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 S07-2005 through a cascade virtual screening approach (AKR1C3 IC₅₀ = 130 ± 30 nM, SI (selective index) > 77). Using cocrystal-guided drug design, 30 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 30 restored sorafenib sensitivity in HCC both in vitro and in vivo. Additionally, compound 30 demonstrated a favorable safety profile and pharmacokinetic properties, suggesting its potential as an adjunct to overcome AKR1C3-mediated chemotherapy resistance in cancer treatment.