ABSTRACT
A series of novel 4-Hydroxyquinazoline derivatives were designed and synthesized to enhance sensitivity in primary PARPi-resistant cells. Among them, the compound B1 has been found to have superior cytotoxicity in primary PARPi-resistant HCT-15 and HCC1937 cell lines, and dose-dependently suppressed the intracellular PAR formation and enhanced the γH2AX aggregation. Mechanistic study showed that B1 stimulated the formation of intracellular ROS and the depolarization of the mitochondrial membrane, which could increase apoptosis and cytotoxicity. An in vivo study showed that B1 significantly suppressed tumor growth at a dose of 25 mg/kg, and an acute toxicity study confirmed its safety. Molecular docking and dynamics simulations revealed that hydrogen bonding between B1 and ASP766 may be helpful to enhance anti-drug resistance ability. This study suggests that B1 is a potent PARP inhibitor that can overcome PARPi resistance and deserves further investigation.
