8Y7L

Crystal Structure of Nur77 LBD in complex with N-(2'-(4-hydroxypiperidin-1-yl)-[4,4'-bipyridin]-2-yl)cinnamamide

これはPDB形式変換不可エントリーです。

8Y7L の概要

• エントリーDOI: 10.2210/pdb8y7l/pdb
• 分子名称: Nuclear receptor subfamily 4immunitygroup A member 1, (~{E})-~{N}-[4-[2-(4-oxidanylpiperidin-1-yl)pyridin-4-yl]pyridin-2-yl]-3-phenyl-prop-2-enamide (3 entities in total)
• 機能のキーワード: complex, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 53410.08

構造登録者

Hong, W.B.,Lin, T.W. (登録日: 2024-02-04, 公開日: 2024-07-24, 最終更新日: 2025-01-29)

主引用文献

Chen, J.,Zhao, T.,Hong, W.,Li, H.,Ao, M.,Zhong, Y.,Chen, X.,Qiu, Y.,Wang, X.,Wu, Z.,Lin, T.,Li, B.,Chen, X.,Fang, M.
Discovery of a novel exceptionally potent and orally active Nur77 ligand NB1 with a distinct binding mode for cancer therapy.
Acta Pharm Sin B, 14:5493-5504, 2024

PubMed Abstract: 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 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.

PubMed: 39807329
DOI: 10.1016/j.apsb.2024.07.012

実験手法

X-RAY DIFFRACTION (2.683 Å)