9LID

Crystal structure of human PKMYT1 protein kinase domain with Naphthyridinone Inhibitor compound 27

これはPDB形式変換不可エントリーです。

9LID の概要

• エントリーDOI: 10.2210/pdb9lid/pdb
• 関連するPDBエントリー: 9LGL 9LGN
• 分子名称: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, 4-[7-azanyl-8-(7-fluoranyl-1H-indazol-4-yl)-6-oxidanylidene-5H-1,5-naphthyridin-3-yl]-N,N-dimethyl-benzamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, transferase
• 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: 65461.91

構造登録者

Xu, Z.H.,Chen, S. (登録日: 2025-01-14, 公開日: 2025-05-14)

主引用文献

Chen, B.,Liu, X.,Mu, T.,Xu, J.,Zhao, D.,Dey, F.,Tang, Y.,Xu, Z.,Yang, J.,Huang, K.,Li, C.,Chen, S.,Zhu, S.,Wang, S.,Yao, X.,Yan, Z.,Tu, Y.,Dai, Y.,Qiu, H.,Yang, J.,Jiang, T.,Qi, Y.,Li, Y.,Shen, H.C.,Zhu, W.,Tan, X.,Wu, J.
Discovery of Naphthyridinone Derivatives as Selective and Potent PKMYT1 Inhibitors with Antitumor Efficacy.
J.Med.Chem., 68:8497-8515, 2025

PubMed Abstract: PKMYT1 is a crucial regulator of the cell cycle, particularly involved in the G2/M transition through the inhibitory phosphorylation of CDK1, and is a promising therapeutic target for cancer therapy. Data mining in the Roche kinome screen database identified a hit characterized by 100% PKMYT1 inhibitory activity at a 10 μM concentration, which was further validated with a PKMYT1 enzymatic assay showing double-digit nanomolar potency. The hit featured a quinolinone central core and a phenol headgroup. The replacement of the problematic phenol headgroup with an indazole moiety induced a flip in the kinase hinge cysteine and glycine residues, resulting in a series of derivatives with enhanced potency, superior kinome selectivity, and no GSH flag. Further structural fine-tuning led to the discovery of compound , a novel, selective, and potent PKMYT1 inhibitor with favorable oral pharmacokinetic profiles and promising in vivo antitumor efficacy.

PubMed: 40198752
DOI: 10.1021/acs.jmedchem.5c00114

実験手法

X-RAY DIFFRACTION (2.06 Å)