RT Journal Article
SR Electronic
T1 The discovery of a new structural class of cyclin-dependent kinase inhibitors, aminoimidazo[1,2-<em>a</em>]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.