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

Title
Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors
Authors
Jianming ZhangFrancisco J. AdrianWolfgang JahnkeSandra W. Cowan-JacoAllen G. LiRoxana E. Iacob심태보John PowersChristine DierksFangxian SunGui-Rong GuoQiang DingBarun OkramYongmun ChoiAmy WojciechowskiXianming DengGuoxun LiuGabriele FendrichAndre StraussNavratna VajpaiStephan GrzesiekTove TuntlandYi LiuBadry BursulayaMohammad AzamPaul W. ManleyJohn R. EngenGeorge Q. DaleyMarkus WarmuthNathanael S. Gray
Issue Date
2010-01
Publisher
Nature
Citation
VOL 463, 501-506
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.
URI
http://pubs.kist.re.kr/handle/201004/38285
ISSN
0028-0836
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