title: Pyridyl aminothiazoles as potent inhibitors of Chk1 with slow dissociation rates.
abstract: Pyridyl aminothiazoles comprise a novel class of ATP-competitive Chk1 inhibitors with excellent inhibitory potential. Modification of the core with ethylenediamine amides provides compounds with low picomolar potency and very high residence times. Investigation of binding parameters of such compounds using X-ray crystallography and molecular dynamics simulations revealed multiple hydrogen bonds to the enzyme backbone as well as stabilization of the conserved water molecules network in the hydrophobic binding region.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. vadim_dudkin@merck.com
authors.forename: Vadim Y
authors.initials: VY
authors.lastname: Dudkin
authors.forename: Keith
authors.initials: K
authors.lastname: Rickert
authors.forename: Constantine
authors.initials: C
authors.lastname: Kreatsoulas
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Arrington
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Yowei
authors.initials: Y
authors.lastname: Yan
authors.forename: Mari
authors.initials: M
authors.lastname: Ikuta
authors.forename: Steven M
authors.initials: SM
authors.lastname: Stirdivant
authors.forename: Robert A
authors.initials: RA
authors.lastname: Drakas
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Walsh
authors.forename: Kelly
authors.initials: K
authors.lastname: Hamilton
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
authors.forename: Robert B
authors.initials: RB
authors.lastname: Lobell
authors.forename: Laura
authors.initials: L
authors.lastname: Sepp-Lorenzino
mesh_terms: D000577:Amides / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D015195:Drug Design; D005029:Ethylenediamines / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014867:Water / Q000737:chemistry
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D005029:Ethylenediamines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013844:Thiazoles; D014867:Water; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1