Allosteric Inhibitors of SHP2 with Therapeutic Potential for Cancer Treatment

SHP2, a cytoplasmic protein-tyrosine phosphatase encoded by the PTPN11 gene, is involved in multiple cell signaling processes including Ras/MAPK and Hippo/YAP pathways. SHP2 has been shown to contribute to the progression of a number of cancer types including leukemia, gastric, and breast cancers. It also regulates T-cell activation by interacting with inhibitory immune checkpoint receptors such as the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA). Thus, SHP2 inhibitors have drawn great attention by both inhibiting tumor cell proliferation and activating T cell immune responses toward cancer cells. In this study, we report the identification of an allosteric SHP2 inhibitor 1-(4-(6-bromonaphthalen-2-yl)­thiazol-2-yl)-4-methylpiperidin-4-amine (<b>23</b>) that locks SHP2 in a closed conformation by binding to the interface of the N-terminal SH2, C-terminal SH2, and phosphatase domains. Compound <b>23</b> suppresses MAPK signaling pathway and YAP transcriptional activity and shows antitumor activity <i>in vivo</i>. The results indicate that allosteric inhibition of SHP2 could be a feasible approach for cancer therapy