Discovery Of Inhibitors Of Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2

Protein phosphorylation and dephosphorylation are common protein modification methods in organisms,that are involved in the processes of cell growth,proliferation,differentiation,and apoptosis.SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene,the function is to remove the phosphate groups of the phosphorylated tyrosine residues in the protein.SHP2 is widely expressed in many human issues.Pathogenic mutations and aberrant expression of SHP2 lead to lots of immune diseases,metabolic diseases and cancers.And SHP2 is involved in varieties of signaling pathways,including RAS/MAPK and PD-1/PD-L1 pathways.The combination of SHP2 inhibitors and other targeted drugs is a promising strategy,therefore the research of SHP2 inhibitors has become a hot topic in recent years.Rational drug design is very important in drug discovery.Structure-based drug design could make full use of the three-dimensional structural information to guide the structural modification and optimization of small molecule drugs,and obtain inhibitors with high specificity and affinity.X-ray crystallography is the most widely used structural biology technology in drug design.By crystal growth,collection of diffraction data and structural analysi,gain the crystal structure of protein-ligand complex and clarify the interaction.In this study,I have purified the prokaryotic expression of amino acids 1-525 of SHP2 protein,grown SHP2 crystals,and soaked small molecules with high affinity for SHP2.Then crystal diffraction data was collected by X-ray diffraction,and finally two structures of the SHP2ligand complex were obtained.The two compounds,PB17-026-01 and PB17-036-01,occupied the classical allosteric site of SHP2 protein,with 2.2 ? and 3 ? respectively.And Both had high affinity for SHP2(IC50=38.89 nM and IC50=645 nM).The compounds offer a new scaffold and provide valuable information for the design of efficient SHP2 inhibitors.