title: Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors.
abstract: Drug design efforts in the emerging 2-aminothiazole-4-carboxamide class of CHK1 inhibitors have uncovered specific combinations of key substructures within the molecule; resulting in significant improvements in cell-based activity while retaining a greater than one hundred-fold selectivity against CDK2. The X-ray crystal structure of a complex between compound 39 and the CHK1 protein detailing a 'U-shaped' topology and key interactions with the protein surface at the ATP site is also reported.
authors.affiliation: Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA. xiaohua.huang@merck.com
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Huang
authors.forename: Cliff C
authors.initials: CC
authors.lastname: Cheng
authors.forename: Thierry O
authors.initials: TO
authors.lastname: Fischmann
authors.forename: José S
authors.initials: JS
authors.lastname: Duca
authors.forename: Matthew
authors.initials: M
authors.lastname: Richards
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Tadikonda
authors.forename: Panduranga Adulla
authors.initials: PA
authors.lastname: Reddy
authors.forename: Lianyun
authors.initials: L
authors.lastname: Zhao
authors.forename: M Arshad
authors.initials: MA
authors.lastname: Siddiqui
authors.forename: David
authors.initials: D
authors.lastname: Parry
authors.forename: Nicole
authors.initials: N
authors.lastname: Davis
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Seghezzi
authors.forename: Derek
authors.initials: D
authors.lastname: Wiswell
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Shipps
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015195:Drug Design; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D000577:Amides; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; C004483:2-aminothiazole; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; D051357:Cyclin-Dependent Kinase 2