Biological Activity of GSK1120212 (JTP-74057):
GSK1120212 (JTP-74057) is a reversible, selective, allosteric MEK1/MEK2 kinase activity inhibitor with IC50 of 0.7 and 0.9 nM for MEK1 and MEK2.  GSK1120212 (JTP-74057) strongly prevented the activities of MEK1 and MEK2 kinases rather than activities of other 98 kinases. After treatment of GSK1120212 (JTP-74057), it led to the growth inhibition and upregulate p15INK4b and/or p27KIP1 in most of the colorectal cancer cell lines tested. In nude animal mice studies, JTP-74057 inhibited tumor growth of HT-29 and COLO205 xenografts when GSK1120212 (JTP-74057) was daily oral administered for 14 days. GSK1120212 (JTP-74057) showed an additive or a synergistic action in combination with the standard-of-care agents, 5-fluorouracil, oxaliplatin or SN-38. Sensitivity to JTP-74057-induced apoptosis may be an important factor for the estimation of in vivo efficacy, and sensitivity was enhanced by an Akt inhibitor.  GSK1120212 (JTP-74057) is originally developed by GlaxoSmithKline and is recruiting for phase I clinical trials for the treatment of solid tumors.