Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase

Autor:	James Hardwick, Xianzhi Mao, Constanine Kreatsoulas, Eileen S. Walsh, Sanjeev Munshi, Marc Abrams, George D. Hartman, Laura Sepp-Lorenzino, Mark E. Fraley, Rob Lobell, Kelly Hamilton, Lawrence Kuo, Carolyn A. Buser, Weikang Tao, Robert M. Garbaccio, Mari Ikuta, Keith W. Rickert, Edward S. Tasber, Bob Drakas, Steve Stirdivant, Stephen C. Beck, Shaei Huang, Youwei Yan
Rok vydání:	2007
Předmět:	Models Molecular Photochemistry Stereochemistry Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Apoptosis Quinolones Crystallography X-Ray Biochemistry Chemical synthesis Inhibitory Concentration 50 Structure-Activity Relationship chemistry.chemical_compound Residue (chemistry) Cell Line Tumor Drug Discovery Humans Transferase Structure–activity relationship Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Binding Sites Molecular Structure biology Organic Chemistry Enzyme chemistry Enzyme inhibitor Checkpoint Kinase 1 Lactam biology.protein Molecular Medicine Amine gas treating Protein Kinases
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 17:6280-6285
ISSN:	0960-894X
DOI:	10.1016/j.bmcl.2007.09.007
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8392ef471e763e4ddf93eeb0d6112007 https://doi.org/10.1016/j.bmcl.2007.09.007 Zobrazit plný text záznamu Full Text from ScienceDirect