Author/Authors :
Robert M. Garbaccio، نويسنده , , Shaei Huang، نويسنده , , Edward S. Tasber، نويسنده , , Mark E. Fraley، نويسنده , , Youwei Yan، نويسنده , , Sanjeev Munshi، نويسنده , , Mari Ikuta، نويسنده , , Lawrence Kuo، نويسنده , , Constanine Kreatsoulas، نويسنده , , Steve Stirdivant، نويسنده , , Bob Drakas، نويسنده , , Keith Rickert، نويسنده , , Eileen S. Walsh، نويسنده , , Kelly A. Hamilton، نويسنده , , Carolyn A. Buser، نويسنده , , James Hardwick، نويسنده , , Xianzhi Mao، نويسنده , , Stephen C. Beck، نويسنده , , Marc T. Abrams، نويسنده , , Weikang Tao، نويسنده , , et al.، نويسنده ,
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.
Keywords :
Mitotic arrest , p53-Deficient cancer , Checkpoint escape , Apoptosis , Chk1 kinase , Chek1 kinase , cancer , Kinases , Photochemistry , Benzoisoquinolinones , DNA damaging agents , PSA
