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- Title
Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors.
- Authors
Jianming Zhang; Adrián, Francisco J.; Jahnke, Wolfgang; Cowan-Jacob, Sandra W.; Li, Allen G.; Iacob, Roxana E.; Taebo Sim; Powers, John; Dierks, Christine; Fangxian Sun; Gui-Rong Guo; Ding, Qiang; Okram, Barun; Yongmun Choi; Wojciechowski, Amy; Xianming Deng; Guoxun Liu; Fendrich, Gabriele; Strauss, André; Vajpai, Navratna
- Abstract
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.
- Subjects
ADENOSINE triphosphate; BINDING sites; ENZYME inhibitors; IMATINIB; MUTAGENESIS; ALLOSTERIC enzymes; HORMONE resistance; BONE marrow; SPECTROMETRY
- Publication
Nature, 2010, Vol 463, Issue 7280, p501
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature08675