Zhang, Jianming Adrian, 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 Okram, Barun Choi, Yongmun Wojciechowski, Amy Deng, Xianming Liu, Guoxun Fendrich, Gabriele Strauss, Andre Vajpai, Navratna Grzesiek, Stephan Tuntland, Tove Liu, Yi Bursulaya, Badry Azam, Mohammad Manley, Paul W. Engen, John R. Daley, George Q. Warmuth, Markus Gray, Nathanael S. 2024-01-20T20:01:52Z 2024-01-20T20:01:52Z 2021-09-02 2010-01-28 0028-0836 https://pubs.kist.re.kr/handle/201004/131770 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. English NATURE PUBLISHING GROUP CHRONIC MYELOID-LEUKEMIA CELL LUNG-CANCER KINASE-INHIBITOR C-ABL TYROSINE KINASE LYMPHOBLASTIC-LEUKEMIA IMATINIB RESISTANCE SELECTIVE INHIBITOR MUTATIONS DYNAMICS Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors Article 10.1038/nature08675 1 NATURE, v.463, no.7280, pp.501 - U116 NATURE 463 7280 501 U116 scie scopus 000273981100042 2-s2.0-75749146563 Multidisciplinary Sciences Science & Technology - Other Topics Article CHRONIC MYELOID-LEUKEMIA CELL LUNG-CANCER KINASE-INHIBITOR C-ABL TYROSINE KINASE LYMPHOBLASTIC-LEUKEMIA IMATINIB RESISTANCE SELECTIVE INHIBITOR MUTATIONS DYNAMICS