title: 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.affiliation: Discovery Oncology, Discovery Chemistry, and Roche Discovery Technologies, Hoffmann-La Roche, Inc., Nutley, New Jersey.
authors.forename: Sherif
authors.initials: S
authors.lastname: Daouti
authors.forename: Huisheng
authors.initials: H
authors.lastname: Wang
authors.forename: Wen-hui
authors.initials: WH
authors.lastname: Li
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kolinsky
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
authors.forename: Anthony
authors.initials: A
authors.lastname: Specian
authors.forename: Norman
authors.initials: N
authors.lastname: Kong
authors.forename: Nicholas
authors.initials: N
authors.lastname: Huby
authors.forename: Yang
authors.initials: Y
authors.lastname: Wen
authors.forename: Qing
authors.initials: Q
authors.lastname: Xiang
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Podlaski
authors.forename: Yang
authors.initials: Y
authors.lastname: He
authors.forename: Nader
authors.initials: N
authors.lastname: Fotouhi
authors.forename: David
authors.initials: D
authors.lastname: Heimbrook
authors.forename: Huifeng
authors.initials: H
authors.lastname: Niu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008252:Macaca fascicularis; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C539198:(2S,3S)-2-((R)-4-(4-(2-hydroxyethoxy)phenyl)-2,5-dioxo-imidazolidin-1-yl)-3-phenyl-N-(4-propionylthiazol-2-yl)butyramide; D000970:Antineoplastic Agents; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; C482128:MAP2K2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human