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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

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Crystallographic landscape of SHP2 provides molecular insights for SHP2 targeted drug discovery

Yihui Song1,2, Xinyu Yang1, Shu Wang1

  • 1School of Pharmaceutical Sciences, Zhengzhou University, 450001, Henan, Zhengzhou, China.

Medicinal Research Reviews
|May 16, 2022
PubMed

Insights

Protein tyrosine phosphatase SHP2 (PTPN11) is a key cancer target. This review details SHP2 structures and inhibitor binding, aiding the development of new cancer therapies like PROTACs.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • The protein tyrosine phosphatase SHP2, encoded by PTPN11, is a critical target in cancer therapy.
  • SHP2's conformational dynamics between closed and open states offer therapeutic intervention points for SHP2-related diseases.
  • Several SHP2 allosteric inhibitors are currently in clinical trials for various cancer treatments.

Purpose of the Study:

  • To review the structural landscape of SHP2 under physiological and pathological conditions.
  • To analyze the binding models of SHP2/inhibitor complexes.
  • To provide insights for structure-guided design of novel SHP2 inhibitors and discuss emerging PROTAC technology.

Main Methods:

  • Literature review focusing on structural data of SHP2.
  • Analysis of co-crystal structures of SHP2/inhibitor complexes.
  • Discussion of proteolysis targeting chimeric (PROTAC) based SHP2 degraders.

Main Results:

  • Detailed overview of SHP2 structural conformations in different conditions.
  • Comprehensive analysis of SHP2-inhibitor binding interactions.
  • Highlighting the therapeutic potential of SHP2 inhibitors and PROTACs in cancer.

Conclusions:

  • Understanding SHP2's structural features under pathological conditions is crucial for designing effective inhibitors.
  • Co-crystal structures provide a foundation for structure-guided drug design targeting SHP2.
  • SHP2 targeted therapies, including inhibitors and PROTACs, show significant promise for cancer treatment.
Keywords:
SHP2 inhibitorsbinding modelsdrug discoveryprotein tyrosine phosphatasestructural landscape

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