Lead optimization and structure-based design of potent and bioavailable deoxycytidine kinase inhibitors

Abstract

A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo. © 2009 Elsevier Ltd. All rights reserved.