Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of raf activity Academic Article uri icon

Overview

MeSH Major

  • Antineoplastic Agents
  • Coumarins
  • MAP Kinase Kinase 1
  • MAP Kinase Signaling System
  • Proto-Oncogene Proteins B-raf

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.

publication date

  • July 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4115369

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-12-3937

PubMed ID

  • 23667175

Additional Document Info

start page

  • 4050

end page

  • 60

volume

  • 73

number

  • 13