Abstract
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.
Highlights
Chronic myelogenous leukaemia (CML) results from a gene defect in a haematological stem cell (HSC) leading to the expression of the BCR-Abl oncoprotein (Ren, 2005)
Further structural biology studies established the mechanisms whereby mutant forms of the oncoprotein were resistant to imatinib (Gorre et al, 2001; Cowan-Jacob et al, 2004)
Based on the structures of imatinib and other lead series bound to Abl kinase, many suggestions were made for synthesis of new and improved compounds with the aim of gaining potency and at least retaining selectivity
Summary
Chronic myelogenous leukaemia (CML) results from a gene defect in a haematological stem cell (HSC) leading to the expression of the BCR-Abl oncoprotein (Ren, 2005). Further structural biology studies established the mechanisms whereby mutant forms of the oncoprotein were resistant to imatinib (Gorre et al, 2001; Cowan-Jacob et al, 2004) This has paved the way for the design of second-generation Bcr-Abl inhibitors designed to inhibit the wild-type kinase and maintain activity against the imatinib-resistant mutants. Crystallographic studies were undertaken in order to contribute to drug-discovery efforts to find new compounds that might inhibit Bcr-Abl with higher affinity while retaining the excellent kinase selectivity profile of imatinib These studies included determining the binding modes of established chemotypes in order to understand the reasons for selectivity towards other kinases and towards particular Bcr-Abl mutants. Construct C was designed based on the results obtained with construct A and the published results with construct B Both the N-terminus and the C-terminus were truncated to give residues 229–500 of human c-Abl with an N-terminal His-tag and a TEV protease cleavage site. The PCR product was inserted into the vector pFastBac-HTA (Invitrogen) using
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