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

  • J Med Chem. 2025 Apr 8. doi: 10.1021/acs.jmedchem.5c00114.
Bo Chen  1 ,  Xiaofeng Liu  1 ,  Tong Mu  1 ,  Jiasu Xu  1 ,  Dan Zhao  1 ,  Fabian Dey  2 ,  Yang Tang  3 ,  Zhiheng Xu  3 ,  June Yang  3 ,  Ke Huang  3 ,  Chiho Li  3 ,  Shuai Chen  3 ,  Sining Zhu  4 ,  Summer Wang  4 ,  XiangYu Yao  4 ,  Zhipeng Yan  4 ,  Yifan Tu  5 ,  Yu Dai  5 ,  Hongxia Qiu  5 ,  Juhao Yang  5 ,  Tianyi Jiang  5 ,  Yunyue Qi  6 ,  Yi Li  6 ,  Hong C Shen  1 ,  Wei Zhu  1 ,  Xuefei Tan  1 ,  Jun Wu  1
Affiliations
  • 1. Medicinal Chemistry, China Innovation Center of Roche, Shanghai 201203, China.
  • 2. Medicinal Chemistry, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel 4070, Switzerland.
  • 3. Lead Discovery, China Innovation Center of Roche, Shanghai 201203, China.
  • 4. Oncology Discovery, China Innovation Center of Roche, Shanghai 201203, China.
  • 5. Pharmaceutical Sciences, China Innovation Center of Roche, Shanghai 201203, China.
  • 6. Technical Research and Development, China Innovation Center of Roche, Shanghai 201203, China.
PMID: 40198752 DOI: 10.1021/acs.jmedchem.5c00114
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 36, a novel, selective, and potent PKMYT1 Inhibitor with favorable oral pharmacokinetic profiles and promising in vivo antitumor efficacy.

Products