Small-Molecule HSP27 Inhibitor Abolishes Androgen Receptors in Glioblastoma
Yaxin Li, Cody M. Orahoske, Werner J. Geldenhuys, Asmita Bhattarai, Abboud Sabbagh, Viharika Bobba, Fatma M. Salem, Wenjing Zhang, Girish C. Shukla, Justin D. Lathia, Bingcheng Wang, Bin Su
Abstract
Androgen receptor (AR) contributes to the progression of glioblastoma (GBM), and antiandrogen agents have the potential to be used for the treatment of GBM. However, AR mutation commonly happens in GBM, which makes the antiandrogen agents less effective. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein to stabilize ARs. Inhibition of HSP27 results in AR degradation regardless of the mutation status of ARs, which makes HSP27 a good target to abolish ARs in GBM. Compound I is a HSP27 inhibitor that significantly induces AR degradation in GBM cells via the proteasomal pathway, and it selectively inhibits AR-overexpressed GBM cell growth with IC50 values around 5 nM. The compound also significantly inhibits in vivo GBM xenograft at 20 mg/kg and does not cause toxicity to mice up to 80 mg/kg. These results suggest that targeting HSP27 to induce AR degradation in GBM is a promising and novel treatment.