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

Henry, Martyn C. and Riley, Christopher M. and Hunter, Irene and Elwood, Jessica. M. L. and Lopez-Fernandez, J. Daniel and Minty, Laura and Coe, Diane M. and McEwan, Iain J. and Jamieson, Craig (2023) Synthesis and evaluation of small molecule inhibitors of the androgen receptor N-terminal domain. ACS Medicinal Chemistry Letters, 14 (12). pp. 1800-1806. ISSN 1948-5875 (

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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.