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

Cowan-Jacob SW, Fendrich G, Floersheimer A, Furet P, Liebetanz J, Rummel G, Rheinberger P, Centeleghe M, Fabbro D, Manley PW - Acta Crystallogr. D Biol. Crystallogr. (2006)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland. sandra.jacob@novartis.com

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.

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Related in: MedlinePlus

(a) Schematic diagram showing the relationship between Abl and Bcr-Abl (top), the constructs used for crystallography (middle) and the amino-acid numbers for structural elements mentioned in the text (bottom). The breakpoint cluster region (Bcr) is shown in red and the Abl gene is shown in light blue. The green segment shows the Abl-SH2-binding region of Bcr that, when phosphorylated, is necessary for the activation of the Abl tyrosine kinase (yellow boxes). The blue segment shows the region of the Abl gene that is lost during the reciprocal translocation, which is involved in the down-regulation of the Abl kinase. (b) Chemical structures of compounds mentioned in the text. 1, NVP-AFN941; 2, imatinib; 3, NVP-AFG210; 4, PD180970; 5, NVP-AEG082; 6, nilotinib.
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fig1: (a) Schematic diagram showing the relationship between Abl and Bcr-Abl (top), the constructs used for crystallography (middle) and the amino-acid numbers for structural elements mentioned in the text (bottom). The breakpoint cluster region (Bcr) is shown in red and the Abl gene is shown in light blue. The green segment shows the Abl-SH2-binding region of Bcr that, when phosphorylated, is necessary for the activation of the Abl tyrosine kinase (yellow boxes). The blue segment shows the region of the Abl gene that is lost during the reciprocal translocation, which is involved in the down-regulation of the Abl kinase. (b) Chemical structures of compounds mentioned in the text. 1, NVP-AFN941; 2, imatinib; 3, NVP-AFG210; 4, PD180970; 5, NVP-AEG082; 6, nilotinib.

Mentions: 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 ▶). In contrast to the tightly regulated c-Abl kinase, an auto-regulatory domain in the oncoprotein is truncated, leading to constitutive activation of the tyrosine kinase activity (Fig. 1 ▶). The resulting unregulated phosphorylation of intracellular proteins in HSCs leads to the uncontrolled growth and survival of the leukaemic cells.


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

Cowan-Jacob SW, Fendrich G, Floersheimer A, Furet P, Liebetanz J, Rummel G, Rheinberger P, Centeleghe M, Fabbro D, Manley PW - Acta Crystallogr. D Biol. Crystallogr. (2006)

(a) Schematic diagram showing the relationship between Abl and Bcr-Abl (top), the constructs used for crystallography (middle) and the amino-acid numbers for structural elements mentioned in the text (bottom). The breakpoint cluster region (Bcr) is shown in red and the Abl gene is shown in light blue. The green segment shows the Abl-SH2-binding region of Bcr that, when phosphorylated, is necessary for the activation of the Abl tyrosine kinase (yellow boxes). The blue segment shows the region of the Abl gene that is lost during the reciprocal translocation, which is involved in the down-regulation of the Abl kinase. (b) Chemical structures of compounds mentioned in the text. 1, NVP-AFN941; 2, imatinib; 3, NVP-AFG210; 4, PD180970; 5, NVP-AEG082; 6, nilotinib.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483489&req=5

fig1: (a) Schematic diagram showing the relationship between Abl and Bcr-Abl (top), the constructs used for crystallography (middle) and the amino-acid numbers for structural elements mentioned in the text (bottom). The breakpoint cluster region (Bcr) is shown in red and the Abl gene is shown in light blue. The green segment shows the Abl-SH2-binding region of Bcr that, when phosphorylated, is necessary for the activation of the Abl tyrosine kinase (yellow boxes). The blue segment shows the region of the Abl gene that is lost during the reciprocal translocation, which is involved in the down-regulation of the Abl kinase. (b) Chemical structures of compounds mentioned in the text. 1, NVP-AFN941; 2, imatinib; 3, NVP-AFG210; 4, PD180970; 5, NVP-AEG082; 6, nilotinib.
Mentions: 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 ▶). In contrast to the tightly regulated c-Abl kinase, an auto-regulatory domain in the oncoprotein is truncated, leading to constitutive activation of the tyrosine kinase activity (Fig. 1 ▶). The resulting unregulated phosphorylation of intracellular proteins in HSCs leads to the uncontrolled growth and survival of the leukaemic cells.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland. sandra.jacob@novartis.com

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.

Show MeSH
Related in: MedlinePlus