Development of Biaryl-Containing Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors for Reversing AKR1C3-Mediated Drug Resistance in Cancer Treatment

Abstract

Aldo-keto reductase 1C3 (AKR1C3) is correlated with tumor development and chemotherapy resistance. The catalytic activity of the enzyme has been recognized as one of the important factors in inducing anthracycline (ANT) resistance in cancer cells. Inhibition of AKR1C3 activity may provide a promising approach to restore the chemosensitivity of ANT-resistant cancers. Herein, a series of biaryl-containing AKR1C3 inhibitors has been developed. The best analogue <b>S07-1066</b> selectively blocked AKR1C3-mediated reduction of doxorubicin (DOX) in MCF-7 transfected cell models. Furthermore, co-treatment of <b>S07-1066</b> significantly synergized DOX cytotoxicity and reversed the DOX resistance in MCF-7 cells overexpressing AKR1C3. The potential synergism of <b>S07-1066</b> over DOX cytotoxicity was demonstrated <i>in vitro</i> and <i>in vivo</i>. Our findings indicate that inhibition of AKR1C3 potentially enhances the therapeutic efficacy of ANTs and even suggests that AKR1C3 inhibitors may serve as effective adjuvants to overcome AKR1C3-mediated chemotherapy resistance in cancer treatment.