1 research outputs found
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