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Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors
Zhang, Jianming,Adriá,n, Francisco J.,Jahnke, Wolfgang,Cowan-Jacob, Sandra W.,Li, Allen G.,Iacob, Roxana E.,Sim, Taebo,Powers, John,Dierks, Christine,Sun, Fangxian,Guo, Gui-Rong,Ding, Qiang,Okra Macmillan Publishers Limited. All rights reserved 2010 Nature Vol.463 No.7280
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.
Expanding the Diversity of Allosteric Bcr-Abl Inhibitors
Deng, Xianming,Okram, Barun,Ding, Qiang,Zhang, Jianming,Choi, Yongmun,Adriá,n, Francisco J.,Wojciechowski, Amy,Zhang, Guobao,Che, Jianwei,Bursulaya, Badry,Cowan-Jacob, Sandra W.,Rummel, Gabriele American Chemical Society 2010 Journal of medicinal chemistry Vol.53 No.19
<P/><P>Inhibition of Bcr-Abl kinase activity by imatinib for the treatment of chronic myeloid leukemia (CML) currently serves as the paradigm for targeting dominant oncogenes with small molecules. We recently reported the discovery of GNF-2 (<B>1</B>) and GNF-5 (<B>2</B>) as selective non-ATP competitive inhibitors of cellular Bcr-Abl kinase activity that target the myristate binding site. Here, we used cell-based structure−activity relationships to guide the optimization and diversification of ligands that are capable of binding to the myristate binding site and rationalize the findings based upon an Abl−compound <B>1</B> cocrystal. We elucidate the structure−activity relationships required to obtain potent antiproliferative activity against Bcr-Abl transformed cells and report the discovery of new compounds (<B>5g</B>,<B> 5h</B>,<B> 6a</B>,<B> 14d</B>, and <B>21j-I)</B> that display improved potency or pharmacological properties. This work demonstrates that a variety of structures can effectively target the Bcr-Abl myristate binding site and provides new leads for developing drugs that can target this binding site.</P>