Structure-based design of a new class of highly selective aminoimidazo[1,2-a]pyridine-based inhibitors of cyclin dependent kinases.
Structure-based design approach was successfully used to guide the evolution of imidazopyridine scaffold yielding new structural class of highly selective inhibitors of cyclin dependent kinases that were able to form a new interaction with an identified residue of the protein, Lys89. Compounds from this series have shown no detectable effect when tested against a representative set of other serine/threonine kinases such as GSK3beta, CAMKII, PKA, PKC-alpha,beta,epsilon,gamma. Compound 2i inhibits proliferation in HCT 116 cells in tissue culture. Synthesis, co-crystal structure of CDK2 in complex with compound 2i, and preliminary SAR study are disclosed.
Hamdouchi
Chafiq
C
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, DC: 0540, Indianapolis, IN 46285, United States. hamdouchi_chafiq@lilly.com
Zhong
Boyu
B
Mendoza
Jose
J
Collins
Elizabeth
E
Jaramillo
Carlos
C
De Diego
Jose Eugenio
JE
Robertson
Daniel
D
Spencer
Charles D
CD
Anderson
Bryan D
BD
Watkins
Scott A
SA
Zhang
Faming
F
Brooks
Harold B
HB
D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008239:Lysine / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018844:Cyclin-Dependent Kinases; D008239:Lysine