Structure-based design of a new class of highly selective aminoimidazo[1,2-a]pyridine-based inhibitors of cyclin dependent kinases.

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Hamdouchi C, Zhong B, Mendoza J, Collins E, Jaramillo C, De Diego JE, Robertson D, Spencer CD, Anderson BD, Watkins SA, Zhang F, Brooks HB

Structure-based design of a new class of highly selective aminoimidazo[1,2-a]pyridine-based inhibitors of cyclin dependent kinases.

Bioorg Med Chem Lett. 2005 Apr 1;15(7):1943-7.

PubMed ID
15780638 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
[2-Amino-6-(2,6-Difluoro-Benzoyl)-Imidazo[1,2-a]Pyridin-3-Yl]-Phenyl-MethanoneCyclin-dependent kinase 2IC 50 (nM)324722Details
AlvocidibCyclin-dependent kinase 1IC 50 (nM)2007.522Details
AlvocidibCyclin-dependent kinase 2IC 50 (nM)960722Details
AlvocidibCyclin-dependent kinase 4IC 50 (nM)180722Details
PHENYLAMINOIMIDAZO(1,2-ALPHA)PYRIDINECyclin-dependent kinase 2IC 50 (nM)560722Details