title: Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma.
abstract: Abrogation of errant signaling along the MAPK pathway through the inhibition of B-RAF kinase is a validated approach for the treatment of pathway-dependent cancers. We report the development of imidazo-benzimidazoles as potent B-RAF inhibitors. Robust in vivo efficacy coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and PD-efficacy relationships led to the identification of RAF265, 1, which has advanced into clinical trials.
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Teresa E
authors.initials: TE
authors.lastname: Williams
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Sharadha
authors.initials: S
authors.lastname: Subramanian
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Joelle
authors.initials: J
authors.lastname: Verhagen
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: McBride
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Abran
authors.initials: A
authors.lastname: Costales
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Leonard
authors.initials: L
authors.lastname: Sung
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: William
authors.initials: W
authors.lastname: Antonios-McCrea
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Maureen
authors.initials: M
authors.lastname: McKenna
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Louie
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Savithri
authors.initials: S
authors.lastname: Ramurthy
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Barry
authors.initials: B
authors.lastname: Levine
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Shafer
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Machajewski
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Renhowe
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Appleton
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Payman
authors.initials: P
authors.lastname: Amiri
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: James
authors.initials: J
authors.lastname: Chou
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Darrin
authors.initials: D
authors.lastname: Stuart
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Aardalen
authors.affiliation: Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Poon
keywords: B-RAF; MAP; VEGF; serine/threonine kinases; tyrosine kinases