title: Inhibitors of the ERK mitogen-activated protein kinase cascade for targeting RAS mutant cancers.
abstract: Although recent success in identifying direct inhibitors of mutant Ras has begun to challenge the perception that Ras is "undruggable," the successful transition of these hits to the clinic remains uncertain. Therefore, current efforts to develop anti-Ras inhibitors are focused on indirect approaches, with inhibitors of the downstream effectors of Ras signaling having attracted the greatest current interest. Of the multitude of effectors, the Raf-MEK-ERK mitogen-activated protein kinase (MAPK) cascade is arguably the most attractive target for these efforts. In this chapter, we review the evidence for a key driver role for the ERK MAPK cascade in RAS mutant cancers and the status of efforts to develop inhibitors of MEK1/2 and ERK1/2 to block this pathway.
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Leanna
authors.initials: L
authors.lastname: Gentry
authors.affiliation: Discovery Oncology Merck Research Laboratories, Boston, Massachusetts, USA.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Samatar
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Electronic address: channing_der@med.unc.edu.
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Der
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins
keywords: MEK; Protein kinase inhibitors; Raf; Small GTPase