首页|Discovery of a novel exceptionally potent and orally active Nur77 ligand NB1 with a distinct binding mode for cancer therapy

Discovery of a novel exceptionally potent and orally active Nur77 ligand NB1 with a distinct binding mode for cancer therapy

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The orphan nuclear receptor Nur77 is emerging as an attractive target for cancer therapy,and activating Nur77's non-genotypic anticancer function has demonstrated strong therapeutic potential.However,few Nur77 site B ligands have been identified as excellent anticancer compounds.There are no co-crystal structures of effective anticancer agents at Nur77 site B,which greatly limits the development of novel Nur77 site B ligands.Moreover,the lack of pharmaceutical ligands restricts Nur77's therapeutic proof of concept.Herein,we developed a first-in-class Nur77 site B ligand(NB1)that significantly inhibited cancer cells by mediating the Nur77/Bcl-2-related apoptotic effect at mitochondria.The X-ray crystallography suggests that NB1 is bound to the Nur77 site B with a distinct binding mode.Importantly,NB1 showed favorable pharmacokinetic profiles and safety,as evidenced by its good oral bioavailability in rats and lack of mortality,bodyweight loss,and pathological damage at the 512.0 mg/kg dose in mice.Furthermore,oral administration of NB1 demonstrated remarkable in vivo anticancer efficacy in an MDA-MB-231 xenograft model.Together,our work discovers NB1 as a new generation Nur77 ligand that activates the Nur77/Bcl-2 apoptotic pathway with a safe and effective cancer therapeutic potency.

Novel Nur77 ligand4,4'-Bipyridine cinnamamide derivativesX-ray crystallographyNur77/Bcl-2 apoptotic pathwayAnticancer activity

Jun Chen、Taige Zhao、Wenbin Hong、Hongsheng Li、Mingtao Ao、Yijing Zhong、Xiaoya Chen、Yingkun Qiu、Xiumin Wang、Zhen Wu、Tianwei Lin、Baicun Li、Xueqin Chen、Meijuan Fang

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State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research,School of Pharmaceutical Science,Xiamen University,Xiamen 361102,China

Xiamen Key Laboratory of Clinical Efficacy and Evidence Studies of Traditional Chinese Medicine,the First Affiliated Hospital of Xiamen University,School of Medicine,Xiamen University,Xiamen 361003,China

School of Pharmacy,Hubei University of Science and Technology,Xianning 437100,China

School of Life Sciences,Xiamen University,Xiamen 361102,China

Center of Respiratory Medicine,China-Japan Friendship Hospital,National Center for Respiratory Medicine,Institute of Respiratory Medicine,Chinese Academy of Medical Sciences,National Clinical Research Center for Respiratory Diseases,State Key Laboratory of Respiratory Health and Multimorbidity,Beijing 100029,China

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2024

10.1016/j.apsb.2024.07.012

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(12)