2401867-58-9

JBJ-08-178-01 is a potent, selective and covalent HER2 inhibitor with IC50 of 2.21 nM and 7.04 nM for HER2 WT and EGFR WT, targets multiple HER2 activating mutations, including exon 20 insertions as well as amplification (IC50 values<50 nM).JBJ-08-178-01 maintained potency against non-insertion mutations, including S310F, L755S, V777L, V842I, and exon 19 indel (755_757LREdelinsRP) of HER2.JBJ-08-178-01 exhibited a much greater degree of HER2-selectivity in Ba/F3 cell lines than in biochemical assays, owing to weak growth inhibition against Ba/F3 cells with WT EGFR (IC50=368 nM).JBJ-08-178-01 showed strong antitumoral activity in HER2- mutant or amplified cancers in vitro and in vivo.Treatment with JBJ-08-178-01 also led to a reduction in total HER2 by promoting proteasomal degradation of the receptor.JBJ-08-178-01 is a selective, dual-action inhibitor and destabilizer of HER2 with potential efficacy and tolerance against NSCLC harboring HER2 genetic alterations or amplification.