2. Academic Validation
  3. Discovery of Naphthyridinone Derivatives as Selective PKMYT1/WEE1 Dual Inhibitors for Cancer Therapy

Discovery of Naphthyridinone Derivatives as Selective PKMYT1/WEE1 Dual Inhibitors for Cancer Therapy

  • J Med Chem. 2026 May 14;69(9):10380-10397. doi: 10.1021/acs.jmedchem.5c03521.
Bo Chen 1,  Xiaofeng Liu 1,  Jiasu Xu 1,  Dan Zhao 1,  Yang Tang 2,  Zhiheng Xu 2,  June Yang 2,  Chiho Li 2,  Shuai Chen 2,  Sining Zhu 3,  Summer Wang 3,  Xiangyu Yao 3,  Zhipeng Yan 3,  Minrui Weng 4,  Pan Wang 4,  Yanna Ma 4,  Xujun Wang 5,  Wenli Kelly Chen 4,  Yifan Tu 4,  Hongxia Qiu 4,  Juhao Yang 4,  Tianyi Jiang 4,  Ying Ji 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 Lead Discovery, China Innovation Center of Roche, Shanghai 201203, China.
  • 3 Oncology Discovery, China Innovation Center of Roche, Shanghai 201203, China.
  • 4 Pharmaceutical Sciences, China Innovation Center of Roche, Shanghai 201203, China.
  • 5 AI, Data and Digital, China Innovation Center of Roche, Shanghai 201203, China.
  • 6 Technical Research and Development, China Innovation Center of Roche, Shanghai 201203, China.
PMID: 42003565 DOI: 10.1021/acs.jmedchem.5c03521
Abstract

Dual inhibition of PKMYT1 and Wee1, key G2/M checkpoint kinases that phosphorylate CDK1 at T14 and Y15, offers a strategy for tumors with abrogated G1/S checkpoint and high replication stress. Building on our prior PKMYT1 chemotype, we designed 1,7-naphthyridinone derivatives by displacing crystallographic water (core 5'-N-Asp251) and adding a 7'-ring nitrogen to retain physicochemical properties. 5'-Site structure fine-tuning enhanced Wee1 engagement while preserving the PKMYT1-preferred hinge flip and superior kinome selectivity. Optimization identified compound 24 with single-digit nM PKMYT1 NanoBRET and sub-μM Wee1 NanoBRET potency, translating to pCDK1 T14 IC50 4.9 nM and pCDK1 Y15 0.186 μM in HCC1569 cells. Kinome profiling confirmed favorable selectivity. In colorectal Cancer organoids, 24 outperformed our prior PKMYT1 Inhibitor (6), RP-6306, and Wee1 Inhibitor AZD1775, with efficacy correlating to improved Wee1 activity. Compound 24 also showed favorable in vitro ADME and early safety profiles, supporting dual checkpoint targeting in checkpoint-deficient cancers.

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