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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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Superposition of the structures of imatinib (magenta) and nilotinib (green) as bound to Abl kinase (cyan and grey, respectively). Potential hydrogen bonds are shown as dotted red lines for the imatinib complex and dotted grey lines for the nilotinib complex.
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fig7: Superposition of the structures of imatinib (magenta) and nilotinib (green) as bound to Abl kinase (cyan and grey, respectively). Potential hydrogen bonds are shown as dotted red lines for the imatinib complex and dotted grey lines for the nilotinib complex.

Mentions: Compounds giving IC50 values against c-Abl in the nanomolar range were found for each series except for the sulfon­amides, where all inhibitors were inactive. Structures were determined for some of these potent inhibitors and were used as a basis for ideas to support the optimization of chemical properties such as chemical stability, metabolic stability and solubility while retaining affinity (Manley et al., to be published; Manley, Breitenstein et al., 2004 ▶). Incorporation of a hydroxyl group into the reverse-amide series to target Asp381 gave a compound (NVP-AHT202) having an excellent kinase inhibition profile but poor drugability characteristics (Manley et al., to be published). The investigation of alternative donor/acceptor groups finally led to the synthesis of NVP-AMN107 (nilotinib), which is highly potent, very selective and active against all but one of the resistance mutants isolated from relapsed imatinib patients, has good pharmacokinetic properties and is now in clinical trials in man (Weisberg et al., 2006 ▶; Kantarjian et al., 2006 ▶). Structures of nilotinib in complex with Abl show that it makes similar hydrogen-bonding interactions to imatinib with Abl kinase, except for those formed by the N-­methylpiperazine group of imatinib to the C-terminal lobe (Fig. 7 ▶; Weisberg et al., 2005 ▶). Nilotinib has a better fit to the DFG-out pocket than imatinib, which probably accounts largely for its increased affinity. There is also a weak electrostatic interaction between a fluorine from the trifluoromethyl group of nilotinib and the polarized C atom of the Ala380 carbonyl group (Manley, Cowan-Jacob, Fendrich et al., 2005 ▶). Its ability to inhibit most of the imatinib-resistant mutants is most likely to primarily be a consequence of the increased affinity of nilotinib compared with imatinib, allowing it to overcome the slight shift of the equilibrium between the inactive and active states of the enzyme towards the active state.


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)

Superposition of the structures of imatinib (magenta) and nilotinib (green) as bound to Abl kinase (cyan and grey, respectively). Potential hydrogen bonds are shown as dotted red lines for the imatinib complex and dotted grey lines for the nilotinib complex.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7: Superposition of the structures of imatinib (magenta) and nilotinib (green) as bound to Abl kinase (cyan and grey, respectively). Potential hydrogen bonds are shown as dotted red lines for the imatinib complex and dotted grey lines for the nilotinib complex.
Mentions: Compounds giving IC50 values against c-Abl in the nanomolar range were found for each series except for the sulfon­amides, where all inhibitors were inactive. Structures were determined for some of these potent inhibitors and were used as a basis for ideas to support the optimization of chemical properties such as chemical stability, metabolic stability and solubility while retaining affinity (Manley et al., to be published; Manley, Breitenstein et al., 2004 ▶). Incorporation of a hydroxyl group into the reverse-amide series to target Asp381 gave a compound (NVP-AHT202) having an excellent kinase inhibition profile but poor drugability characteristics (Manley et al., to be published). The investigation of alternative donor/acceptor groups finally led to the synthesis of NVP-AMN107 (nilotinib), which is highly potent, very selective and active against all but one of the resistance mutants isolated from relapsed imatinib patients, has good pharmacokinetic properties and is now in clinical trials in man (Weisberg et al., 2006 ▶; Kantarjian et al., 2006 ▶). Structures of nilotinib in complex with Abl show that it makes similar hydrogen-bonding interactions to imatinib with Abl kinase, except for those formed by the N-­methylpiperazine group of imatinib to the C-terminal lobe (Fig. 7 ▶; Weisberg et al., 2005 ▶). Nilotinib has a better fit to the DFG-out pocket than imatinib, which probably accounts largely for its increased affinity. There is also a weak electrostatic interaction between a fluorine from the trifluoromethyl group of nilotinib and the polarized C atom of the Ala380 carbonyl group (Manley, Cowan-Jacob, Fendrich et al., 2005 ▶). Its ability to inhibit most of the imatinib-resistant mutants is most likely to primarily be a consequence of the increased affinity of nilotinib compared with imatinib, allowing it to overcome the slight shift of the equilibrium between the inactive and active states of the enzyme towards the active state.

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