Discovery of Naphthyridinone Derivatives as Selective and Potent PKMYT1 Inhibitors with Antitumor Efficacy
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 <b>36</b>, a novel, selective, and potent PKMYT1 inhibitor with favorable oral pharmacokinetic profiles and promising in vivo antitumor efficacy.
Authors
- Tong Mu (ORCID: https://orcid.org/0009-0007-6717-1946)
- Zhiheng Xu (ORCID: https://orcid.org/0000-0002-4809-2851)
- Chi-Ho Li
- Dan Zhao (ORCID: https://orcid.org/0000-0001-5745-8010)
- Xuefei Tan (ORCID: https://orcid.org/0000-0001-7629-2255)
- Yunyue Qi
- Yifan Tu (ORCID: https://orcid.org/0000-0002-2728-6753)
- Yu Dai (ORCID: https://orcid.org/0000-0002-7432-226X)
- Juhao Yang
- Xiangyu Yao (ORCID: https://orcid.org/0000-0003-3672-5217)
- Fabian Dey (ORCID: https://orcid.org/0000-0002-4903-2869)
- Hong C. Shen (ORCID: https://orcid.org/0000-0002-3477-8932)
- Zhipeng Yan (ORCID: https://orcid.org/0000-0002-8463-1891)
- Jiasu Xu (ORCID: https://orcid.org/0000-0003-3625-8129)
- Jinbo Yang (ORCID: https://orcid.org/0000-0003-3517-9701)
- Xiaofeng Liu (ORCID: https://orcid.org/0000-0001-8990-8362)
- Shuai Chen (ORCID: https://orcid.org/0000-0003-0519-816X)
- Yi Li (ORCID: https://orcid.org/0000-0002-5048-6075)
- Wei Zhu (ORCID: https://orcid.org/0000-0003-4701-2474)
- Jun Wu (ORCID: https://orcid.org/0000-0002-5971-5057)
- Siyu Zhu (ORCID: https://orcid.org/0000-0001-5352-2273)
- Yang Tang (ORCID: https://orcid.org/0000-0003-1516-5433)
- Ke Huang (ORCID: https://orcid.org/0000-0003-1772-469X)
- Tianyi Jiang
- Hong-Xia Qiu
- Bo Chen
- Si‐Ling Wang
Institutions
- Roche (Switzerland) (CH)
- Roche (China) (CN)
- Medicina (PL)
- Institute of Medicinal Plant Development (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-04-08
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00114
- Citations
- 8
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 8.36