Structure-based design, synthesis and biological evaluation of aminopyrazines as highly potent, selective, and cellularly active allosteric SHP2 inhibitors

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) encoded by the proto-oncogene PTPN11 is the first identified non-receptor protein tyrosine phosphatase. SHP2 dysregulation contrib-utes to the pathogenesis of different cancers, making SHP2 a promising therapeutic target for cancer therapy. In this article, we report the structure-guided design based on the well-characterized SHP2 inhibitor SHP099, extensive structure-activity relationship studies (SARs) of aminopyrazines, biochem-ical characterization and cellular potency. These medicinal chemistry efforts lead to the discovery of the lead compound TK-453, which potently inhibits SHP2 (SHP2(WT) IC50 = 0.023 mu M, Delta Tm = 7.01 degrees C) in a reversible and noncompetitive manner. TK-453 exhibits high selectivity over SHP2(PTP), SHP1 and PTP1B, and may bind at the tunnel allosteric site of SHP2 as SHP099. As the key pharmacophore, the ami-nopyrazine scaffold not only reorganizes the cationic-pi stacking interaction with R111 via the novel hydrogen bond interaction between the S atom of thioether linker and T219, but also mediates a hydrogen bond with E250. In vitro studies indicate that TK-453 inhibits proliferation of HeLa, KYSE-70 and THP-1 cells moderately and induces apoptosis of Hela cells. Further mechanistic studies suggest that TK-453 can decrease the phosphorylation levels of AKT and Erk1/2 in HeLa and KYSE-70 cells. Collectively, TK-453 is a highly potent, selective, and cellularly active allosteric SHP2 inhibitor that modulates the phosphorylation of SHP2-mediated AKT and Erk cell signaling pathways by inhibiting the phosphatase activity of SHP2. (C) 2022 Elsevier Masson SAS. All rights reserved.

Automated summary

The study presents a highly potent, selective, and cellularly active allosteric SHP2 inhibitor TK-453, which modulates the phosphorylation of cell signaling pathways by inhibiting the phosphatase activity of SHP2.