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

Abstract

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 IC₅₀ = 0.09 μM, AKR1C2 IC₅₀ = 0.28 μM, AKR1C3 IC₅₀ = 0.05 μM, AKR1C4 IC₅₀ = 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.