Dual mechanism MAP2K inhibitors bind MAP2Ks

Stable Identifier
Reaction [binding]
Homo sapiens
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Although mutations in MAP2K proteins are infrequent in human cancers, the position of these kinases downstream of RAS and RAF make them good candidates for therapeutic targeting. Dual mechanism inhibitors such as trametinib bind to non-phosphorylated MAP2K proteins, inhibiting their MAPK-directed kinase activity as well as preventing their phosphorylation by RAF proteins (Hatzivassiliou et al, 2013; Lito et al, 2014; Ishii et al, 2013; reviewed in Samatar and Poulikakos, 2014).

Literature References
PubMed ID Title Journal Year
24746704 Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors

Lukacs, C, Morikami, K, Solomon, M, Gadal, S, Lowe, S, Ohara, K, Miura, T, Joseph, E, Fellmann, C, Lito, P, Saborowski, M, Kastenhuber, E, Rosen, N, Ishii, N, Saborowski, A, Yue, J

Cancer Cell 2014
23667175 Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity

Sakai, T, Shimma, N, Tomii, Y, Sowa, Y, Tachibana-Kondo, Y, Aoki, T, Poulikakos, PI, Matsuda, Y, Joseph, EW, Sakamoto, H, Aoki, Y, Iikura, H, Arisawa, M, Harada, N, Ohara, K, Miura, T, Rosen, N, Ishii, N

Cancer Res. 2013
23934108 Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers

Merchant, M, Haling, JR, Luoh, SM, Wiesmann, C, Price, S, Heald, R, Ultsch, M, Hatzivassiliou, G, Belvin, M, Peck, A, Ludlam, MJ, Zak, M, Hewitt, JF, Malek, S, Chan, J, Orr, C, Friedman, LS, Anderson, DJ, Hoeflich, KP, Song, K, Chen, H

Nature 2013
25435214 Targeting RAS-ERK signalling in cancer: promises and challenges

Poulikakos, PI, Samatar, AA

Nat Rev Drug Discov 2014
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