Discovery of Naphthyridinone Derivatives as Selective and Potent PKMYT1 Inhibitors with Antitumor Efficacy DOI

Bo Chen,

Xiaofeng Liu, Tong Mu

и другие.

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 8, 2025

PKMYT1 is a crucial regulator of the cell cycle, particularly involved in G2/M transition through inhibitory phosphorylation CDK1, and promising therapeutic target for cancer therapy. Data mining Roche kinome screen database identified hit characterized by 100% activity at 10 μM concentration, which was further validated with enzymatic assay showing double-digit nanomolar potency. The featured quinolinone central core phenol headgroup. replacement problematic headgroup an indazole moiety induced flip kinase hinge cysteine glycine residues, resulting series derivatives enhanced potency, superior selectivity, no GSH flag. Further structural fine-tuning led to discovery compound 36, novel, selective, potent inhibitor favorable oral pharmacokinetic profiles vivo antitumor efficacy.

Язык: Английский

Discovery of Naphthyridinone Derivatives as Selective and Potent PKMYT1 Inhibitors with Antitumor Efficacy DOI

Bo Chen,

Xiaofeng Liu, Tong Mu

и другие.

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 8, 2025

PKMYT1 is a crucial regulator of the cell cycle, particularly involved in G2/M transition through inhibitory phosphorylation CDK1, and promising therapeutic target for cancer therapy. Data mining Roche kinome screen database identified hit characterized by 100% activity at 10 μM concentration, which was further validated with enzymatic assay showing double-digit nanomolar potency. The featured quinolinone central core phenol headgroup. replacement problematic headgroup an indazole moiety induced flip kinase hinge cysteine glycine residues, resulting series derivatives enhanced potency, superior selectivity, no GSH flag. Further structural fine-tuning led to discovery compound 36, novel, selective, potent inhibitor favorable oral pharmacokinetic profiles vivo antitumor efficacy.

Язык: Английский

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