Discovery of Highly Potent AKR1C3 Inhibitors Treating Sorafenib-Resistant Hepatocellular Carcinoma

Aldo-keto reductase 1C3 (AKR1C3) plays a key role in tumor progression and chemotherapy resistance, particularly in sorafenib-resistant hepatocellular carcinoma (HCC). Targeting AKR1C3 represents a promising strategy to restore chemosensitivity in resistant HCC. Previous research identified the lead compound <b>S07-2005</b> through a cascade virtual screening approach (AKR1C3 IC₅₀ = 130 ± 30 nM, SI (selective index) > 77). Using cocrystal-guided drug design, <b>30</b> was optimized to adopt an "L"-shaped conformation targeting AKR1C3's subpocket 1 (SP1) and oxyanion site (OS), enhancing inhibitory potency and selectivity (AKR1C3 IC₅₀ = 5 ± 1 nM, SI > 2000). It enhanced sorafenib-induced ROS generation, promoted apoptosis, and restored sorafenib sensitivity in HCC models. In combination with sorafenib, compound <b>30</b> restored sorafenib sensitivity in HCC both <i>in vitro</i> and <i>in vivo</i>. Additionally, compound <b>30</b> demonstrated a favorable safety profile and pharmacokinetic properties, suggesting its potential as an adjunct to overcome AKR1C3-mediated chemotherapy resistance in cancer treatment.