The design and preliminary structure-activity relationship studies of benzotriazines as potent inhibitors of Abl and Abl-T315I enzymes.
We describe the design, synthesis and structure-activity relationship studies in optimizing a series of benzotriazine compounds as potent inhibitors of both Abl and Abl-T315I enzymes. The design includes targeting of an acid functional residue on the alphaC-helix that is available only upon kinase activation. This designed interaction provides an advantage in overcoming the challenges arising from the T315I mutation of Abl and transforms poor (ca. 10 microM) inhibitors into those with low nM potency.
Cao
Jianguo
J
TargeGen, Inc., 9380 Judicial Drive, San Diego, CA 92121, USA.
Fine
Richard
R
Gritzen
Colleen
C
Hood
John
J
Kang
Xinshan
X
Klebansky
Boris
B
Lohse
Dan
D
Mak
Chi Ching
CC
McPherson
Andrew
A
Noronha
Glenn
G
Palanki
Moorthy S S
MS
Pathak
Ved P
VP
Renick
Joel
J
Soll
Richard
R
Zeng
Binqi
B
Zhu
Hong
H
D015195:Drug Design; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology*