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

Qingqing Ye; Jingkun Ma; Peipei Wang; Chang Wang; Mei Sun; Yubo Zhou; Jia Li; Tao Liu

doi:10.1016/j.bmc.2023.117312

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. Epub 2023 May 2.

Authors

Qingqing Ye¹, Jingkun Ma², Peipei Wang³, Chang Wang⁴, Mei Sun¹, Yubo Zhou⁵, Jia Li⁶, Tao Liu⁷

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Apoptosis
Cell Cycle
Cell Cycle Proteins
Cell Line, Tumor
Cell Proliferation
Mice
Protein Kinase Inhibitors / pharmacology
Pyrimidines / pharmacology
Pyrimidinones* / pharmacology

Substances

Pyrimidinones
Pyrimidines
Cell Cycle Proteins
Protein Kinase Inhibitors
Antineoplastic Agents