title: Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2.
abstract: 5-(Hetero)aryl-3-(4-carboxamidophenyl)-2-aminopyridine inhibitors of CHK2 were identified from high throughput screening of a kinase-focussed compound library. Rapid exploration of the hits through straightforward chemistry established structure-activity relationships and a proposed ATP-competitive binding mode which was verified by X-ray crystallography of several analogues bound to CHK2. Variation of the 5-(hetero)aryl substituent identified bicyclic dioxolane and dioxane groups which improved the affinity and the selectivity of the compounds for CHK2 versus CHK1. The 3-(4-carboxamidophenyl) substituent could be successfully replaced by acyclic omega-aminoalkylamides, which made additional polar interactions within the binding site and led to more potent inhibitors of CHK2. Compounds from this series showed activity in cell-based mechanistic assays for inhibition of CHK2.
authors.affiliation: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hilton
authors.forename: Sebastien
authors.initials: S
authors.lastname: Naud
authors.forename: John J
authors.initials: JJ
authors.lastname: Caldwell
authors.forename: Kathy
authors.initials: K
authors.lastname: Boxall
authors.forename: Samantha
authors.initials: S
authors.lastname: Burns
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Anderson
authors.forename: Laurent
authors.initials: L
authors.lastname: Antoni
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Allen
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
authors.forename: Antony W
authors.initials: AW
authors.lastname: Oliver
authors.forename: G
authors.initials: G
authors.lastname: Wynne Aherne
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Garrett
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D064447:Checkpoint Kinase 2; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D047428:Protein Kinase Inhibitors; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; C032439:alpha-aminopyridine