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

• Published in: Cancer letters Vol. 437; pp. 35 - 43
• Main Authors: Dalal, Kush, Ban, Fuqiang, Li, Huifang, Morin, Hélène, Roshan-Moniri, Mani, Tam, Kevin J., Shepherd, Ashley, Sharma, Aishwariya, Peacock, James, Carlson, Michael L., LeBlanc, Eric, Perez, Carl, Duong, Franck, Ong, Christopher J., Rennie, Paul S., Cherkasov, Artem
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.11.2018; Elsevier Limited
• Subjects: Androgen receptor; Androgen receptors; Androgens; Castration; Cloning; Deoxyribonucleic acid; Dimerization; DNA; Drug development; Drug resistance; Localization; Mutation; Nuclear transport; Plasmids; Prostate cancer; Small molecule inhibitor; Therapeutic applications; Translocation; Prostate cancer; Dimerization; Small molecule inhibitor; Androgen receptor
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2018.08.016

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-dependent resistance mechanisms and directly target CRPC tumor growth. •The androgen receptor dimerization interface contains a targetable region for inhibitors.•A lead compound can suppress the transcriptional activity the androgen receptor.•The compound blocks androgen receptor dimerization in the cell nucleus.•Mutagenesis provides evidence for on-target compound binding.