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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| Institution: | 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)arylimidazo1,2-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 imidazo1,2-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 imidazo1,2-a]pyrazines appear to represent a general kinase inhibitor scaffold. |
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