Small-Molecule HSP27 Inhibitor Abolishes Androgen Receptors in Glioblastoma
Yaxin Li1, Cody M Orahoske1, Werner J Geldenhuys2
1Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio 44115, United States.
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.
Insights
Targeting Heat Shock Protein 27 (HSP27) effectively degrades androgen receptors (ARs) in glioblastoma (GBM), overcoming resistance to antiandrogen therapies. This novel approach shows promise for treating aggressive brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Androgen receptor (AR) signaling drives glioblastoma (GBM) progression, making it a therapeutic target.
- AR mutations in GBM reduce the efficacy of conventional antiandrogen agents.
- Heat shock 27 kDa protein (HSP27) stabilizes AR, promoting glioblastoma growth.
Purpose of the Study:
- To investigate HSP27 as a therapeutic target for GBM by inhibiting AR.
- To evaluate the efficacy of a novel HSP27 inhibitor, Compound I, in preclinical GBM models.
Main Methods:
- Compound I was used to inhibit HSP27 in GBM cells.
- AR degradation and proteasomal pathway involvement were assessed.
- Cell viability assays determined the IC50 of Compound I against AR-overexpressing GBM cells.
- In vivo efficacy and toxicity studies were performed using GBM xenografts in mice.
Main Results:
- Compound I effectively induced AR degradation in GBM cells via the proteasomal pathway.
- Compound I selectively inhibited AR-overexpressing GBM cell growth with low nanomolar IC50 values.
- Significant inhibition of GBM xenograft growth was observed in vivo at 20 mg/kg.
- Compound I demonstrated a favorable safety profile in mice, with no observed toxicity up to 80 mg/kg.
Conclusions:
- Inhibiting HSP27 is a viable strategy to induce AR degradation in GBM.
- Compound I represents a promising novel therapeutic agent for glioblastoma treatment.
- Targeting HSP27 overcomes resistance mechanisms associated with AR mutations in GBM.
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