Imidazole piperazines: SAR and development of a potent class of cyclin-dependent kinase inhibitors with a novel binding mode.

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Finlay MR, Acton DG, Andrews DM, Barker AJ, Dennis M, Fisher E, Graham MA, Green CP, Heaton DW, Karoutchi G, Loddick SA, Morgentin R, Roberts A, Tucker JA, Weir HM

Imidazole piperazines: SAR and development of a potent class of cyclin-dependent kinase inhibitors with a novel binding mode.

Bioorg Med Chem Lett. 2008 Aug 1;18(15):4442-6. doi: 10.1016/j.bmcl.2008.06.027. Epub 2008 Jun 12.

PubMed ID

18617397 [ View in PubMed

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Abstract

A piperazine series of cyclin-dependent kinase (CDK) inhibitors have been identified. The compounds exhibit excellent physiochemical properties and a novel binding mode, whereby a bridging interaction via a water molecule with Asp 86 of CDK2, leads to selectivity for the CDK family of enzymes over other kinases. Piperazines 2e and 2i were subsequently shown to inhibit tumour growth when dosed orally in a nude mouse xenograft study. Additional chemical series that exploit this unexpected interaction with Asp 86 are also described.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
2-{4-[4-({4-[2-methyl-1-(1-methylethyl)-1H-imidazol-5-yl]pyrimidin-2-yl}amino)phenyl]piperazin-1-yl}-2-oxoethanol	Cyclin-dependent kinase 2	IC 50 (nM)	17	N/A	N/A	Details