Allosteric Inhibitors\nof SHP2 with Therapeutic Potential for Cancer Treatment

SHP2,\na cytoplasmic protein-tyrosine phosphatase encoded by the PTPN11 gene,\nis involved in multiple cell signaling processes including Ras/MAPK\nand Hippo/YAP pathways. SHP2 has been shown to contribute to the progression\nof a number of cancer types including leukemia, gastric, and breast\ncancers. It also regulates T-cell activation by interacting with inhibitory\nimmune checkpoint receptors such as the programmed cell death 1 (PD-1)\nand B- and T-lymphocyte attenuator (BTLA). Thus, SHP2 inhibitors have\ndrawn great attention by both inhibiting tumor cell proliferation\nand activating T cell immune responses toward cancer cells. In this\nstudy, we report the identification of an allosteric SHP2 inhibitor\n1-(4-(6-bromonaphthalen-2-yl)­thiazol-2-yl)-4-methylpiperidin-4-amine\n(<b>23</b>) that locks SHP2 in a closed conformation by binding\nto the interface of the N-terminal SH2, C-terminal SH2, and phosphatase\ndomains. Compound <b>23</b> suppresses MAPK signaling pathway\nand YAP transcriptional activity and shows antitumor activity <i>in vivo</i>. The results indicate that allosteric inhibition\nof SHP2 could be a feasible approach for cancer therapy.