Characterization of a novel mitogen-activated protein kinase kinase 1/2 inhibitor with a unique mechanism of action for cancer therapy.

Abstract

The mitogen-activated protein kinase (MAPK) signal transduction pathway plays a central role in regulating tumor cell growth, survival, differentiation, and angiogenesis. The key components of the Ras/Raf/MEK/ERK signal module are frequently altered in human cancers. Targeting this pathway represents a promising anticancer strategy. Small molecule inhibitors targeting MEK1/2 have shown promise in the clinic; however, ultimate clinical proof-of-concept remains elusive. Here, we report a potent and highly selective non-ATP-competitive MEK1/2 inhibitor, RO4927350, with a novel chemical structure and unique mechanism of action. It selectively blocks the MAPK pathway signaling both in vitro and in vivo, which results in significant antitumor efficacy in a broad spectrum of tumor models. Compared with previously reported MEK inhibitors, RO4927350 inhibits not only ERK1/2 but also MEK1/2 phosphorylation. In cancer cells, high basal levels of phospho-MEK1/2 rather than phospho-ERK1/2 seem to correlate with greater sensitivity to RO4927350. Furthermore, RO4927350 prevents a feedback increase in MEK phosphorylation, which has been observed with other MEK inhibitors. We show that B-Raf rather than C-Raf plays a critical role in the feedback regulation. The unique MAPK signaling blockade mediated by RO4927350 in cancer may reduce the risk of developing drug resistance. Thus, RO4927350 represents a novel therapeutic modality in cancers with aberrant MAPK pathway activation.

• Authors: Sherif Daouti, Huisheng Wang, Wen-hui Li, Brian Higgins, Kenneth Kolinsky, Kathryn Packman, Anthony Specian Jr, Norman Kong, Nicholas Huby, Yang Wen, Qing Xiang, Frank J Podlaski, Yang He, Nader Fotouhi, David Heimbrook, Huifeng Niu
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 5 Pg. 1924-32 (Mar 01 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19244124 (Publication Type: Journal Article)

Chemical References

• (2S,3S)-2-((R)-4-(4-(2-hydroxyethoxy)phenyl)-2,5-dioxo-imidazolidin-1-yl)-3-phenyl-N-(4-propionylthiazol-2-yl)butyramide
• Antineoplastic Agents
• Imidazoles
• Protein Kinase Inhibitors
• Thiazoles
• MAP2K2 protein, human
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Female
• Humans
• Imidazoles (pharmacology)
• MAP Kinase Kinase 1 (antagonists & inhibitors, metabolism)
• MAP Kinase Kinase 2 (antagonists & inhibitors, metabolism)
• MAP Kinase Signaling System (drug effects)
• Macaca fascicularis
• Mice
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Thiazoles (pharmacology)