Discovery of highly potent AKR1Cs pan-inhibitors as chemotherapeutic potentiators to restore breast cancer drug resistance.

The acquired resistance of doxorubicin (DOX) significantly limits their application in breast cancer treatment. In earlier investigations, a pan-inhibitor, S07-2010, exhibiting inhibitory activity against Aldo-Keto Reductase 1C1-1C4 (AKR1C1-1C4) was discovered through virtual screening. In this study, four rounds of structural modifications were conducted, and the optimized compound 29 exhibited potent inhibitory activity against AKR1C1-1C4 (AKR1C1 IC = 0.09 μM, AKR1C2 IC = 0.28 μM, AKR1C3 IC = 0.05 μM, AKR1C4 IC = 0.51 μM). Molecular dynamics (MD) simulations revealed that 29 consistently occupied both SP2 and SP3 pockets, which may explain its pan-inhibitory activity. Utilizing highly DOX resistant MCF-7/ADR cells, 29 demonstrated superior potential as a therapeutic agent for re-sensitizing drug-resistant cell lines to chemotherapy both in vitro and in vivo, suggesting that pan-inhibition of AKR1C1-1C4 may serve as a more promising therapeutic strategy for drug-resistant breast cancer. In summary, Compound 29 may be a promising therapeutic adjuvant in the development of novel strategies to overcome drug resistance.