| Reference: |
Gilmartin, A.G., Bleam, M.R., Groy, A., et al. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res 17(5) 989-1000 (2011); Jing, J., Greshock, J., Holbrook, J.D., et al. Comprehensive predictive biomarker analysis for MEK inhibitor GSK1120212. Mol Cancer Ther 11(3) 720-729 (2012); Leung, E.Y., Kim, J.E., Askarian-Amiri, M., et al. Relationships between signaling pathway usage and sensitivity to a pathway inhibitor: Examination of trametinib responses in cultured breast cancer lines. PLoS One 9(8) 1-12 (2014).
;Uitdehaag, J.C.M., de Roos, J.A.D.M., van Doornmalen, A.M., et al. Comparison of the cancer gene targeting and biochemical selectivities of all targeted kinase inhibitors approved for clinical use. PLoS One 9(3) 1-13 (2014). |
| Application: |
The dual specificity mitogen-activated protein kinase kinases (MEK) isoforms MEK1 and MEK2 function in a RAS/RAF/MEK/ERK signaling pathway to control cell growth, survival, and differentiation. Trametinib is a potent inhibitor of both MEK 1 and 2 that works in an ATP-noncompetitive fashion (IC50s = 0.7 and 0.9 nM, respectively).1 It shows specificity for MEK1/2 over a panel of more than 180 kinases, including B-Raf, C-Raf, and MEK5.1 Trametinib blocks dual phosphorylation of ERK1/2 and stops cell cycling in cancer cell lines, both in vitro and in multiple tumor models in mice.1 Trametinib, alone or in combination with other chemotherapeutic drugs, targets a subset of cancer cells that can be characterized by specific biomarkers, such as BRAF, RAS, or CTNNB1 mutations. |
