Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases.
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.
Matthews
Thomas P
TP
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
McHardy
Tatiana
T
Klair
Suki
S
Boxall
Kathy
K
Fisher
Martin
M
Cherry
Michael
M
Allen
Charlotte E
CE
Addison
Glynn J
GJ
Ellard
John
J
Aherne
G Wynne
GW
Westwood
Isaac M
IM
van Montfort
Rob
R
Garrett
Michelle D
MD
Reader
John C
JC
Collins
Ian
I
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*
D047428:Protein Kinase Inhibitors; D011719:Pyrazines