2. Academic Validation
  3. Discovery of pyrido[4,3-d]pyrimidinone derivatives as novel Wee1 inhibitors

Discovery of pyrido[4,3-d]pyrimidinone derivatives as novel Wee1 inhibitors

  • Bioorg Med Chem. 2023 May 3:87:117312. doi: 10.1016/j.bmc.2023.117312.
Qingqing Ye 1,  Jingkun Ma 2,  Peipei Wang 3,  Chang Wang 4,  Mei Sun 1,  Yubo Zhou 5,  Jia Li 6,  Tao Liu 7
Affiliations

Affiliations

  • 1 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong 528400, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong 528400, China. Electronic address: ybzhou@mail.shcnc.ac.cn.
  • 6 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong 528400, China. Electronic address: jli@simm.ac.cn.
  • 7 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: lt601@zju.edu.cn.
PMID: 37167712 DOI: 10.1016/j.bmc.2023.117312
Abstract

Wee1 has emerged as a potential target in Cancer therapy due to its critical role in the regulation of the cell cycle. Here, we describe a series of Wee1 inhibitors with a novel scaffold that are potent inhibitors of this kinase (IC50 = 19-1485 nM). These inhibitors demonstrated robust cytotoxicity in MV-4-11 and T47D cell lines (MV-4-11 IC50 = 660-2690 nM, T47D IC50 = 2670-20,000 nM) and displayed good stability in mouse liver microsomes in vitro. Additionally, compound 34 showed remarkable selectivity (more than 500-fold) over the Other 9 kinases. Further mechanistic studies demonstrated that compound 34 displayed measurable effects on downstream biomarkers and induced Cancer cell Apoptosis and cell cycle arrest in the G0/G1 phase. Taken together, these results show that compound 34, potentially a leading Wee1 Inhibitor, warrants further investigation.

Keywords

Scaffold hopping; Wee1 inhibitor.

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