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Updated: Sep 30, 2025
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Proteolysis-targeting chimera molecules targeting SHP2
Dandan Yu1, Mengzhu Zheng1, Yang Liu2
1Hubei Key Laboratory of Natural Medicinal Chemistry & Resource Evaluation, School of Pharmacy, Tongji-Rongcheng Center for Biomedicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China.
Abstract:
SHP2 is a member of the non-receptor protein tyrosine phosphatases, encoded by PTPN11, and exhibits oncogenic activities. The close association between SHP2 and human cancer has made SHP2 a promising target for clinical therapy. Proteolysis-targeting chimera (PROTAC) technology utilizes the degradation mechanism of the ubiquitin proteasome system to degrade specific proteins. It has strong advantages compared with inhibitors. Here we list the four reported PROTAC molecules targeting SHP2 and summarize the recently reported SHP2 inhibitors which can provide lead compounds for designing new SHP2 PROTACs. We also introduce the dual PROTAC technology which may replace drug combinations to treat SHP2-related diseases.
Insights
SHP2 protein, a target in cancer therapy, can be degraded using Proteolysis-targeting chimera (PROTAC) technology. This review covers existing SHP2 PROTACs and inhibitors, exploring dual PROTACs for treating SHP2-related diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- SHP2 (encoded by PTPN11) is a non-receptor protein tyrosine phosphatase implicated in oncogenesis.
- The link between SHP2 and cancer makes it a significant therapeutic target.
- Proteolysis-targeting chimera (PROTAC) technology offers advantages over traditional inhibitors by inducing protein degradation.
Purpose of the Study:
- To review reported PROTAC molecules targeting SHP2.
- To summarize recent SHP2 inhibitors as potential leads for PROTAC development.
- To introduce dual PROTAC technology for SHP2-related diseases.
Main Methods:
- Literature review of published SHP2 PROTACs.
- Summary of recently reported SHP2 inhibitors.
- Discussion of dual PROTAC technology principles.
Main Results:
- Four PROTAC molecules targeting SHP2 have been reported.
- SHP2 inhibitors identified can serve as starting points for new PROTAC designs.
- Dual PROTAC technology presents a novel approach for treating SHP2-driven diseases.
Conclusions:
- PROTAC technology is a promising strategy for targeting SHP2 in cancer.
- Further development of SHP2 PROTACs is warranted.
- Dual PROTACs may offer an alternative to combination therapies for SHP2-related cancers.
