posted on 2021-09-10, 19:34authored byNane C. Kuznik, Valeria Solozobova, Nicole Jung, Simone Gräßle, Qing Lei, Eric M. Lewandowski, Ravi Munuganti, Amina Zoubeidi, Yu Chen, Stefan Bräse, Andrew C. B. Cato
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.