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Lead Optimization of Androgen Receptor-HSP27 Disrupting Agents in Glioblastoma
Yaxin Li1, Cody Orahoske1, Fatma Salem1
1Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Arts and Sciences, Cleveland State University, 2121 Euclid Ave., Cleveland, Ohio 44115, United States.
Abstract:
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.
Insights
New HSP27 inhibitors targeting androgen receptor degradation show potent anti-glioblastoma (GBM) activity. Compounds 4 and 6 significantly inhibit GBM cell proliferation and reduce tumor growth in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options.
- Sex differences in GBM suggest a role for the androgen receptor (AR) as a therapeutic target.
- Heat shock 27 kDa protein (HSP27) stabilizes AR, making HSP27 inhibition a potential strategy.
Purpose of the Study:
- To develop novel HSP27 inhibitors for targeting AR-overexpressed GBM.
- To optimize lead compounds for enhanced anti-GBM efficacy and drug distribution.
Main Methods:
- Identification and optimization of HSP27 inhibitors.
- Assessment of compounds' ability to induce AR degradation.
- Evaluation of anti-proliferative activity (IC50) in GBM cells.
- In vivo studies to assess tumor growth inhibition.
Main Results:
- A lead HSP27 inhibitor was identified, capable of inducing AR degradation.
- Two optimized derivatives, compounds 4 and 26, demonstrated potent anti-GBM activity.
- Compounds 4 and 6 showed low nanomolar IC50 values for inhibiting cell proliferation (35 nM and 23 nM, respectively).
- Significant reduction in tumor growth was observed in vivo with these compounds.
Conclusions:
- HSP27 inhibitors represent a promising therapeutic strategy for GBM.
- Optimized compounds 4 and 6 exhibit significant potential for treating AR-overexpressed GBM.
- Further development of these HSP27 inhibitors could lead to improved GBM therapies.
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