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.