title: Identification of novel, selective and potent Chk2 inhibitors.
abstract: A series of isothiazole carboxamidine compounds were synthesized and discovered as novel and selective inhibitors for Chk2. They are not active against the related Chk1 kinase. The structure-activity relationship studies were performed on the scaffold, and enzymatic kinetic analysis showed they are simple ATP competitive inhibitors with K(i) values as low as 11 nM for Chk2. Computer modeling studies were employed to comprehend the mechanism of action and SAR of these compounds.
authors.affiliation: Drug Discovery, Valeant Pharmaceutical Research and Development 3300 Hyland Avenue, Costa Mesa, CA 92626, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Larson
authors.forename: Shunqi
authors.initials: S
authors.lastname: Yan
authors.forename: Huanming
authors.initials: H
authors.lastname: Chen
authors.forename: Frank
authors.initials: F
authors.lastname: Rong
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong
authors.forename: Jim Zhen
authors.initials: JZ
authors.lastname: Wu
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry*; D001667:Binding, Competitive; D064447:Checkpoint Kinase 2; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000578:Amidines; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D000255:Adenosine Triphosphate; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases