title: DNA-dependent protein kinase (DNA-PK) inhibitors: structure-activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain.
abstract: Introduction of an O-alkoxyphenyl substituent at the 8-position of the 2-morpholino-4H-chromen-4-one pharmacophore enabled regions of the ATP-binding site of DNA-dependent protein kinase (DNA-PK) to be probed further. Structure-activity relationships have been elucidated for inhibition of DNA-PK and PI3K (p110α), with N-(2-(cyclopropylmethoxy)-4-(2-morpholino-4-oxo-4H-chromen-8-yl)phenyl)-2-morpholinoacetamide 11a being identified as a potent and selective DNA-PK inhibitor (IC(50)=8 nM).
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle Upon Tyne, United Kingdom.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Clapham
authors.forename: Julia
authors.initials: J
authors.lastname: Bardos
authors.forename: M Raymond V
authors.initials: MR
authors.lastname: Finlay
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Griffen
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
authors.forename: Keith A
authors.initials: KA
authors.lastname: Menear
authors.forename: Attilla
authors.initials: A
authors.lastname: Ting
authors.forename: Paul
authors.initials: P
authors.lastname: Turner
authors.forename: Gail L
authors.initials: GL
authors.lastname: Young
authors.forename: Céline
authors.initials: C
authors.lastname: Cano
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000255:Adenosine Triphosphate; D002867:Chromones; D051747:DNA-Activated Protein Kinase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors