Selectively targeting the dimerization interface of human androgen receptor with small-molecules to treat castration-resistant prostate cancer

Cancer Letters
Kush DalalArtem Cherkasov

Abstract

Prostate cancer (PCa) is a leading cause of death for men in North America. The androgen receptor (AR) - a hormone inducible transcription factor - drives expression of tumor promoting genes and represents an important therapeutic target in PCa. The AR is activated by steroid recruitment to its ligand binding domain (LBD), followed by receptor nuclear translocation and dimerization via the DNA binding domain (DBD). Clinically used small molecules interfere with steroid recruitment and prevent AR-driven tumor growth, but are rendered ineffective by emergence of LBD mutations or expression of constitutively active variants, such as ARV7, that lack the LBD. Both drug-resistance mechanisms confound treatment of this 'castration resistant' stage of PCa (CRPC), characterized by return of AR signalling. Here, we employ computer-aided drug-design to develop small molecules that block the AR-DBD dimerization interface, an attractive target given its role in AR activation and independence from the LBD. Virtual screening on the AR-DBD structure led to development of prototypical compounds that block AR dimerization, inhibiting AR-transcriptional activity through a LBD-independent mechanism. Such inhibitors may potentially circumvent AR-de...Continue Reading

Citations

Mar 21, 2019·Current Opinion in Oncology·David J EinsteinSteven P Balk
Dec 20, 2018·Medicinal Research Reviews·N G R Dayan ElshanMichael E Jung
Dec 21, 2018·Medicinal Research Reviews·Dan LiTingjun Hou
Jun 18, 2020·International Journal of Molecular Sciences·Divya BafnaArtem Cherkasov
Aug 6, 2020·International Journal of Molecular Sciences·Mari Ishigami-Yuasa, Hiroyuki Kagechika
Mar 7, 2021·International Journal of Molecular Sciences·Michael L MohlerRamesh Narayanan
Mar 30, 2021·Computational and Structural Biotechnology Journal·Veronika Temml, Zsofia Kutil
Apr 4, 2021·International Journal of Molecular Sciences·Mariia RadaevaArtem Cherkasov
May 23, 2020·Drug Discovery Today·Xueping HuTingjun Hou
Feb 1, 2019·Molecular and Cellular Endocrinology·Helder Veras Ribeiro FilhoAna Carolina Migliorini Figueira

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