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Updated: Jun 23, 2025
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Advances in SHP2 tunnel allosteric inhibitors and bifunctional molecules
Zhichao Guo1, Yiping Duan1, Kai Sun1
1Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu, 211198, China.
Abstract:
SHP2 is a non-receptor tyrosine phosphatase encoded by PTPN11, which performs the functions of regulating cell proliferation, differentiation, apoptosis, and survival through removing tyrosine phosphorylation and modulating various signaling pathways. The overexpression of SHP2 or its mutations is related to developmental diseases and several cancers. Numerous allosteric inhibitors with striking inhibitory potency against SHP2 allosteric pockets have recently been identified, and several SHP2 tunnel allosteric inhibitors have been applied in clinical trials to treat cancers. However, based on clinical results, the efficacy of single-agent treatments has been proven to be suboptimal. Most clinical trials involving SHP2 inhibitors have adopted drug combination strategies. This review briefly discusses the research progress on SHP2 allosteric inhibitors and pathway-dependent drug combination strategies for SHP2 in cancer therapy. In addition, we summarize the current bifunctional molecules of SHP2 and elaborate on the design and structural optimization strategies of these bifunctional molecules in detail, offering further direction for the research on novel SHP2 inhibitors.
Insights
SHP2 inhibitors show promise in cancer therapy, but single-agent treatments are suboptimal. This review explores SHP2 allosteric inhibitors, combination strategies, and novel bifunctional molecule designs for improved efficacy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- SHP2 (PTPN11) is a tyrosine phosphatase regulating key cellular processes like proliferation and survival.
- SHP2 dysregulation, via overexpression or mutations, is linked to developmental disorders and cancers.
- Current SHP2 allosteric inhibitors show potent activity, with some in clinical cancer trials.
Purpose of the Study:
- To review research progress on SHP2 allosteric inhibitors.
- To discuss pathway-dependent drug combination strategies for SHP2 in cancer therapy.
- To summarize and elaborate on the design of bifunctional SHP2 molecules.
Main Methods:
- Literature review of SHP2 inhibitors and combination therapies.
- Analysis of clinical trial data regarding SHP2 inhibitor efficacy.
- Summary of structural optimization strategies for bifunctional SHP2 molecules.
Main Results:
- Single-agent SHP2 inhibitor therapy demonstrates suboptimal clinical efficacy.
- Drug combination strategies are prevalent in ongoing SHP2 inhibitor clinical trials.
- Bifunctional molecules targeting SHP2 are an emerging area of research.
Conclusions:
- Novel SHP2 inhibitors and combination strategies are crucial for effective cancer therapy.
- Understanding SHP2 pathway dependencies informs rational drug design.
- Further research into bifunctional SHP2 molecules may yield improved therapeutic agents.
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