Targeting wild-type and T315I Bcr-Abl by combining allosteric with ATP-site inhibitors
| Autor: | Zhang, Jianming, Adrián, 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. |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Male
Models Molecular Transplantation Heterologous Fusion Proteins bcr-abl Antineoplastic Agents Article Mass Spectrometry Piperazines Inhibitory Concentration 50 Mice hemic and lymphatic diseases Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive Antineoplastic Combined Chemotherapy Protocols Animals Humans Bone Marrow Transplantation Binding Sites Protein Structure Tertiary Disease Models Animal Pyrimidines Drug Resistance Neoplasm Benzamides Mutation Imatinib Mesylate Female Crystallization |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|