2. Academic Validation
  3. Development of 2-(5,6,7-Trifluoro-1 H-Indol-3-yl)-quinoline-5-carboxamide as a Potent, Selective, and Orally Available Inhibitor of Human Androgen Receptor Targeting Its Binding Function-3 for the Treatment of Castration-Resistant Prostate Cancer

Development of 2-(5,6,7-Trifluoro-1 H-Indol-3-yl)-quinoline-5-carboxamide as a Potent, Selective, and Orally Available Inhibitor of Human Androgen Receptor Targeting Its Binding Function-3 for the Treatment of Castration-Resistant Prostate Cancer

  • J Med Chem. 2021 Oct 28;64(20):14968-14982. doi: 10.1021/acs.jmedchem.1c00681.
Eric Leblanc 1,  Fuqiang Ban 1,  Ayse Derya Cavga 2,  Sam Lawn 1,  Chia-Chi Flora Huang 1,  Sankar Mohan 3,  Matthew E K Chang 4,  Mark R Flory 4,  Fariba Ghaidi 1,  Shreyas Lingadahalli 1,  Gang Chen 3,  Ivan Pak Lok Yu 1,  Hélène Morin 1,  Nada Lallous 1,  Martin E Gleave 1,  Hisham Mohammed 4,  Robert N Young 3,  Paul S Rennie 1,  Nathan A Lack 1 2,  Artem Cherkasov 1
Affiliations

Affiliations

  • 1 Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia V6H 3Z6, Canada.
  • 2 School of Medicine, Koç University, Rumelifeneri Yolu, Istanbul 34450, Turkey.
  • 3 Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.
  • 4 Knight Cancer Institute, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, United States.
PMID: 34661404 DOI: 10.1021/acs.jmedchem.1c00681
Abstract

Prostate Cancer (PCa) patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate Cancer (CRPC). Targeting the Androgen Receptor (AR) Binding Function-3 (BF3) site offers a promising option to treat CRPC. However, BF3 inhibitors have been limited by poor potency or inadequate metabolic stability. Through extensive medicinal chemistry, molecular modeling, and biochemistry, we identified 2-(5,6,7-trifluoro-1H-Indol-3-yl)-quinoline-5-carboxamide (VPC-13789), a potent AR BF3 antagonist with markedly improved pharmacokinetic properties. We demonstrate that VPC-13789 suppresses AR-mediated transcription, chromatin binding, and recruitment of coregulatory proteins. This novel AR antagonist selectively reduces the growth of both androgen-dependent and enzalutamide-resistant PCa cell lines. Having demonstrated in vitro efficacy, we developed an orally bioavailable prodrug that reduced PSA production and tumor volume in animal models of CRPC with no observed toxicity. VPC-13789 is a potent, selective, and orally bioavailable antiandrogen with a distinct mode of action that has a potential as novel CRPC therapeutics.

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