Small Molecule Inhibitor that Stabilizes the Autoinhibited Conformation of the Oncogenic Tyrosine Phosphatase SHP2

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Genetic mutations in PTPN11 (SHP2) are linked to childhood leukemias.
• These mutations lead to SHP2 hyperactivation by disrupting its autoinhibitory conformation.

Purpose of the Study:

• To identify and characterize a novel small molecule inhibitor targeting the activation-associated conformational change of SHP2.

Main Methods:

• Computer-aided drug design database screening.
• Cell-based assays.
• Biophysical techniques (fluorescence titration, thermal shift, microscale thermophoresis) for binding confirmation.

Main Results:

• Identified (E)-1-(1-(5-(3-(2,4-dichlorophenyl)acryloyl)-2-ethoxy-4-hydroxybenzyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-one (LY6) as an SHP2 inhibitor with IC50 of 9.8 μM.
• LY6 demonstrated 7-fold selectivity for SHP2 over SHP1.
• Confirmed direct binding of LY6 to SHP2.
• LY6 effectively inhibited SHP2-mediated signaling and proliferation in leukemia cells.
• Leukemia cells with PTPN11 mutations showed increased sensitivity to LY6.

Conclusions:

• LY6 is a potent and selective small molecule inhibitor of SHP2.
• This compound effectively targets SHP2 in leukemia cells, including those with activating mutations.
• LY6 serves as a promising lead compound for developing new anti-SHP2 therapies for leukemia.