title: Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors.
abstract: The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical efficacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors.
authors.affiliation: Discovery Oncology Merck Research Laboratories, Merck Research Laboratories, Rahway, New Jersey, USA.
authors.forename: Erick J
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authors.lastname: Morris
authors.forename: Sharda
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authors.lastname: Jha
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Restaino
authors.forename: Priya
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authors.lastname: Cooper
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authors.initials: D
authors.lastname: Carr
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authors.initials: Y
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authors.forename: Weihong
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authors.lastname: Dinunzio
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authors.forename: Shuxia
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authors.initials: EM
authors.lastname: Pinheiro
authors.forename: Jagdish
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authors.lastname: Desai
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authors.lastname: Xiao
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authors.lastname: Hruza
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authors.initials: J
authors.lastname: Wang
authors.forename: Joe
authors.initials: J
authors.lastname: Kelly
authors.forename: Sunil
authors.initials: S
authors.lastname: Paliwal
authors.forename: Xiaolei
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authors.lastname: Gao
authors.forename: Boga Sobhana
authors.initials: BS
authors.lastname: Babu
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.forename: Pierre
authors.initials: P
authors.lastname: Daublain
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Bart A
authors.initials: BA
authors.lastname: Lutterbach
authors.forename: Marc R
authors.initials: MR
authors.lastname: Pelletier
authors.forename: Ulrike
authors.initials: U
authors.lastname: Philippar
authors.forename: Phieng
authors.initials: P
authors.lastname: Siliphaivanh
authors.forename: David
authors.initials: D
authors.lastname: Witter
authors.forename: Paul
authors.initials: P
authors.lastname: Kirschmeier
authors.forename: W Robert
authors.initials: WR
authors.lastname: Bishop
authors.forename: Daniel
authors.initials: D
authors.lastname: Hicklin
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Lata
authors.initials: L
authors.lastname: Jayaraman
authors.forename: Leigh
authors.initials: L
authors.lastname: Zawel
authors.forename: Stephen
authors.initials: S
authors.lastname: Fawell
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Samatar
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases