Identified as an inhibitor of AP-1-driven transcription, U0126 selectively inhibits the dual-specificity MAPK kinases MEK1 (IC50 = 72 nM) and MEK2 (IC50 = 58 nM) without significantly inhibiting PKC, Raf, ERK, JNK, p38, or CDKs.
Unlike ATP-competitive kinase inhibitors, U0126 binds an allosteric pocket adjacent to the Mg-ATP site on MEK1/2, locking the enzyme in a catalytically inactive conformation so it cannot phosphorylate ERK1/2.
U0126 is a standard preclinical tool compound for abolishing growth-factor- and RAS-driven ERK1/2 phosphorylation in oncology, synaptic plasticity, and long-term memory consolidation studies.