2. Academic Validation
  3. A Novel Redox Modulator Induces a GPX4-Mediated Cell Death That Is Dependent on Iron and Reactive Oxygen Species

A Novel Redox Modulator Induces a GPX4-Mediated Cell Death That Is Dependent on Iron and Reactive Oxygen Species

  • J Med Chem. 2020 Sep 10;63(17):9838-9855. doi: 10.1021/acs.jmedchem.0c01016.
Shuai Hu 1 2,  Mario Sechi 3,  Pankaj Kumar Singh 3,  Lipeng Dai 4,  Sean McCann 1,  Duxin Sun 4,  Mats Ljungman 5,  Nouri Neamati 1
Affiliations

Affiliations

  • 1 Departments of Medicinal Chemistry, College of Pharmacy, Rogel Cancer center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2 Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3 Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100 Sassari, Italy.
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5 Department of Radiation Oncology, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 32809827 DOI: 10.1021/acs.jmedchem.0c01016
Abstract

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.

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