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https://hdl.handle.net/2440/54024
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Type: | Journal article |
Title: | Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/Meriolin complex |
Author: | Echalier, A. Bettayeb, K. Ferandin, Y. Lozach, O. Clement, M. Valette, A. Liger, F. Marquet, B. Morris, J. Endicott, J. Joseph, B. Meijer, L. |
Citation: | Journal of Medicinal Chemistry, 2008; 51(4):737-751 |
Publisher: | Amer Chemical Soc |
Issue Date: | 2008 |
ISSN: | 0022-2623 1520-4804 |
Statement of Responsibility: | Aude Echalier, Karima Bettayeb, Yoan Ferandin, Olivier Lozach, Monique Clement, Annie Valette, François Liger, Bernard Marquet, Jonathan C. Morris, Jane A. Endicott, Benoît Joseph and Laurent Meijer |
Abstract: | We report the synthesis and biological characterization of 3-(pyrimidin-4-yl)-7-azaindoles (meriolins), a chemical hybrid between the natural products meridianins and variolins, derived from marine organisms. Meriolins display potent inhibitory activities toward cyclin-dependent kinases (CDKs) and, to a lesser extent, other kinases (GSK-3, DYRK1A). The crystal structures of 1e (meriolin 5) and variolin B (Bettayeb, K.; Tirado, O. M.; Marionneau-Lambert, S.; Ferandin, Y.; Lozach, O.; Morris, J.; Mateo-Lozano, S.; Drückes, P.; Schächtele, C.; Kubbutat, M.; Liger, F.; Marquet, B.; Joseph, B.; Echalier, A.; Endicott, J.; Notario, V.; Meijer, L. Cancer Res. 2007, 67, 8325−8334) in complex with CDK2/cyclin A reveal that the two inhibitors are orientated in very different ways inside the ATP-binding pocket of the kinase. A structure−activity relationship provides further insight into the molecular mechanism of action of this family of kinase inhibitors. Meriolins are also potent antiproliferative and proapoptotic agents in cells cultured either as monolayers or in spheroids. Proapoptotic efficacy of meriolins correlates best with their CDK2 and CDK9 inhibitory activity. Meriolins thus constitute a promising class of pharmacological agents to be further evaluated against the numerous human diseases that imply abnormal regulation of CDKs including cancers, neurodegenerative disorders, and polycystic kidney disease. |
Keywords: | Cell Line Cell Line, Tumor Spheroids, Cellular Humans Aza Compounds Pyrimidines Indoles Cyclin A Antineoplastic Agents Crystallization Crystallography, X-Ray Drug Screening Assays, Antitumor Apoptosis Cell Survival Structure-Activity Relationship Models, Molecular Cyclin-Dependent Kinase 9 Cyclin-Dependent Kinase 2 Bridged Bicyclo Compounds, Heterocyclic |
DOI: | 10.1021/jm700940h |
Published version: | http://dx.doi.org/10.1021/jm700940h |
Appears in Collections: | Aurora harvest 5 Chemistry publications |
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