2. Academic Validation
  3. Design, synthesis and activity study of a novel PI3K degradation by hijacking VHL E3 ubiquitin ligase

Design, synthesis and activity study of a novel PI3K degradation by hijacking VHL E3 ubiquitin ligase

  • Bioorg Med Chem. 2022 May 1;61:116707. doi: 10.1016/j.bmc.2022.116707.
Haili Wang 1,  Chuchu Li 1,  Xiaoqing Liu 2,  Mingliang Ma 3
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
  • 2 Shanghai University of Medicine & Health Sciences affiliated Zhoupu Hospital, Shanghai 201318, China. Electronic address: 18121248686@126.com.
  • 3 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China; Key Laboratory of Brain Functional Genomics-Ministry of Education, School of Life Science, East China Normal University, Shanghai 200062, China. Electronic address: mlma@brain.ecnu.edu.cn.
PMID: 35344835 DOI: 10.1016/j.bmc.2022.116707
Abstract

PI3K kinase plays an important role in regulating key processes in cells, such as cell growth, metabolism, proliferation, and Apoptosis. The overexpression of PI3K kinase exists in many cancers. The proteolytic target chimera (PROTAC) technology is a new technology that uses the ubiquitin-proteasome system to degrade a given target protein. It has been described that CRBN-based PROTAC targets the degradation of PI3K kinase. However, PROTAC based on VHL has not been reported yet. Here, we connected the previously obtained highly active PI3K Inhibitor to the VHL ligand through different small molecules, and obtained a series of PROTAC molecules targeting PI3K kinase. Obtain the most active compound through screening. It provides evidence for the feasibility of PROTAC technology to recruit VHL E3 Ligase in PI3K kinase.

Keywords

Degradation; PI3K; PROTAC; VHL.

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