A Structure—Activity Relationship Study of Bis-Benzamides as Inhibitors of Androgen Receptor—Coactivator Interaction

Abstract

The interaction between androgen receptor (AR) and coactivator proteins plays a critical role in AR-mediated prostate cancer (PCa) cell growth, thus its inhibition is emerging as a promising strategy for PCa treatment. To develop potent inhibitors of the AR−coactivator interaction, we have designed and synthesized a series of bis-benzamides by modifying functional groups at the N/C-terminus and side chains. A structure−activity relationship study showed that the nitro group at the N-terminus of the bis-benzamide is essential for its biological activity while the C-terminus can have either a methyl ester or a primary carboxamide. Surveying the side chains with various alkyl groups led to the identification of a potent compound 14d that exhibited antiproliferative activity (IC50 value of 16 nM) on PCa cells. In addition, biochemical studies showed that 14d exerts its anticancer activity by inhibiting the AR−PELP1 interaction and AR transactivation.

Keywords

• α-helix mimetics
• bis-benzamide scaffold
• protein–protein interaction
• prostate cancer
• androgen receptor
• coactivator PELP1