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

• DOI: 10.1016/j.apsb.2024.07.012
• Publication Date: 2024-07-14T09:29:09Z
• Authors: 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
• Keywords: Novel Nur77 ligand; Short Communication; Nur77/Bcl-2 apoptotic pathway; Therapeutics. Pharmacology; RM1-950; Anticancer activity; 4,4′-Bipyridine cinnamamide derivatives; X-ray crystallography

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 site B ligands have been identified excellent compounds. There are no co-crystal structures of effective agents at B, which greatly limits the development novel ligands. Moreover, lack pharmaceutical restricts proof concept. Herein, we developed a first-in-class ligand (NB1) that significantly inhibited cells by mediating Nur77/Bcl-2-related apoptotic effect mitochondria. X-ray crystallography suggests NB1 bound to with distinct binding mode. Importantly, showed favorable pharmacokinetic profiles safety, evidenced its good oral bioavailability in rats mortality, bodyweight loss, pathological damage 512.0 mg/kg dose mice. Furthermore, administration remarkable vivo efficacy MDA-MB-231 xenograft model. Together, our work discovers new generation activates Nur77/Bcl-2 pathway safe potency.