Antagonizing the Androgen Receptor with a Biomimetic Acyltransferase

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 NCp7. 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 BF-3 site of AR, proximal to the coactivator “FXXLF” binding surface. The thiosalicylamide-tolfenamic acid conjugate, YZ03, but not the separate thiosalicylamide plus tolfenamic acid, significantly enhanced acetylation of endogenous AR in CWR22Rv1 cells. Further analysis confirms that Lys720, a residue critical to FXXLF coactivator peptide binding, is a site of acyl-YZ03 acetylation. Under acyl-transfer conditions, YZ03 significantly enhances the ability of BF-3 site binding ligands to inhibit AR-coactivator peptide association. These data suggest that biomimetic acyltransferases can enhance protein-protein interaction inhibitors through covalent modification of critical interfacial residues.

Synthetic Chromatin Acylation by an Artificial Catalyst System

“…A recent study using thiosalicylamide conjugated with a ligand for the androgen receptor (tolfenamic acid) demonstrated site-selective acetylation of the androgen receptor without using exogenous acetylating reagents. 50 Therefore, developing chemical systems for site-selective histone acetylation could be possible, and the system can be complementary to the SynCAc or SynCMal system. SynCAc or SynCMal attenuates intra-and inter-nucleosome interactions, which could lead to the disruption of higher-order chromatin structures and enhancement of gene expression.…”

Probing Mercaptobenzamides as HIV Inactivators via Nucleocapsid Protein 7

“…The molecule MB2 also has the same anti‐HIV activity as MB1 in cell‐based assays due to a unique intracellular mechanism through which MB2 is acetylated in cells by acetyl coenzyme A (CoA) to generate MB1 . The MB1 generated by activation inside cells then inactivates NCp7 by the same mechanism described previously . Both MB1 and MB2 are too chemically unstable to develop into drugs due to hydrolysis of the thioester and oxidation of the free thiol.…”

“…The MB1 generated by activation inside cells then inactivates NCp7 by the same mechanism described previously. [16,18] Both MB1 and MB2 are too chemically unstable to develop into drugs due to hydrolysis of the thioester and oxidation of the free thiol. In addition, these molecules display EC 50 values in the low micromolar range in cell-based assays that test for anti-HIV activity.…”

Androgen Receptor-Directed Molecular Conjugates for Targeting Prostate Cancer

“…The interaction of AR with co-activators critically regulates receptor functions and compounds that interfere with this binding impact on tumor growth. In this regard, two hybrid derivatives containing a AR binder and endowed with AR/co-activator interfering action (YZ03, 3f , and MPC6, 3g ) have been reported (Wang et al, 2016b; Zhang et al, 2016). The acetyl-transfer activity of thiosalycilamides has been directed toward AR by conjugating tolfenamic acid (AR binder) with the thiosalycilamide (Figure 2) (Zhang et al, 2016).…”