A Novel Redox Modulator Induces a GPX4-Mediated Cell Death That Is Dependent on Iron and Reactive Oxygen Species.
Shuai HuMario SechiPankaj Kumar SinghLipeng DaiSean McCannDuxin SunMats LjungmanNouri NeamatiPublished in: Journal of medicinal chemistry (2020)
Redox modulators have been developed as an attractive approach to treat cancer. Herein, we report the synthesis, identification, and biological evaluation of a quinazolinedione reactive oxygen species (ROS) inducer, QD394, with significant cytotoxicity in pancreatic cancer cells. QD394 shows a transcriptomic profile remarkably similar to napabucasin, a cancer stemness inhibitor. Both small molecules inhibit STAT3 phosphorylation, increase cellular ROS, and decrease the GSH/GSSG ratio. Moreover, QD394 causes an iron- and ROS-dependent, GPX4 mediated cell death, suggesting ferroptosis as a major mechanism. Importantly, QD394 decreases the expression of LRPPRC and PNPT1, two proteins involved in mitochondrial RNA catabolic processes and both negatively correlated with the overall survival of pancreatic cancer patients. Pharmacokinetics-guided lead optimization resulted in the derivative QD394-Me, which showed improved plasma stability and reduced toxicity in mice compared to QD394. Overall, QD394 and QD394-Me represent novel ROS-inducing drug-like compounds warranting further development for the treatment of pancreatic cancer.
Keyphrases
- cell death
- reactive oxygen species
- cell cycle arrest
- papillary thyroid
- dna damage
- oxidative stress
- stem cells
- poor prognosis
- squamous cell
- cell proliferation
- epithelial mesenchymal transition
- squamous cell carcinoma
- metabolic syndrome
- emergency department
- skeletal muscle
- signaling pathway
- young adults
- combination therapy
- adverse drug
- protein kinase