Jonathan Winger - The structure of the leukemia drug imatinib bound to human quinone reductase 2 (NQO2)

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      BMC STRUCTURAL BIOLOGY Volume: 9 Published: FEB 24 2009


      Background: Imatinib represents the first in a class of drugs   targeted against chronic myelogenous leukemia to enter the   clinic, showing excellent efficacy and specificity for Abl, Kit,   and PDGFR kinases. Recent screens carried out to find off-target   proteins that bind to imatinib identified the oxidoreductase   NQO2, a flavoprotein that is phosphorylated in a chronic   myelogenous leukemia cell line.

      Results: We examined the inhibition of NQO2 activity by the Abl   kinase inhibitors imatinib, nilotinib, and dasatinib, and   obtained IC50 values of 80 nM, 380 nM, and > 100 mu M,   respectively. Using electronic absorption spectroscopy, we show   that imatinib binding results in a perturbation of the protein   environment around the flavin prosthetic group in NQO2. We have   determined the crystal structure of the complex of imatinib with   human NQO2 at 1.75 angstrom resolution, which reveals that   imatinib binds in the enzyme active site, adjacent to the flavin   isoalloxazine ring. We find that phosphorylation of NQO2 has   little effect on enzyme activity and is therefore likely to   regulate other aspects of NQO2 function.

      Conclusion: The structure of the imatinib-NQO2 complex   demonstrates that imatinib inhibits NQO2 activity by competing   with substrate for the active site. The overall conformation of   imatinib when bound to NQO2 resembles the folded conformation   observed in some kinase complexes. Interactions made by imatinib   with residues at the rim of the active site provide an   explanation for the binding selectivity of NQO2 for imatinib,   nilotinib, and dasatinib. These interactions also provide a   rationale for the lack of inhibition of the related   oxidoreductase NQO1 by these compounds. Taken together, these   studies provide insight into the mechanism of NQO2 inhibition by   imatinib, with potential implications for drug design and   treatment of chronic myelogenous leukemia in patients.

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