TY - JOUR
T1 - Synthesis and evaluation of small molecule inhibitors of the androgen receptor N-terminal domain
AU - Henry, Martyn C.
AU - Riley, Christopher M.
AU - Hunter, Irene
AU - Elwood, Jessica. M. L.
AU - Lopez-Fernandez, J. Daniel
AU - Minty, Laura
AU - Coe, Diane M.
AU - McEwan, Iain J.
AU - Jamieson, Craig
PY - 2023/12/14
Y1 - 2023/12/14
N2 - 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.
AB - 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.
KW - prostate cancer
KW - androgen receptor
KW - intrinsically disordered protein
U2 - 10.1021/acsmedchemlett.3c00426
DO - 10.1021/acsmedchemlett.3c00426
M3 - Article
SN - 1948-5875
VL - 14
SP - 1800
EP - 1806
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 12
ER -