title: A general strategy for creating "inactive-conformation" abl inhibitors.
abstract: 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.
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Barun
authors.initials: B
authors.lastname: Okram
authors.forename: Advait
authors.initials: A
authors.lastname: Nagle
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Adrián
authors.forename: Christian
authors.initials: C
authors.lastname: Lee
authors.forename: Pingda
authors.initials: P
authors.lastname: Ren
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.forename: Yongping
authors.initials: Y
authors.lastname: Xie
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Xia
authors.forename: Glen
authors.initials: G
authors.lastname: Spraggon
authors.forename: Markus
authors.initials: M
authors.lastname: Warmuth
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D003461:Crystallography; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D016315:Proto-Oncogene Proteins c-abl