American Association for Cancer Research
00085472can123937-sup-fig_s2.pdf (92.95 kB)

Supplementary Figure S2 from Enhanced Inhibition of ERK Signaling by a Novel Allosteric MEK Inhibitor, CH5126766, That Suppresses Feedback Reactivation of RAF Activity

Download (92.95 kB)
journal contribution
posted on 2023-03-30, 21:33 authored by Nobuya Ishii, Naoki Harada, Eric W. Joseph, Kazuhiro Ohara, Takaaki Miura, Hiroshi Sakamoto, Yutaka Matsuda, Yasushi Tomii, Yukako Tachibana-Kondo, Hitoshi Iikura, Toshihiro Aoki, Nobuo Shimma, Mikio Arisawa, Yoshihiro Sowa, Poulikos I. Poulikakos, Neal Rosen, Yuko Aoki, Toshiyuki Sakai

Supplementary Figure S2 - PDF file 92K, Inhibition of CRAF catalytic activity in a cell free CRAF assay with a peptide substrate of RAF family enzymes



Tumors with mutant RAS are often dependent on extracellular signal–regulated kinase (ERK) signaling for growth; however, MEK inhibitors have only marginal antitumor activity in these tumors. MEK inhibitors relieve ERK-dependent feedback inhibition of RAF and cause induction of MEK phosphorylation. We have now identified a MEK inhibitor, CH5126766 (RO5126766), that has the unique property of inhibiting RAF kinase as well. CH5126766 binding causes MEK to adopt a conformation in which it cannot be phosphorylated by and released from RAF. This results in formation of a stable MEK/RAF complex and inhibition of RAF kinase. Consistent with this mechanism, this drug does not induce MEK phosphorylation. CH5126766 inhibits ERK signaling output more effectively than a standard MEK inhibitor that induces MEK phosphorylation and has potent antitumor activity as well. These results suggest that relief of RAF feedback limits pathway inhibition by standard MEK inhibitors. CH5126766 represents a new type of MEK inhibitor that causes MEK to become a dominant-negative inhibitor of RAF and that, in doing so, may have enhanced therapeutic activity in ERK-dependent tumors with mutant RAS. Cancer Res; 73(13); 4050–60. ©2013 AACR.

Usage metrics

    Cancer Research



    Ref. manager