title: The design and preliminary structure-activity relationship studies of benzotriazines as potent inhibitors of Abl and Abl-T315I enzymes.
abstract: 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.
authors.affiliation: TargeGen, Inc., 9380 Judicial Drive, San Diego, CA 92121, USA.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Cao
authors.forename: Richard
authors.initials: R
authors.lastname: Fine
authors.forename: Colleen
authors.initials: C
authors.lastname: Gritzen
authors.forename: John
authors.initials: J
authors.lastname: Hood
authors.forename: Xinshan
authors.initials: X
authors.lastname: Kang
authors.forename: Boris
authors.initials: B
authors.lastname: Klebansky
authors.forename: Dan
authors.initials: D
authors.lastname: Lohse
authors.forename: Chi Ching
authors.initials: CC
authors.lastname: Mak
authors.forename: Andrew
authors.initials: A
authors.lastname: McPherson
authors.forename: Glenn
authors.initials: G
authors.lastname: Noronha
authors.forename: Moorthy S S
authors.initials: MS
authors.lastname: Palanki
authors.forename: Ved P
authors.initials: VP
authors.lastname: Pathak
authors.forename: Joel
authors.initials: J
authors.lastname: Renick
authors.forename: Richard
authors.initials: R
authors.lastname: Soll
authors.forename: Binqi
authors.initials: B
authors.lastname: Zeng
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
mesh_terms: 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*