Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of raf activity Journal Article
| Authors: | Ishii, N.; Harada, N.; Joseph, E. W.; Ohara, K.; Miura, T.; Sakamoto, H.; Matsuda, Y.; Tomii, Y.; Tachibana-Kondo, Y.; Iikura, H.; Aoki, T.; Shimma, N.; Arisawa, M.; Sowa, Y.; Poulikakos, P. I.; Rosen, N.; Aoki, Y.; Sakai, T. |
| Article Title: | Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of raf activity |
| Abstract: | 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. Wehave 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 standardMEKinhibitor 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. © 2013 American Association for Cancer Research. |
| Journal Title: | Cancer Research |
| Volume: | 73 |
| Issue: | 13 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2013-07-01 |
| Start Page: | 4050 |
| End Page: | 4060 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-12-3937 |
| PROVIDER: | scopus |
| PUBMED: | 23667175 |
| PMCID: | PMC4115369 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 August 2013" - "CODEN: CNREA" - "Source: Scopus" |
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