title: Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973).
abstract: The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials.
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Rice
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Naing
authors.initials: N
authors.lastname: Aay
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Neel K
authors.initials: NK
authors.lastname: Anand
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Blazey
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Bowles
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Joerg
authors.initials: J
authors.lastname: Bussenius
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Simona
authors.initials: S
authors.lastname: Costanzo
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Jeffry K
authors.initials: JK
authors.lastname: Curtis
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Defina
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Larisa
authors.initials: L
authors.lastname: Dubenko
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Stefan
authors.initials: S
authors.lastname: Engst
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Anagha A
authors.initials: AA
authors.lastname: Joshi
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Abigail R
authors.initials: AR
authors.lastname: Kennedy
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Angie I
authors.initials: AI
authors.lastname: Kim
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Elena S
authors.initials: ES
authors.lastname: Koltun
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Lougheed
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Jean-Claire L
authors.initials: JC
authors.lastname: Manalo
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Martini
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Nuss
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Csaba J
authors.initials: CJ
authors.lastname: Peto
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Tsze H
authors.initials: TH
authors.lastname: Tsang
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Peiwen
authors.initials: P
authors.lastname: Yu
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Stuart
authors.initials: S
authors.lastname: Johnston
keywords: GDC-0973; MAPK pathway; MEK; XL518; cancer; kinase inhibitor