SYHA1815 (SYHA-1815) is a novel potent, selective RET inhibitor, inhibits the kinase activity of RET wild type (IC50=0.9 nM) and V804 mutant (IC50=3.1 nM).SYHA1815 demonstrated approximately 20-fold selectivity for RET over KDR, exhibited a favorable selectivity profile, with> 100-fold selectivity over 347 kinases, and >10-fold selectivity over 44 other kinases in a panel of 395 kinases.SYHA1815 significantly inhibited RET phosphorylation and activation of its key adaptor protein SHC and the downstream signaling molecules p-AKT and p-ERK1/2 in classical RET mutant-driven MTC cell line TT (RETC634W), effectively inhibited p-RET, p-SHC, and downstream p-AKT and p-ERK activity.SYHA1815 inhibited RET-induced cell proliferation and overcame V804 mutants (TT cell proliferation IC50<1.6 nM), suppressed RET-driven cell proliferation via cell-cycle arrest through c-Myc downregulation.SYHA1815 showed potent antitumor efficacy against RET- and RET gatekeeper mutant-driven cancers in vivo.
