Antagonizing the androgen receptor with a biomimetic acyltransferase
Date
2016
Authors
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Journal ISSN
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Publisher
University of Delaware
Abstract
The androgen receptor (AR) remains the leading target of advanced prostate cancer therapies. Thiosalicylamide analogs have previously been shown to act in cells as acyltransfer catalysts that are capable of transferring cellular acetate, presumably from Acetyl-CoA, to HIV NCP. Here we explore if the cellular acetyl-transfer activity of thiosalicylamides can be redirected to other cellular targets guided by ligands for AR. We constructed conjugates of thiosalicylamides and the AR-binding small molecule tolfenamic acid, which binds the BF3 site of AR, proximal to the coactivator “FXXLF” binding surface. The thiosalicylamide-tolfenamic acid conjugate, YZ03, but not the separate thiosalicylamide and tolfenamic acid, significantly enhanced acetylation of endogenous AR in CWR22 cells. Further analysis confirms that Lys720, a residue critical to FXXLF coactivator peptide binding, is a primary site of YZ03 acetylation. Acyl-transfer conditions significantly enhance YZ03’s ability to inhibit AR-coactivator association. These data suggest that biomimetic acyltransferases can enhance protein-protein interaction inhibitors through covalent modification of critical interfacial residues.