Structural factors contributing to the Abl/Lyn dual inhibitory activity of 3-substituted benzamide derivatives.
To investigate why 3-substituted benzamide derivatives show dual inhibition of Abl and Lyn protein tyrosine kinases, we determined their inhibitory activities against Abl and Lyn, carried out molecular modeling, and conducted a structure-activity relationship study with the aid of a newly determined X-ray structure of the Abl/Lyn dual inhibitor INNO-406 (formerly known as NS-187) bound to human Abl. We found that this series of compounds interacted with both kinases in very similar ways, so that they can inhibit both kinases effectively.
Horio
Tatsuya
T
Research Laboratories, Nippon Shinyaku Co. Ltd., 3-14-1 Sakura, Tsukuba, Ibaraki 305-0003, Japan.
Hamasaki
Tomohiro
T
Inoue
Toshihiko
T
Wakayama
Tatsushi
T
Itou
Shinsaku
S
Naito
Haruna
H
Asaki
Tetsuo
T
Hayase
Hiroki
H
Niwa
Tomoko
T
D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008968:Molecular Conformation; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D001549:Benzamides; D004791:Enzyme Inhibitors; D011743:Pyrimidines; C037689:benzamide; D016315:Proto-Oncogene Proteins c-abl; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C506918:bafetinib