title: Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors.
abstract: Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-Raf(V600E) mutated enzyme has been observed in a number of human tumors, including melanomas. Herein we report the discovery and biological evaluation of GSK2118436, a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-Raf(V600E) human melanoma. GSK2118436 was identified as a development candidate, and early clinical results have shown significant activity in patients with B-Raf mutant melanoma.
authors.affiliation: Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States.
authors.forename: Tara R
authors.initials: TR
authors.lastname: Rheault
authors.affiliation: Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: Stellwagen
authors.affiliation: Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States.
authors.forename: George M
authors.initials: GM
authors.lastname: Adjabeng
authors.affiliation: Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Hornberger
authors.affiliation: Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States.
authors.forename: Kimberly G
authors.initials: KG
authors.lastname: Petrov
authors.affiliation: Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States.
authors.forename: Alex G
authors.initials: AG
authors.lastname: Waterson
authors.affiliation: Computational and Structural Chemistry, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Dickerson
authors.affiliation: Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mook
authors.affiliation: Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Sylvie G
authors.initials: SG
authors.lastname: Laquerre
authors.affiliation: Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: King
authors.affiliation: Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Olivia W
authors.initials: OW
authors.lastname: Rossanese
authors.affiliation: Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Arnone
authors.affiliation: Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: Smitheman
authors.affiliation: Platform Technology & Science, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Laurie S
authors.initials: LS
authors.lastname: Kane-Carson
authors.affiliation: Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Chao
authors.initials: C
authors.lastname: Han
authors.affiliation: Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Ganesh S
authors.initials: GS
authors.lastname: Moorthy
authors.affiliation: Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Katherine G
authors.initials: KG
authors.lastname: Moss
authors.affiliation: Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States.
authors.forename: David E
authors.initials: DE
authors.lastname: Uehling
keywords: B-Raf; GSK2118436; MAP kinase; dabrafenib; melanoma