App Note: InCELL Pulse Cellular Target Engagement Assays for Characterizing Novel Small Molecule Inhibitors of Oncogenic SHP2 Variants

Version:: 20201
Year:: 2021

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SHP2 (Src-homology 2 domain-containing phosphatase 2) is a protein tyrosine phosphatase encoded by the human PTPN11 gene.SHP2 is a key player in many signaling cascades such as the JAK/STAT, Ras-Raf-MAP kinase, and PI3 kinase pathways. Mutations of PTPN11 that cause aberrant SHP2 activity have been implicated in several cancers including leukemia and breast cancer. Abnormal SHP2 function has also been well-documented in 50% of Noonan Syndrome patients. Because of its role in multiple pathways and diseases, SHP2 continues to be a critical therapeutic target.

Inhibiting SHP2 with orthosteric small molecules has been challenging in the past. Drugs either exhibited low efficacy, or failed to bind selectively to SHP2 owing to its highly conserved active site. Recently however, a novel allosteric SHP2 inhibitor (SHP099) by Novartis has revealed the existence of druggable allosteric sites on SHP2, opening a new avenue for SHP2 drug discovery. SHP099 displayed remarkable selectivity and efficacy for SHP25. However, further research revealed that SHP099 and similar inhibitors were only effective on wild-type SHP2 (SHP2-WT) and not the oncogenic variants. Such a finding has created a need for allosteric SHP2 inhibitors that selectively bind to disease relevant SHP2 variants. Since the discovery of allosteric SHP2 inhibitors, efforts to find similar therapeutics that successfully target SHP2 variants continues.