HSP27 can lead to AR degradation and suppress AR activity in GBM. Through lead optimization, two new derivatives (compounds 4 and 26) have been developed with improved anti-GBM activity and drug distribution compared to the lead compound. These compounds exhibit potent inhibition of cell proliferation (IC(50) of 35 and 23 nM for compounds 4 and 6, respectively) and show significant activity in decreasing tumor growth in vivo.