Blood-Brain Barrier (BBB)-Penetrable Androgen Receptor (AR) Degrader as a Potential Therapeutic Agent for Glioblastoma.

Overview

1. Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, Ohio 44115, United States
2. Genomic Medicine Institute, Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
3. Animal Research Facility, Cleveland State University, 2121 Euclid Ave., Cleveland, Ohio 44115, United States
4. Department of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, Ohio 44106, United States
5. Department of Mechanic Engineering, College of Engineering, Cleveland State University, 2121 Euclid Ave., Cleveland, Ohio 44115, United States
6. Department of Cancer Sciences, Cleveland Clinic Research, Cleveland, Ohio 44195, United States
7. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, United States
8. Case Comprehensive Cancer Center, Cleveland, Ohio 44195, United States
9. Department of Biological, Geological, andEnvironmental Sciences, 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

Androgen receptor (AR) contributes to the progression of glioblastoma (GBM), which is consistent with the sex difference in GBM, which has a higher incidence in males than in females. Therefore, targeting AR is a potential therapeutic approach for GBM treatment. However, AR mutation commonly occurs in GBM, which makes conventional AR antagonists less effective. AR degraders abolish AR at the protein level regardless of the mutation status of AR, which makes it a better strategy in GBM. Compound A is an analog of the cyclooxygenase-2 (COX-2) inhibitor Nimesulide. Mechanistically, compound A targets HSP27, disrupts the HSP27-AR complex, and thereby promotes AR degradation in GBM cells at 1 μM, leading to inhibition of AR-overexpressing GBM cell growth with IC50s around 0.2 μM. In a GBM patient-derived cell line, DI318, compound A (1 μΜ) also significantly decreases AR protein levels. The compound significantly inhibits GBM xenograft growth at 20 mg/kg and does not cause toxicity in mice up to 200 mg/kg. Pharmacokinetic studies reveal that compound A has a half-life (t 1/2) of 3.11 h and a BBB penetration of 52%, which is even higher than the standard chemotherapy Temozolomide. These results suggest that the AR degrader has great potential as a novel GBM treatment.

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• rcsb.org/structure/6dv5 — at PDB; found in the text, “Docking Study”

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 17 authors, 5 keywords, 2 funders, 33 references.

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This paper

Zhao, X., Li, Y., Martin, W. R., Salem, F., Korem, R., Bolbol, S., Worden, G., Sajid, M., Al-Rousan, A., Wilt, B., Zhang, W., Turchyn, L., Hubert, C., Ning, L., Lathia, J. D., Zhou, A., & Su, B. (2026). Blood-Brain Barrier (BBB)-Penetrable Androgen Receptor (AR) Degrader as a Potential Therapeutic Agent for Glioblastoma. ACS pharmacology & translational science, 9(5), 1164-1176. https://doi.org/10.1021/acsptsci.5c00821

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