2. Academic Validation
  3. Discovery of Naphthyridinone Derivatives as Selective and Potent PKMYT1 Inhibitors with Antitumor Efficacy

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-172759
    PKMYT1抑制剂
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