title: Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase.
abstract: From HTS lead 1, a novel benzoisoquinolinone class of ATP-competitive Chk1 inhibitors was devised and synthesized via a photochemical route. Using X-ray crystallography as a guide, potency was rapidly enhanced through the installation of a tethered basic amine designed to interact with an acidic residue (Glu91) in the enzyme pocket. Further SAR was explored at the solvent front and near to the H1 pocket and resulted in the discovery of low MW, sub-nanomolar inhibitors of Chk1.
authors: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. robert_garbaccio@merck.com
authors: Robert M
authors: RM
authors: Garbaccio
authors: Shaei
authors: S
authors: Huang
authors: Edward S
authors: ES
authors: Tasber
authors: Mark E
authors: ME
authors: Fraley
authors: Youwei
authors: Y
authors: Yan
authors: Sanjeev
authors: S
authors: Munshi
authors: Mari
authors: M
authors: Ikuta
authors: Lawrence
authors: L
authors: Kuo
authors: Constanine
authors: C
authors: Kreatsoulas
authors: Steve
authors: S
authors: Stirdivant
authors: Bob
authors: B
authors: Drakas
authors: Keith
authors: K
authors: Rickert
authors: Eileen S
authors: ES
authors: Walsh
authors: Kelly A
authors: KA
authors: Hamilton
authors: Carolyn A
authors: CA
authors: Buser
authors: James
authors: J
authors: Hardwick
authors: Xianzhi
authors: X
authors: Mao
authors: Stephen C
authors: SC
authors: Beck
authors: Marc T
authors: MT
authors: Abrams
authors: Weikang
authors: W
authors: Tao
authors: Rob
authors: R
authors: Lobell
authors: Laura
authors: L
authors: Sepp-Lorenzino
authors: George D
authors: GD
authors: Hartman
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010777:Photochemistry; D011494:Protein Kinases / Q000737:chemistry / Q000187:drug effects*; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D015363:Quinolones; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1