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Adriá,n-Martí,nez, S.,Albert, A.,André,, M.,Anton, G.,Ardid, M.,Aubert, J.-J.,Baret, B.,Barrios-Martí,, J.,Basa, S.,Bertin, V.,Biagi, S.,Bormuth, R.,Bouwhuis, M. C.,Bruijn, R. American Astronomical Society 2016 The Astrophysical journal Vol.823 No.1
<P>We present the results of searches for point-like sources of neutrinos based on the first combined analysis of data from both the ANTARES and IceCube neutrino telescopes. The combination of both detectors, which differ in size and location, forms a window in the southern sky where the sensitivity to point sources improves by up to a factor of 2 compared with individual analyses. Using data recorded by ANTARES from 2007 to 2012, and by IceCube from 2008 to 2011, we search for sources of neutrino emission both across the southern sky and from a preselected list of candidate objects. No significant excess over background has been found in these searches, and flux upper limits for the candidate sources are presented for E-2.5 and E-2 power-law spectra with different energy cut-offs.</P>
High-energy neutrino follow-up search of gravitational wave event GW150914 with ANTARES and IceCube
Adriá,n-Martí,nez, S.,Albert, A.,André,, M.,Anghinolfi, M.,Anton, G.,Ardid, M.,Aubert, J.-J.,Avgitas, T.,Baret, B.,Barrios-Martí,, J.,Basa, S.,Bertin, V.,Biagi, S.,Bormuth, R. American Physical Society 2016 Physical Review D Vol.93 No.12
<P>We present the high-energy-neutrino follow-up observations of the first gravitational wave transient GW150914 observed by the Advanced LIGO detectors on September 14, 2015. We search for coincident neutrino candidates within the data recorded by the IceCube and ANTARES neutrino detectors. A possible joint detection could be used in targeted electromagnetic follow-up observations, given the significantly better angular resolution of neutrino events compared to gravitational waves. We find no neutrino candidates in both temporal and spatial coincidence with the gravitational wave event. Within +/- 500 s of the gravitational wave event, the number of neutrino candidates detected by IceCube and ANTARES were three and zero, respectively. This is consistent with the expected atmospheric background, and none of the neutrino candidates were directionally coincident with GW150914. We use this nondetection to constrain neutrino emission from the gravitational-wave event.</P>
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>