As a crucial target which is overexpressed in a variety
of cancers,
aldo-keto reductase 1C3 (AKR1C3) confers chemotherapeutic resistance
to many clinical agents. However, a limited number of AKR1C3-selective
inhibitors are applied clinically, which indicates the importance
of identifying active compounds. Herein, we report the discovery,
synthesis, and evaluation of novel and potent AKR1C3 inhibitors with
structural diversity. Molecular dynamics simulations of these active
compounds provide reasonable clarification of the interpreted biological
data. Moreover, we demonstrate that AKR1C3 inhibitors have the potential
to be superior therapeutic agents for re-sensitizing drug-resistant
cell lines to chemotherapy, especially the pan-AKR1C inhibitor S07-2010. Our study identifies new structural classes of AKR1C3
inhibitors and enriches the structural diversity, which facilitates
the future rational design of inhibitors and structural optimization.
Moreover, these compounds may serve as promising therapeutic adjuvants
toward new therapeutics for countering drug resistance.
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.
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