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Cancer Res. 2013 Jul 1;73(13):4050-4060. doi: 10.1158/0008-5472.CAN-12-3937. Epub 2013 May 10.

Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity.

Author information

1
Kamakura Research Laboratory, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
2
Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York.
3
Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
#
Contributed equally

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. 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.

PMID:
23667175
PMCID:
PMC4115369
DOI:
10.1158/0008-5472.CAN-12-3937
[Indexed for MEDLINE]
Free PMC Article

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