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

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 S07-1066 selectively
blocked AKR1C3-mediated reduction of doxorubicin (DOX) in MCF-7 transfected
cell models. Furthermore, co-treatment of S07-1066 significantly
synergized DOX cytotoxicity and reversed the DOX resistance in MCF-7
cells overexpressing AKR1C3. The potential synergism of S07-1066 over DOX cytotoxicity was demonstrated in vitro and in vivo. 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.