Aminoimidazo[1,2-a]pyridines as a new structural class of cyclin-dependent kinase inhibitors. Part 1: Design, synthesis, and biological evaluation.
We have identified a novel structural class of protein serine/threonine kinase inhibitors comprised of an aminoimidazo[1,2-a]pyridine nucleus. Compounds from this family are shown to potently inhibit cyclin-dependent kinases by competing with ATP for binding to a catalytic subunit of the protein. Structure-based design approach was used to direct this chemical scaffold toward generating potent and selective CDK2 inhibitors. The discovery of this new class of ATP-site directed protein kinase inhibitors, aminoimidazo[1,2-a]pyridines, provides the basis of new medicinal chemistry tool in search for an effective treatment of cancer and other diseases that involve protein kinase signaling pathways.
Jaramillo
Carlos
C
Centro de Investigación Lilly, Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain.
de Diego
J Eugenio
JE
Hamdouchi
Chafiq
C
Collins
Elizabeth
E
Keyser
Heather
H
Sánchez-Martínez
Concha
C
del Prado
Miriam
M
Norman
Bryan
B
Brooks
Harold B
HB
Watkins
Scott A
SA
Spencer
Charles D
CD
Dempsey
Jack Alan
JA
Anderson
Bryan D
BD
Campbell
Robert M
RM
Leggett
Tellie
T
Patel
Bharvin
B
Schultz
Richard M
RM
Espinosa
Juan
J
Vieth
Michal
M
Zhang
Faming
F
Timm
David E
DE
D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D018844:Cyclin-Dependent Kinases