Synthesis and evaluation of novel thiazole-based derivatives as selective inhibitors of DNA-binding domain of the androgen receptor

Abstract

A series of thiazole-based inhibitors selectively targeting DNA-binding domain of the androgen receptor (AR) were synthesized and evaluated, and the SAR data were summarized. We identified a novel compound SKLB-C2807 that effectively inhibited the human prostate cancer cell line LNCaP/AR with the IC₅₀ value of 0.38 μm without significant antiproliferative effects on other cell lines PC-3 (AR-negative), SW620, MCF-7 (ER-positive), and L-O2 (non-cancerous). This compound also considerably decreased the expression of prostate-specific antigen. Its binding mode to the AR-DBD was studied. These efforts lay the foundation for developing the next generation of anti-androgens.

Keywords: DNA-binding domain; androgen receptor; antitumor activity; selective inhibition; structure-activity relationships (SARs).