Enhanced Inhibition of ERK Signaling by a Novel Allosteric MEK Inhibitor, CH5126766, That Suppresses Feedback Reactivation of RAF Activity
| Autor: | Yasushi Tomii, Hiroshi Sakamoto, Toshihiro Aoki, Kazuhiro Ohara, Poulikos I. Poulikakos, Yoshihiro Sowa, Nobuo Shimma, Yuko Aoki, Neal Rosen, Mikio Arisawa, Yukako Tachibana-Kondo, Nobuya Ishii, Eric W. Joseph, Hitoshi Iikura, Naoki Harada, Toshiyuki Sakai, Takaaki Miura, Yutaka Matsuda |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Proto-Oncogene Proteins B-raf
MAPK/ERK pathway Cancer Research MAP Kinase Signaling System Allosteric regulation MAP Kinase Kinase 1 Mice Nude Antineoplastic Agents Biology Article Proto-Oncogene Proteins p21(ras) Mice Enzyme activator Allosteric Regulation Coumarins Cell Line Tumor Proto-Oncogene Proteins Animals Humans Phosphorylation Extracellular Signal-Regulated MAP Kinases Feedback Physiological Mice Inbred BALB C Kinase MEK inhibitor Xenograft Model Antitumor Assays Cell biology Enzyme Activation Proto-Oncogene Proteins c-raf Oncology ras Proteins Female Protein Processing Post-Translational Protein Binding |
| Zdroj: | Cancer Research. 73:4050-4060 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-12-3937 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|