title: Structure-based design of a new class of highly selective aminoimidazo[1,2-a]pyridine-based inhibitors of cyclin dependent kinases.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, DC: 0540, Indianapolis, IN 46285, United States. hamdouchi_chafiq@lilly.com
authors.forename: Chafiq
authors.initials: C
authors.lastname: Hamdouchi
authors.forename: Boyu
authors.initials: B
authors.lastname: Zhong
authors.forename: Jose
authors.initials: J
authors.lastname: Mendoza
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Collins
authors.forename: Carlos
authors.initials: C
authors.lastname: Jaramillo
authors.forename: Jose Eugenio
authors.initials: JE
authors.lastname: De Diego
authors.forename: Daniel
authors.initials: D
authors.lastname: Robertson
authors.forename: Charles D
authors.initials: CD
authors.lastname: Spencer
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Anderson
authors.forename: Scott A
authors.initials: SA
authors.lastname: Watkins
authors.forename: Faming
authors.initials: F
authors.lastname: Zhang
authors.forename: Harold B
authors.initials: HB
authors.lastname: Brooks
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018844:Cyclin-Dependent Kinases; D008239:Lysine