Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors

Article

关键词: CHRONIC MYELOID-LEUKEMIA;    CELL LUNG-CANCER;    KINASE-INHIBITOR;    C-ABL;    TYROSINE KINASE;    LYMPHOBLASTIC-LEUKEMIA;    IMATINIB RESISTANCE;    SELECTIVE INHIBITOR;    MUTATIONS;    DYNAMICS;   

DOI  :  10.1038/nature08675

来源: SCIE

【 摘 要 】

In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.

【 授权许可】

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