Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors
- Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors
- Jianming Zhang; Francisco J. Adrian; Wolfgang Jahnke; Sandra W. Cowan-Jaco; Allen G. Li; Roxana E. Iacob; 심태보; John Powers; Christine Dierks; Fangxian Sun; Gui-Rong Guo; Qiang Ding; Barun Okram; Yongmun Choi; Amy Wojciechowski; Xianming Deng; Guoxun Liu; Gabriele Fendrich; Andre Strauss; Navratna Vajpai; Stephan Grzesiek; Tove Tuntland; Yi Liu; Badry Bursulaya; Mohammad Azam; Paul W. Manley; John R. Engen; George Q. Daley; Markus Warmuth; Nathanael S. Gray
- Issue Date
- VOL 463, 501-506
- 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.
- Appears in Collections:
- KIST Publication > Article
- Files in This Item:
There are no files associated with this item.
- RIS (EndNote)
- XLS (Excel)
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.