Small-Molecule HSP27 Inhibitor Abolishes Androgen Receptors in Glioblastoma

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.

雄激素受体（Androgen receptor, AR）参与胶质母细胞瘤（Glioblastoma, GBM）的进展过程，抗雄激素药物具备用于治疗GBM的潜力。然而，AR突变在GBM中较为常见，这会削弱抗雄激素药物的治疗效果。热休克蛋白27（Heat shock 27 kDa protein, HSP27）是一种被广泛研究的分子伴侣蛋白，可稳定AR蛋白。抑制HSP27能够促使AR蛋白降解，且不受AR突变状态的影响，这使得HSP27成为在GBM中清除AR的理想靶点。化合物I是一种HSP27抑制剂，可通过蛋白酶体通路（proteasomal pathway）显著诱导GBM细胞中的AR蛋白降解，并能选择性抑制过表达AR的GBM细胞增殖，其半最大效应浓度（IC50）约为5 nM。该化合物在20 mg/kg剂量下可显著抑制体内GBM异种移植（xenograft）模型的生长，且在80 mg/kg剂量下未对小鼠产生毒性反应。上述结果表明，靶向HSP27以诱导GBM中的AR蛋白降解，是一种极具前景的新型治疗策略。