Synthesis and evaluation of small molecule inhibitors of the androgen receptor N-terminal domain

Martyn C. Henry, Christopher M. Riley, Irene Hunter, Jessica. M. L. Elwood, J. Daniel Lopez-Fernandez, Laura Minty, Diane M. Coe, Iain J. McEwan, Craig Jamieson

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
43 Downloads (Pure)

Abstract

The androgen receptor (AR) is central to prostate cancer pathogenesis and has been extensively validated as a drug target. However, small-molecule anti-androgen therapies remain limited due to resistance and will eventually fail to suppress tumor growth, resulting in progression to castration-resistant prostate cancer (CRPC). The intrinsically disordered N-terminal domain (NTD) is crucial for AR transactivation and has been investigated as a suitable target in the presence of ligand binding domain mutations. A screening campaign identified biaryl isoxazole compound 7 as a weak inhibitor of the AR NTD. A library of biaryl analogues were synthesized, and their biological activities were assessed in a VCaP cell-based luciferase reporter gene assay. A structure-activity relationship (SAR) study revealed that indazole analogue 16 exhibited increased potency and favorable physicochemical properties with a benchmarked pharmacokinetic profile, providing a suitable starting point for further optimization of 16 as a CRPC therapeutic in the presence of AR mutations.

Original languageEnglish
Pages (from-to)1800-1806
Number of pages7
JournalACS Medicinal Chemistry Letters
Volume14
Issue number12
Early online date17 Nov 2023
DOIs
Publication statusPublished - 14 Dec 2023

Keywords

  • prostate cancer
  • androgen receptor
  • intrinsically disordered protein

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