9LGL
Crystal structure of human PKMYT1 protein kinase domain with Naphthyridinone Inhibitor compound 6
This is a non-PDB format compatible entry.
Summary for 9LGL
| Entry DOI | 10.2210/pdb9lgl/pdb |
| Descriptor | Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, 3-azanyl-7-chloranyl-4-(2-methyl-5-oxidanyl-phenyl)-1H-1,5-naphthyridin-2-one, 1,2-ETHANEDIOL, ... (5 entities in total) |
| Functional Keywords | inhibitor, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 64309.34 |
| Authors | |
| Primary citation | 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 Cited by 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: 40198752DOI: 10.1021/acs.jmedchem.5c00114 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.17 Å) |
Structure validation
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