ML162 derivatives incorporating a naphthoquinone unit as ferroptosis/apoptosis inducers: Design, synthesis, anti-cancer activity, and drug-resistance reversal evaluation

Activating Apoptosis has long been viewed as an anti-cancer process, but recently increasing evidence has accumulated that induction of Ferroptosis has emerged as a promising strategy for Cancer therapeutics. Glutathione Peroxidase 4 (GPX4) is one of the pivotal factors regulating Ferroptosis that targeted inhibition or degradation of GPX4 could effectively trigger Ferroptosis. In this study, a series of ML162-quinone conjugates were constructed by using pharmacophore hybridization and bioisosterism strategies, with the aim of obtaining more active Anticancer agents via the Ferroptosis and Apoptosis dual cell death processes. Of these compounds, GIC-20 was identified as the most active one that exhibited promising Anticancer activity both in vitro and in vivo via Ferroptosis and Apoptosis dual-targeting processes, without obvious toxicity compared with ML162. On one hand, GIC-20 could trigger Ferroptosis in cells by inducing intracellular lipid peroxide and ROS accumulation, and destroying mitochondrial structure. In addition to GPX4 inhibition, GIC-20 can also trigger Ferroptosis via proteasomal-mediated degradation of GPX4, suggesting GIC-20 may function as a molecule glue degrader. On the other hand, GIC-20 can also induce Apoptosis via upregulating the level of apoptotic protein Bax and downregulating the level of anti-apoptotic protein Bcl-2 in HT1080 cells. Furthermore, GIC-20 also enhanced the sensitivity of resistant MIA-PaCa-2-AMG510R cells to AMG510, suggesting the great potential of GIC-20 in overcoming the acquired resistance of KRAS^G12C inhibitors. Overall, GIC-20 represents a novel dual Ferroptosis/Apoptosis inducer warranting further development for Cancer therapeutics and overcoming drug resistance.

Anti-cancer; Apoptosis; Degrader; Ferroptosis; Glutathione peroxidase 4; Inhibitor.