23ES

Crystal structure of human PKMYT1 protein kinase domain with Naphthyridinone Inhibitor compound 11

This is a non-PDB format compatible entry.

Summary for 23ES

• Entry DOI: 10.2210/pdb23es/pdb
• Descriptor: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, 3-azanyl-5-chloranyl-4-(7-fluoranyl-2H-indazol-4-yl)-7-methyl-1H-1,6-naphthyridin-2-one, SULFATE ION, ... (4 entities in total)
• Functional Keywords: structural genomics, structural genomics consortium, sgc, protein kinase, tyrosine- and threonine-specific kinase, membrane-associated protein kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 64601.87

Authors

Xu, Z.,Chen, S. (deposition date: 2026-02-04, release date: 2026-03-25, Last modification date: 2026-05-06)

Primary citation

Chen, B.,Liu, X.,Xu, J.,Zhao, D.,Tang, Y.,Xu, Z.,Yang, J.,Li, C.,Chen, S.,Zhu, S.,Wang, S.,Yao, X.,Yan, Z.,Weng, M.,Wang, P.,Ma, Y.,Wang, X.,Chen, W.K.,Tu, Y.,Qiu, H.,Yang, J.,Jiang, T.,Ji, Y.,Shen, H.C.,Zhu, W.,Tan, X.,Wu, J.
Discovery of Naphthyridinone Derivatives as Selective PKMYT1/WEE1 Dual Inhibitors for Cancer Therapy.
J.Med.Chem., 2026

PubMed Abstract: Dual inhibition of PKMYT1 and WEE1, key G2/M checkpoint kinases that phosphorylate CDK1 at T14 and Y15, offers a strategy for tumors with abrogated G1/S checkpoint and high replication stress. Building on our prior PKMYT1 chemotype, we designed 1,7-naphthyridinone derivatives by displacing crystallographic water (core 5'-N-Asp251) and adding a 7'-ring nitrogen to retain physicochemical properties. 5'-Site structure fine-tuning enhanced WEE1 engagement while preserving the PKMYT1-preferred hinge flip and superior kinome selectivity. Optimization identified compound with single-digit nM PKMYT1 NanoBRET and sub-μM WEE1 NanoBRET potency, translating to pCDK1 T14 IC50 4.9 nM and pCDK1 Y15 0.186 μM in HCC1569 cells. Kinome profiling confirmed favorable selectivity. In colorectal cancer organoids, outperformed our prior PKMYT1 inhibitor (), RP-6306, and WEE1 inhibitor AZD1775, with efficacy correlating to improved WEE1 activity. Compound also showed favorable ADME and early safety profiles, supporting dual checkpoint targeting in checkpoint-deficient cancers.

PubMed: 42003565
DOI: 10.1021/acs.jmedchem.5c03521

Experimental method

X-RAY DIFFRACTION (1.74 Å)