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Updated: Jun 1, 2026
Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
Small molecule inhibitors of SHP2 tyrosine phosphatase discovered by virtual screening
1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
Abstract:
SHP2, encoded by PTPN11, is a non-receptor protein tyrosine phosphatase (PTP) containing two tandem Src homology-2 (SH2) domains. It is expressed ubiquitously and plays critical roles in growth factor mediated processes, primarily by promoting the activation of the RAS/ERK signaling pathway. Genetic and biochemical studies have identified SHP2 as the first bona fide oncoprotein in the PTP superfamily, and a promising target for anti-cancer and anti-leukemia therapy. Here, we report a structure-based approach to identify SHP2 inhibitors with a novel scaffold. Through sequential virtual screenings and in vitro inhibition assays, a reversible competitive SHP2 inhibitor (C21) was identified. C21 is structurally distinct from all known SHP2 inhibitors. Combining molecular dynamics simulation and binding free energy calculation, a most likely binding mode of C21 with SHP2 is proposed, and further validated by site-directed mutagenesis and structure-activity relationship studies. This binding mode is consistent with the observed potency and specificity of C21, and reveals the molecular determinants for further optimization based on the new scaffold.
Insights
Researchers identified a novel SHP2 inhibitor (C21) using a structure-based approach. This discovery offers a new therapeutic strategy for cancers driven by SHP2 (protein tyrosine phosphatase, non-receptor type 11) signaling.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- SHP2 (encoded by PTPN11) is a protein tyrosine phosphatase crucial for growth factor signaling pathways like RAS/ERK.
- SHP2 is recognized as an oncoprotein and a therapeutic target for various cancers and leukemia.
Purpose of the Study:
- To identify novel SHP2 inhibitors using a structure-based drug discovery approach.
- To characterize a newly identified inhibitor with a unique chemical scaffold.
Main Methods:
- Structure-based virtual screening and in vitro inhibition assays were employed.
- Molecular dynamics simulations and binding free energy calculations were used to determine the binding mode.
- Site-directed mutagenesis and structure-activity relationship studies validated the findings.
Main Results:
- A novel, reversible, competitive SHP2 inhibitor, designated C21, was identified.
- C21 possesses a chemical structure distinct from existing SHP2 inhibitors.
- The study elucidated the binding mode of C21 with SHP2, confirming its potency and specificity.
Conclusions:
- The identified inhibitor C21 represents a promising lead compound with a novel scaffold for SHP2-targeted therapies.
- The structure-activity relationship and binding mode provide a foundation for further optimization of C21.
- This work expands the chemical space for developing effective SHP2 inhibitors for anti-cancer applications.
