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

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

  • Cancer Res. 2013 Jul 1;73(13):4050-4060. doi: 10.1158/0008-5472.CAN-12-3937.
Nobuya Ishii  # 1,  Naoki Harada  # 1,  Eric W Joseph 2,  Kazuhiro Ohara 1,  Takaaki Miura 1,  Hiroshi Sakamoto 1,  Yutaka Matsuda 1,  Yasushi Tomii 1,  Yukako Tachibana-Kondo 1,  Hitoshi Iikura 1,  Toshihiro Aoki 1,  Nobuo Shimma 1,  Mikio Arisawa 1,  Yoshihiro Sowa 3,  Poulikos I Poulikakos 2,  Neal Rosen 2,  Yuko Aoki 1,  Toshiyuki Sakai 3
Affiliations

Affiliations

  • 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.
PMID: 23667175 DOI: 10.1158/0008-5472.CAN-12-3937
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18652
    98.99%, MEK/RAF 抑制剂
    MEK; Raf
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