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Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia.

Jacob, Sandra, Fendrich, Gabriele, Floersheimer, Andreas, Furet, Pascal, Liebetanz, Janis, Rummel, Gabriele, Rheinberger, Paul, Centeleghe, Mario, Fabbro, Doriano and Manley, Paul W. (2007) Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia. Acta Crystallographica. Section D, Biological crystallography, 63 (Pt 1). pp. 80-93. ISSN 0907-4449


Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy owing to the emergence of drug-resistant mutants of the protein. More than 40 such point mutations have been observed in imatinib-resistant patients. The crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small-molecule Abl inhibitors were determined, with the aim of understanding the molecular basis of resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way that this information is used to support drug discovery.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); On author's personal web site, an employer's web site/repository, or free public servers in the subject area
Keywords: tyrosine kinase; drug discovery; imatinib; nilotinib
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Date Deposited: 14 Dec 2009 13:58
Last Modified: 31 Jan 2013 01:13


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