| First Author | Zhang J | Year | 2010 |
| Journal | Nature | Volume | 463 |
| Issue | 7280 | Pages | 501-6 |
| PubMed ID | 20072125 | Mgi Jnum | J:384516 |
| Mgi Id | MGI:8328710 | Doi | 10.1038/nature08675 |
| Citation | Zhang J, et al. (2010) Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463(7280):501-6 |
| abstractText | 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. |
