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

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

  • ACS Chem Biol. 2021 Nov 19;16(11):2103-2108. doi: 10.1021/acschembio.1c00390.
Nane C Kuznik 1,  Valeria Solozobova 1,  Nicole Jung 2,  Simone Gräßle 2,  Qing Lei 1,  Eric M Lewandowski 3,  Ravi Munuganti 4,  Amina Zoubeidi 4 5,  Yu Chen 3,  Stefan Bräse 2 6,  Andrew C B Cato 1
Affiliations

Affiliations

  • 1 Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
  • 2 Institute of Biological and Chemical Systems, Functional Molecular Systems, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
  • 3 Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612-4799, United States.
  • 4 Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
  • 5 Department of Urology, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
  • 6 Institute of Organic Chemistry, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany.
PMID: 34506104 DOI: 10.1021/acschembio.1c00390
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.

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