title: Development of isoform selective PI3-kinase inhibitors as pharmacological tools for elucidating the PI3K pathway.
abstract: Using a parallel synthesis approach to target a non-conserved region of the PI3K catalytic domain a pan-PI3K inhibitor 1 was elaborated to provide alpha, delta and gamma isoform selective Class I PI3K inhibitors 21, 24, 26 and 27. The compounds had good cellular activity and were selective against protein kinases and other members of the PI3K superfamily including mTOR and DNA-PK.
authors.affiliation: Novartis Institutes for Biomedical Research, Respiratory Disease Area, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK. ian.bruce@novartis.com
authors.forename: Ian
authors.initials: I
authors.lastname: Bruce
authors.forename: Mohammed
authors.initials: M
authors.lastname: Akhlaq
authors.forename: Graham C
authors.initials: GC
authors.lastname: Bloomfield
authors.forename: Emma
authors.initials: E
authors.lastname: Budd
authors.forename: Brian
authors.initials: B
authors.lastname: Cox
authors.forename: Bernard
authors.initials: B
authors.lastname: Cuenoud
authors.forename: Peter
authors.initials: P
authors.lastname: Finan
authors.forename: Peter
authors.initials: P
authors.lastname: Gedeck
authors.forename: Julia
authors.initials: J
authors.lastname: Hatto
authors.forename: Judy F
authors.initials: JF
authors.lastname: Hayler
authors.forename: Denise
authors.initials: D
authors.lastname: Head
authors.forename: Thomas
authors.initials: T
authors.lastname: Keller
authors.forename: Louise
authors.initials: L
authors.lastname: Kirman
authors.forename: Catherine
authors.initials: C
authors.lastname: Leblanc
authors.forename: Darren
authors.initials: D
authors.lastname: Le Grand
authors.forename: Clive
authors.initials: C
authors.lastname: McCarthy
authors.forename: Desmond
authors.initials: D
authors.lastname: O'Connor
authors.forename: Charles
authors.initials: C
authors.lastname: Owen
authors.forename: Mrinalini S
authors.initials: MS
authors.lastname: Oza
authors.forename: Gaynor
authors.initials: G
authors.lastname: Pilgrim
authors.forename: Nicola E
authors.initials: NE
authors.lastname: Press
authors.forename: Lilya
authors.initials: L
authors.lastname: Sviridenko
authors.forename: Lewis
authors.initials: L
authors.lastname: Whitehead
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D005260:Female; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; C004483:2-aminothiazole