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Imidazole piperazines: SAR and development of a potent class of cyclin-dependent kinase inhibitors with a novel binding mode |
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| Authors: | Finlay M Raymond V Acton David G Andrews David M Barker Andrew J Dennis Michael Fisher Eric Graham Mark A Green Clive P Heaton David W Karoutchi Galith Loddick Sarah A Morgentin Rémy Roberts Andrew Tucker Julie A Weir Hazel M |
| Affiliation: | aCancer and Infection Research Area, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK;bLead Generation Discovery Enabling Capabilities and Sciences, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK;cAstraZeneca Research Unit, Chemin de Vrilly, Z.I. la Pompelle BP 1050, 51689 Reims Cedex 2, France |
| 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. |
| Keywords: | CDK Kinase Inhibitor Cancer |
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