2. Academic Validation
  3. Design, synthesis, and biological evaluation of Wee1 kinase degraders

Design, synthesis, and biological evaluation of Wee1 kinase degraders

  • Eur J Med Chem. 2022 Dec 5:243:114786. doi: 10.1016/j.ejmech.2022.114786.
Shulei Zhu 1,  Jieyu Liu 2,  Donghuai Xiao 1,  Peipei Wang 3,  Jingkun Ma 2,  Xiaobei Hu 4,  Jingfeng Fu 2,  Yubo Zhou 5,  Jia Li 6,  Wei Lu 7
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China.
  • 2 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China.
  • 3 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
  • 4 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, PR China.
  • 5 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, PR China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. Electronic address: [email protected].
  • 6 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, PR China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. Electronic address: [email protected].
  • 7 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China. Electronic address: [email protected].
PMID: 36170799 DOI: 10.1016/j.ejmech.2022.114786
Abstract

Proteolysis targeting chimera (PROTAC) technology has received widespread attention in recent years as a promising strategy for drug development. Herein, we report a series of novel Wee1 degraders, which were designed and synthesized based on PROTAC technology by linking AZD1775 with CRBN ligands through linkers of different lengths and types. All degraders could effectively and completely degrade cellular Wee1 protein in MV-4-11 cell line at IC50 concentrations. Preliminary assessments identified 42a as the most active degrader, which possessed potent antiproliferative activity and induced CRBN- and proteasome-dependent degradation of Wee1. Moreover, 42a also exhibited a time- and concentration-dependent depletion manner and inducing cell cycle arrest in G0/G1 phase and Cancer cell Apoptosis. More importantly, 42a showed acceptable in vitro and in vivo pharmacokinetic properties and displayed rapid and sustained Wee1 degradation ability in vivo. Taken together, these findings contribute to understanding the development of PROTACs and demonstrate that our Wee1-targeting PROTAC strategy has potential novel applications in Cancer therapy.

Keywords

CRBN; Degradation; PROTAC; Wee1.

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