Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases |
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| Authors: | Thomas P. Matthews Tatiana McHardy Suki Klair Kathy Boxall Martin Fisher Michael Cherry Charlotte E. Allen Glynn J. Addison John Ellard G. Wynne Aherne Isaac M. Westwood Rob van Montfort Michelle D. Garrett John C. Reader Ian Collins |
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| Affiliation: | 1. Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom;2. Sections of Cancer Therapeutics and Structural Biology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom;3. Sareum Ltd, Unit 2A, Langford Arch, London Road, Pampisford, Cambridge CB22 3FX, United Kingdom |
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| 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. |
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