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
(23) that locks SHP2 in a closed conformation by binding
to the interface of the N-terminal SH2, C-terminal SH2, and phosphatase
domains. Compound 23 suppresses MAPK signaling pathway
and YAP transcriptional activity and shows antitumor activity in vivo. The results indicate that allosteric inhibition
of SHP2 could be a feasible approach for cancer therapy.