title: Development of thioquinazolinones, allosteric Chk1 kinase inhibitors.
abstract: A high throughput screening campaign was designed to identify allosteric inhibitors of Chk1 kinase by testing compounds at high concentration. Activity was then observed at K(m) for ATP and at near-physiological concentrations of ATP. This strategy led to the discovery of a non-ATP competitive thioquinazolinone series which was optimized for potency and stability. An X-ray crystal structure for the complex of our best inhibitor bound to Chk1 was solved, indicating that it binds to an allosteric site approximately 13A from the ATP binding site. Preliminary data is presented for several of these compounds.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486, USA. antonella_converso@merck.com
authors.forename: Antonella
authors.initials: A
authors.lastname: Converso
authors.forename: Timothy
authors.initials: T
authors.lastname: Hartingh
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
authors.forename: Edward
authors.initials: E
authors.lastname: Tasber
authors.forename: Keith
authors.initials: K
authors.lastname: Rickert
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Constantine
authors.initials: C
authors.lastname: Kreatsoulas
authors.forename: Steve
authors.initials: S
authors.lastname: Stirdivant
authors.forename: Bob
authors.initials: B
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: Xianzhi
authors.initials: X
authors.lastname: Mao
authors.forename: Marc T
authors.initials: MT
authors.lastname: Abrams
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Beck
authors.forename: Weikang
authors.initials: W
authors.lastname: Tao
authors.forename: Rob
authors.initials: R
authors.lastname: Lobell
authors.forename: Laura
authors.initials: L
authors.lastname: Sepp-Lorenzino
authors.forename: Joan
authors.initials: J
authors.lastname: Zugay-Murphy
authors.forename: Vinod
authors.initials: V
authors.lastname: Sardana
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Munshi
authors.forename: Sylvie Marie
authors.initials: SM
authors.lastname: Jezequel-Sur
authors.forename: Paul D
authors.initials: PD
authors.lastname: Zuck
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
mesh_terms: D001665:Binding Sites; D000071877:Checkpoint Kinase 1; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1