Trametinib (GSK1120212) is an orally-available, tetrahydropyridopyrimidine-based, allosteric inhibitor of MEK1 and MEK2, with an IC50 of 1.6 and 3.4 nM when using B-Raf as its activator. [1] It is highly selective over broad inhibitory panel of 98 kinases at 10 uM. In vitro, Trametinib strongly inhibits human colorectal cancer cell lines known to have a constitutively active B-Raf or Ras mutation; in particular, IC50 inhibition values of HT-29, COLO205, HCT116, LS-174T, and SW620 are 0.48, 0.52, 5.7, 4.1, and 2.3 nM, respectively. [1]

Trametinib prevents Raf-dependent MEK phosphorylation (S217 for MEK1), resulting in prolonged p-Erk1/2 inhibition. [2] In a broad panel of cancer cell lines, Trametinib was shown to inhibit the MEK1/2-dependent activating dual phosphorylation of ERK1/2 on both T202 and Y204.

Trametinib has been shown to work in combination with other B-Raf inhibitors, overcoming resistant lines mediated by NRAS or MEK mutations. [3]