Structure based design of selective SHP2 inhibitors by De novo design, synthesis and biological evaluation.

SHP2 phosphatase, encoded by the PTPN11 gene, is a non-receptor PTP, which plays an important role in growth factor, cytokine, integrin, hormone signaling pathways, and regulates cellular responses, such as proliferation, differentiation, adhesion migration and apoptosis. Many studies have reported that upregulation of SHP2 expression is closely related to human cancer, such as breast cancer, liver cancer and gastric cancer. Hence, SHP2 has become a promising target for cancer immunotherapy.

Scaffold-based novel SHP2 allosteric inhibitors design using Receptor-Ligand pharmacophore model, virtual screening and molecular dynamics.

SHP2 is a potential target for the development of novel therapies for SHP2-dependent cancers. In our research, with the aid of the 'Receptor-Ligand Pharmacophore' technique, a 3D-QSAR method was carried out to explore structure activity relationship of SHP2 allosteric inhibitors. Structure-based drug design was employed to optimize SHP099, an efficacious, potent, and selective SHP2 allosteric inhibitor.

3D QSAR Pharmacophore Based Virtual Screening for Identification of Potential Inhibitors for CDC25B.

Owing to its fundamental roles in cell cycle phases, the cell division cycle 25B (CDC25B) was broadly considered as potent clinical drug target for cancers. In this study, 3D QSAR pharmacophore models for CDC25B inhibitors were developed by the module of Hypogen. Three methods (cost analysis, test set prediction, and Fisher's test) were applied to validate that the models could be used to predict the biological activities of compounds.

Exploring the effect of D61G mutation on SHP2 cause gain of function activity by a molecular dynamics study.

Noonan syndrome (NS) is a common autosomal dominant congenital disorder which could cause the congenital cardiopathy and cancer predisposition. Previous studies reported that the knock-in mouse models of the mutant D61G of SHP2 exhibited the major features of NS, which demonstrated that the mutation D61G of SHP2 could cause NS. To explore the effect of D61G mutation on SHP2 and explain the high activity of the mutant, molecular dynamic simulations were performed on wild type (WT) of SHP2 and the mutated SHP2-D61G, respectively.

Synthesis, bioactivity, 3D-QSAR studies of novel dibenzofuran derivatives as PTP-MEG2 inhibitors.

PTP-MEG2 plays a critical role in the diverse cell signalling processes, so targeting PTP-MEG2 is a promising strategy for various human diseases treatments. In this study, a series of novel dibenzofuran derivatives was synthesized and assayed for their PTP-MEG2 inhibitory activities. 10a with highest inhibitory activity (320 nM) exhibited significant selectivity for PTP-MEG2 over its close homolog SHP2, CDC25 (IC50 > 50 μM).