Design, synthesis, and biological evaluation of quinolinyl-ureido-phenyl-hydrazide derivatives and quinolinyl-hydrazide derivatives as anticancer agents targeting Nur77-mediated ferroptosis.

In the recent decade, targeting ferroptosis for cancer therapy has attracted remarkable attention. Interestingly, the transcriptional regulator Nur77, a promising therapeutic target in cancer, has been recently identified as a crucial regulator of ferroptosis. However, no ferroptosis inducer targeting Nur77 has been reported currently. In this study, we built upon our prior research on Nur77 modulator 4-PQBH to design and synthesize four series of new compounds, with the objective of developing novel Nur77-mediated ferroptosis inducers. Among them, compound 8f exhibited the most potency against the tested cancer cell lines, including human estrogen positive breast cancer and triple-negative breast cancer cell lines, while displaying lower toxicity towards human normal cell lines HaCaT and MCF-10A (IC50> 50 μM). Furthermore, 8f demonstrated superior Nur77-binding activity in comparison to the reference compound Csn-B, and it has the capacity to activate the Nur77-driven luciferase activity and increase the protein level of Nur77. Remarkably, 8f induced an increase in the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and lipid peroxidation, concurrently with a reduction in the expression of GPX4 protein, culminating in the induction of ferroptosis in a Nur77-dependent manner. In vivo, 8f treatment has been observed to significantly suppress MCF7 xenograft tumor growth. Consequently, a novel ferroptosis inducer targeting Nur77 (8f) is first reported as a potent anti-EPBC agent, providing may serve as a promising lead for further drug development targeting Nur77-mediated ferroptosis.