Delving into the Latest Updates on RO4927350 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

MEK1 inhibitors(Dual specificity mitogen-activated protein kinase kinase 1 inhibitors), MEK2 inhibitors(Dual specificity mitogen-activated protein kinase kinase 2 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

Neoplasms

Originator Organization

Hoffmann-La Roche, Inc.

Active Organization-

Inactive Organization

Hoffmann-La Roche, Inc.

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC27H28N4O6S

InChIKeyRKKBPPTYPGTSEA-FNVCAUGXSA-N

CAS Registry876755-27-0

AbstractThe 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. [Cancer Res 2009;69(5):1924–32

100 Deals associated with RO4927350

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