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

Article

Author: Gao, Yan-Fang ; Qin, Jing-Bo ; Yang, Yi-Jing ; Fang, Mei-Juan ; Zeng, Jin-Zhang ; Zhang, Hao-Fan ; Yu, Ming-Yue ; Hu, Sheng-Wei ; Hu, Hong-Yu ; Lin, Fan-Hong

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.

01 Apr 2022·Bioorganic ChemistryQ2 · CHEMISTRY

Discovery of a Nur77-mediated cytoplasmic vacuolation and paraptosis inducer (4-PQBH) for the treatment of hepatocellular carcinoma

Q2 · CHEMISTRY

Article

Author: Wen, Fangfang ; Wu, Tong ; Yao, Jie ; Qiu, Yingkun ; Wu, Zhen ; Huang, Jiangang ; Zeng, Jinzhang ; Zhao, Taige ; He, Fengming ; Liu, Jie ; Yang, Changming ; Wang, Wang ; Li, Baicun ; Liu, Shunzhi ; Fang, Meijuan

Nur77, an orphan nuclear receptor, has antitumor activity in hepatocellular carcinoma (HCC). However, its antitumor mechanisms of action in HCC are complicated and rarely reported. Our recent work demonstrated that certain quinoline-Schiff-base derivatives were good Nur77 mediators that exerted excellent anti-HCC activities in vitro and in vivo. Interestingly, these compounds shared similar chemical structures, but they displayed different Nur77-targeted anticancer mechanisms of action. As a continuous work, we synthesized a series of 4-(quinoline-4-amino) benzoylhydrazide derivatives and evaluated their anti-HCC activity and binding affinity to Nur77 in vitro. Compound 4-PQBH emerged as the best Nur77 binder (K_D = 1.17 μM) and has potentially selective cytotoxicity to HCC cells. Mechanistically, 4-PQBH extensively induced caspase-independent cytoplasmic vacuolization and paraptosis through Nur77-mediated ER stress and autophagy. Moreover, 4-PQBH exhibited an effective xenograft tumor inhibition by modulating Nur77-dependent cytoplasmic vacuolation and paraptosis. This paper is the first to disclose that chemotherapeutic agents targeting Nur77-mediated cytoplasmic vacuolization and paraptosis may provide a promising strategy to combat HCC that frequently evade the apoptosis program.

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatocellular Carcinoma	Preclinical	China	Xiamen University	01 Apr 2022

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