title: Structure-based design of thienobenzoxepin inhibitors of PI3-kinase.
abstract: Starting from thienobenzopyran HTS hit 1, co-crystallization, molecular modeling and metabolic analysis were used to design potent and metabolically stable inhibitors of PI3-kinase. Compound 15 demonstrated PI3K pathway suppression in a mouse MCF7 xenograft model.
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. stevents@gene.com
authors.forename: Steven T
authors.initials: ST
authors.lastname: Staben
authors.forename: Michael
authors.initials: M
authors.lastname: Siu
authors.forename: Richard
authors.initials: R
authors.lastname: Goldsmith
authors.forename: Alan G
authors.initials: AG
authors.lastname: Olivero
authors.forename: Steven
authors.initials: S
authors.lastname: Do
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Burdick
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffron
authors.forename: Jenna
authors.initials: J
authors.lastname: Dotson
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sutherlin
authors.forename: Bing-Yan
authors.initials: BY
authors.lastname: Zhu
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.forename: Hoa
authors.initials: H
authors.lastname: Le
authors.forename: Leslie
authors.initials: L
authors.lastname: Lee
authors.forename: John
authors.initials: J
authors.lastname: Lesnick
authors.forename: Cristina
authors.initials: C
authors.lastname: Lewis
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Murray
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.forename: Wei Wei
authors.initials: WW
authors.lastname: Prior
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Lionel
authors.initials: L
authors.lastname: Rouge
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
mesh_terms: D000818:Animals; D001584:Benzoxepins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D001584:Benzoxepins; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013876:Thiophenes