title: Highly potent and selective 3-N-methylquinazoline-4(3H)-one based inhibitors of B-Raf(V600E) kinase.
abstract: Herein we describe the design of a novel series of ATP competitive B-Raf inhibitors via structure-based methods. These 3-N-methylquinazoline-4(3H)-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 16, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. Our work also demonstrates that by replacing an aryl amide with an aryl sulfonamide, a multikinase inhibitor such as AZ-628, can be converted to a selective B-Raf inhibitor, a finding that should have broad application in kinase drug discovery.
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Wenglowsky
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States. Electronic address: li.ren@arraybiopharma.com.
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Jonas
authors.initials: J
authors.lastname: Grina
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hansen
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: David
authors.initials: D
authors.lastname: Moreno
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Victoria
authors.initials: V
authors.lastname: Dinkel
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gloor
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Gregg
authors.initials: G
authors.lastname: Hastings
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Sumeet
authors.initials: S
authors.lastname: Rana
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rasor
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Hillary L
authors.initials: HL
authors.lastname: Sturgis
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Walter C
authors.initials: WC
authors.lastname: Voegtli
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Guy
authors.initials: G
authors.lastname: Vigers
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Brandon
authors.initials: B
authors.lastname: Willis
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080-4990, United States.
authors.forename: Simon
authors.initials: S
authors.lastname: Mathieu
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080-4990, United States.
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C578786:4-methylquinazoline; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C000592454:AZ-628; D048493:Proto-Oncogene Proteins B-raf
keywords: B-Raf inhibitors; Kinase drug discovery; Melonoma; Type IIB inhibitor