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 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.
Okram
Barun
B
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Nagle
Advait
A
Adrián
Francisco J
FJ
Lee
Christian
C
Ren
Pingda
P
Wang
Xia
X
Sim
Taebo
T
Xie
Yongping
Y
Wang
Xing
X
Xia
Gang
G
Spraggon
Glen
G
Warmuth
Markus
M
Liu
Yi
Y
Gray
Nathanael S
NS
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
D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D016315:Proto-Oncogene Proteins c-abl