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Publication Abstract from PubMed

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 muM 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 36, a novel, selective, and potent PKMYT1 inhibitor with favorable oral pharmacokinetic profiles and promising in vivo antitumor efficacy.

Discovery of Naphthyridinone Derivatives as Selective and Potent PKMYT1 Inhibitors with Antitumor Efficacy.,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 HC, Zhu W, Tan X, Wu J J Med Chem. 2025 Apr 8. doi: 10.1021/acs.jmedchem.5c00114. PMID:40198752^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.