title: Pyrazolopyridine Inhibitors of B-Raf(V600E). Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors.
abstract: The V600E mutation of B-Raf kinase results in constitutive activation of the MAPK signaling pathway and is present in approximately 7% of all cancers. Using structure-based design, a novel series of pyrazolopyridine inhibitors of B-Raf(V600E) was developed. Optimization led to the identification of 3-methoxy pyrazolopyridines 17 and 19, potent, selective, and orally bioavailable agents that inhibited tumor growth in a mouse xenograft model driven by B-Raf(V600E) with no effect on body weight. On the basis of their in vivo efficacy and preliminary safety profiles, 17 and 19 were selected for further preclinical evaluation.
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Wenglowsky
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Kateri A
authors.initials: KA
authors.lastname: Ahrendt
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aliagas
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Bruno
authors.initials: B
authors.lastname: Alicke
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Buckmelter
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Edna F
authors.initials: EF
authors.lastname: Choo
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Victoria
authors.initials: V
authors.lastname: Dinkel
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Bainian
authors.initials: B
authors.lastname: Feng
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gloor
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gross
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Janet
authors.initials: J
authors.lastname: Gunzner-Toste
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hansen
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Georgia
authors.initials: G
authors.lastname: Hatzivassiliou
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Liu
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Kim
authors.initials: K
authors.lastname: Malesky
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Simon
authors.initials: S
authors.lastname: Mathieu
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Brad
authors.initials: B
authors.lastname: Newhouse
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Raddatz
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Ran
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Sumeet
authors.initials: S
authors.lastname: Rana
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Nikole
authors.initials: N
authors.lastname: Randolph
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Tyler
authors.initials: T
authors.lastname: Risom
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Savage
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: LeAnn T
authors.initials: LT
authors.lastname: Selby
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Shrag
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Kyung
authors.initials: K
authors.lastname: Song
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Hillary L
authors.initials: HL
authors.lastname: Sturgis
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Walter C
authors.initials: WC
authors.lastname: Voegtli
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Wen
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Willis
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Woessner
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Wen-I
authors.initials: WI
authors.lastname: Wu
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Young
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Jonas
authors.initials: J
authors.lastname: Grina
keywords: B-RafV600E; MAPK pathway; amorphous spray-dried dispersion; pyrazolopyridine; targeted therapy