Novel PROTACs for degradation of SHP2 protein

Mengzhu Zheng; Yang Liu; Canrong Wu; Kaiyin Yang; Qiqi Wang; Yirong Zhou; Lixia Chen; Hua Li

doi:10.1016/j.bioorg.2021.104788

Novel PROTACs for degradation of SHP2 protein

Bioorg Chem. 2021 May:110:104788. doi: 10.1016/j.bioorg.2021.104788. Epub 2021 Mar 1.

Authors

Mengzhu Zheng¹, Yang Liu², Canrong Wu¹, Kaiyin Yang¹, Qiqi Wang², Yirong Zhou³, Lixia Chen⁴, Hua Li⁵

Affiliations

¹ Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
² Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
³ Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: zhouyirong@hust.edu.cn.
⁴ Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: syzyclx@163.com.
⁵ Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: li_hua@hust.edu.cn.

PMID: 33706076
DOI: 10.1016/j.bioorg.2021.104788

Abstract

Protein tyrosine phosphatase SHP2 is a member of PTPs family associated with cancer such as leukemia, non-small cell lung cancer, breast cancer, and so on. SHP2 is a promising target for drug development, and consequently it is of great significance to develop SHP2 inhibitors. Herein, we report CRBN-recruiting PROTAC molecules targeting SHP2 by connecting pomalidomide with SHP099, an allosteric inhibitor of SHP2. Among them, SP4 significantly inhibited the growth of Hela cells, compared with SHP099, its activity increased 100 times. In addition, it can significantly induce SHP2 degradation and cell apoptosis. Further study of SHP2-protac may have important significance for the treatment of SHP2 related diseases.

Keywords: PROTAC; Protein degrader; SHP2.

Publication types

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

MeSH terms

Cell Cycle / drug effects
Cell Survival / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Docking Simulation
Molecular Structure
Piperidines / chemistry
Piperidines / pharmacology*
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors*
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
Thalidomide / analogs & derivatives*
Thalidomide / chemistry
Thalidomide / pharmacology

Substances

Enzyme Inhibitors
Piperidines
Pyrimidines
SHP099
Thalidomide
pomalidomide
PTPN11 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 11