title: Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases.
abstract: A range of 3,6-di(hetero)arylimidazo[1,2-a]pyrazine ATP-competitive inhibitors of CHK1 were developed by scaffold hopping from a weakly active screening hit. Efficient synthetic routes for parallel synthesis were developed to prepare analogues with improved potency and ligand efficiency against CHK1. Kinase profiling showed that the imidazo[1,2-a]pyrazines could inhibit other kinases, including CHK2 and ABL, with equivalent or better potency depending on the pendant substitution. These 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines appear to represent a general kinase inhibitor scaffold.
authors.affiliation: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom. tom.matthews@icr.ac.uk
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Matthews
authors.forename: Tatiana
authors.initials: T
authors.lastname: McHardy
authors.forename: Suki
authors.initials: S
authors.lastname: Klair
authors.forename: Kathy
authors.initials: K
authors.lastname: Boxall
authors.forename: Martin
authors.initials: M
authors.lastname: Fisher
authors.forename: Michael
authors.initials: M
authors.lastname: Cherry
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Allen
authors.forename: Glynn J
authors.initials: GJ
authors.lastname: Addison
authors.forename: John
authors.initials: J
authors.lastname: Ellard
authors.forename: G Wynne
authors.initials: GW
authors.lastname: Aherne
authors.forename: Isaac M
authors.initials: IM
authors.lastname: Westwood
authors.forename: Rob
authors.initials: R
authors.lastname: van Montfort
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Garrett
authors.forename: John C
authors.initials: JC
authors.lastname: Reader
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011719:Pyrazines