RT Journal Article SR Electronic T1 The discovery of a new structural class of cyclin-dependent kinase inhibitors, aminoimidazo[1,2-a]pyridines JF Molecular Cancer Therapeutics JO Mol Cancer Ther FD American Association for Cancer Research SP 1 OP 9 VO 3 IS 1 A1 Hamdouchi, Chafiq A1 Keyser, Heather A1 Collins, Elizabeth A1 Jaramillo, Carlos A1 De Diego, Jose Eugenio A1 Spencer, Charles D. A1 Dempsey, Jack Alan A1 Anderson, Bryan D. A1 Leggett, Tillie A1 Stamm, Nancy B. A1 Schultz, Richard M. A1 Watkins, Scott A. A1 Cocke, Kim A1 Lemke, Stephanie A1 Burke, Teresa F. A1 Beckmann, Richard P. A1 Dixon, Jeffrey T. A1 Gurganus, Thomas M. A1 Rankl, Nancy B. A1 Houck, Keith A. A1 Zhang, Faming A1 Vieth, Michal A1 Espinosa, Juan A1 Timm, David E. A1 Campbell, Robert M. A1 Patel, Bharvin K. R. A1 Brooks, Harold B. YR 2004 UL http://mct.aacrjournals.org/content/3/1/1.abstract AB The protein kinase family represents an enormous opportunity for drug development. However, the current limitation in structural diversity of kinase inhibitors has complicated efforts to identify effective treatments of diseases that involve protein kinase signaling pathways. We have identified a new structural class of protein serine/threonine kinase inhibitors comprising an aminoimidazo[1,2-a]pyridine nucleus. In this report, we describe the first successful use of this class of aza-heterocycles to generate potent inhibitors of cyclin-dependent kinases that compete with ATP for binding to a catalytic subunit of the protein. Co-crystal structures of CDK2 in complex with lead compounds reveal a unique mode of binding. Using this knowledge, a structure-based design approach directed this chemical scaffold toward generating potent and selective CDK2 inhibitors, which selectively inhibited the CDK2-dependent phosphorylation of Rb and induced caspase-3-dependent apoptosis in HCT 116 tumor cells. The discovery of this new class of ATP-site-directed protein kinase inhibitors, aminoimidazo[1,2-a]pyridines, provides the basis for a new medicinal chemistry tool to be used in the search for effective treatments of cancer and other diseases that involve protein kinase signaling pathways.