Development of a Benzothiazole Scaffold-Based Androgen Receptor N-Terminal Inhibitor for Treating Androgen-Responsive Prostate Cancer.

Abstract

All current clinically approved androgen deprivation therapies for prostate cancer target the C-terminal ligand-binding domain of the androgen receptor (AR). However, the main transactivation function of the receptor is localized at the AR N-terminal domain (NTD). Targeting the AR NTD directly is a challenge because of its intrinsically disordered structure and the lack of pockets for drugs to bind. Here, we have taken an alternative approach using the cochaperone BAG1L, which interacts with the NTD, to develop a novel AR inhibitor. We describe the identification of 2-(4-fluorophenyl)-5-(trifluoromethyl)-1,3-benzothiazole (A4B17), a small molecule that inhibits BAG1L-AR NTD interaction, attenuates BAG1L-mediated AR NTD activity, downregulates AR target gene expression, and inhibits proliferation of AR-positive prostate cancer cells. This compound represents a prototype of AR antagonists that could be key in the development of future prostate cancer therapeutics.

• Authors: Nane C Kuznik, Valeria Solozobova, Nicole Jung, Simone Gräßle, Qing Lei, Eric M Lewandowski, Ravi Munuganti, Amina Zoubeidi, Yu Chen, Stefan Bräse, Andrew C B Cato
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 16 Issue 11 Pg. 2103-2108 (11 19 2021) ISSN: 1554-8937 [Electronic] United States
• PMID: 34506104 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AR protein, human
• Androgen Receptor Antagonists
• Antineoplastic Agents
• BCL2-associated athanogene 1 protein
• Benzothiazoles
• DNA-Binding Proteins
• Receptors, Androgen
• Transcription Factors

Topics

• Androgen Receptor Antagonists (pharmacology)
• Antineoplastic Agents (pharmacology)
• Benzothiazoles (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA-Binding Proteins (metabolism)
• Down-Regulation (drug effects)
• Humans
• Male
• Prostatic Neoplasms (drug therapy, metabolism)
• Protein Binding (drug effects)
• Protein Domains
• Receptors, Androgen (chemistry, metabolism)
• Transcription Factors (metabolism)