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In an effort to find new pharmacological modalities to overcome resistance to ATP-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 demonstrate 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 analog of GNF-2 having improved pharmacokinetic properties, when utilized 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 Bcr-Abl and displayed in vivo efficacy against the recalcitrant T315I Bcr-Abl mutant in a murine bone-marrow transplantation model. These results demonstrate that therapeutically relevant inhibition of Bcr-Abl activity can be achieved using inhibitors that bind to the myristate binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.

Adopting the model of fractional Brownian motion, this paper presents the method of deducing Hurst exponent based on the observed sea clutter of S-band radar. Secondly the prediction technology of chaotic time series is studied based on memory-based predictor. Furthermore, adopting the method of support vector machine classifiers of the improved radial basis kernel function, this paper proposes a novel method of target detection based on the sea clutter. Thirdly, on the basis of observed sea clutter of S-band radar, the fractal dimension and the largest Lyapunov exponent are obtained, which proves its chaos and fractal characteristic. Finally, the computer simulation is carried out and the results prove the effective detection performance and noise tolerance.