TK-453 (TK453) is a potent, selective SHP2 allosteric inhibitor with IC50 of 18.76 and 179 nM for SHP2-WT and SHP2-E76K, respectively.
TK-453 has strong inhibitory effect on the enzyme activity of the SHP2-WT, and does not inhibit the activity of the SHP2-PTP catalytic domain, and homologues (SHP1 and PTP1B).
TK-453 binds SHP2-WT (KD=150 nM) and SHP2-E76K, higher affinity with SHP2 than SHP099.
TK-453 binds in the allosteric binding pocket at the junction of three domains and stabilizes the autoinhibition conformation of SHP2.
TK-453 alleviates imiquimod (IMQ)-induced inflammation in macrophages, inhibits the phosphorylation levels of p-IKKα/β and p-p65.
TK-453 significantly ameliorates imiquimod-triggered skin-like inflammation in mice via inhibition of IL-23/Th17 axis.
