title: Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase β isoform.
abstract: A series of suitable five-membered heterocyclic alternatives to thiophenes within a thienobenzoxepin class of PI3-kinase (PI3K) inhibitors was discovered. Specific thiazolobenzoxepin 8-substitution was identified that increased selectivity over PI3Kβ. PI3Kβ-sparing compound 27 (PI3Kβ Ki,app/PI3Kα Ki,app=57) demonstrated dose-dependent knockdown of pAKT, pPRAS40 and pS6RP in vivo as well as differential effects in an in vitro proliferation cell line screen compared to pan PI3K inhibitor GDC-0941. A new structure-based hypothesis for reducing inhibition of the PI3K β isoform while maintaining activity against α, δ and γ isoforms is presented.
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: Chudi
authors.initials: C
authors.lastname: Ndubaku
authors.forename: Nicole
authors.initials: N
authors.lastname: Blaquiere
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bull
authors.forename: Danette
authors.initials: D
authors.lastname: Dudley
authors.forename: Kyle
authors.initials: K
authors.lastname: Edgar
authors.forename: Daniel
authors.initials: D
authors.lastname: Gray
authors.forename: Robert
authors.initials: R
authors.lastname: Heald
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffron
authors.forename: Graham E
authors.initials: GE
authors.lastname: Jones
authors.forename: Mark
authors.initials: M
authors.lastname: Jones
authors.forename: Aleks
authors.initials: A
authors.lastname: Kolesnikov
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
authors.initials: J
authors.lastname: Murray
authors.forename: Neville J
authors.initials: NJ
authors.lastname: McLean
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Alan G
authors.initials: AG
authors.lastname: Olivero
authors.forename: Rachel
authors.initials: R
authors.lastname: Ord
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.forename: Stephen
authors.initials: S
authors.lastname: Price
authors.forename: Wei Wei
authors.initials: WW
authors.lastname: Prior
authors.forename: Lionel
authors.initials: L
authors.lastname: Rouge
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Jeff
authors.initials: J
authors.lastname: Wallin
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.forename: BinQing
authors.initials: B
authors.lastname: Wei
authors.forename: Christian
authors.initials: C
authors.lastname: Weismann
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
mesh_terms: D001584:Benzoxepins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D001584:Benzoxepins; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D013844:Thiazoles; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt