A General Strategy for Creating “Inactive-Conformation” Abl Inhibitors
Kinase inhibitors that bind to the ATP cleft can be broadly classified into two groups: those that bind exclusively to the ATP site with the kinase assuming a conformation otherwise conducive to phosphotransfer (type I), and those that exploit a hydrophobic site immediately adjacent to the ATP pocke...
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| Veröffentlicht in: | Chemistry & biology 2006-07, Vol.13 (7), p.779-786 |
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| container_title | Chemistry & biology |
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| creator | Okram, Barun Nagle, Advait Adrián, Francisco J. Lee, Christian Ren, Pingda Wang, Xia Sim, Taebo Xie, Yongping Wang, Xing Xia, Gang Spraggon, Glen Warmuth, Markus Liu, Yi Gray, Nathanael S. |
| description | Kinase inhibitors that bind to the ATP cleft can be broadly classified into two groups: those that bind exclusively to the ATP site with the kinase assuming a conformation otherwise conducive to phosphotransfer (type I), and those that exploit a hydrophobic site immediately adjacent to the ATP pocket made accessible by a conformational rearrangement of the activation loop (type II). To date, all type II inhibitors were discovered by using structure-activity-guided optimization strategies. Here, we describe a general pharmacophore model of type II inhibition that enables a rational “hybrid-design” approach whereby a 3-trifluoromethylbenzamide functionality is appended to four distinct type I scaffolds in order to convert them into their corresponding type II counterparts. We demonstrate that the designed compounds function as type II inhibitors by using biochemical and cellular kinase assays and by cocrystallography with Abl. |
| doi_str_mv | 10.1016/j.chembiol.2006.05.015 |
| format | Article |
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To date, all type II inhibitors were discovered by using structure-activity-guided optimization strategies. Here, we describe a general pharmacophore model of type II inhibition that enables a rational “hybrid-design” approach whereby a 3-trifluoromethylbenzamide functionality is appended to four distinct type I scaffolds in order to convert them into their corresponding type II counterparts. 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| subjects | Adenosine Triphosphate - metabolism CHEMBIO Crystallography Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism Hydrogen Bonding Models, Molecular Molecular Conformation Phosphorylation Proto-Oncogene Proteins c-abl - antagonists & inhibitors Proto-Oncogene Proteins c-abl - metabolism SIGNALING Structure-Activity Relationship Substrate Specificity |
| title | A General Strategy for Creating “Inactive-Conformation” Abl Inhibitors |
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