Abstract
A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited a strong ability to abrogate G2 arrest and increased the cytotoxicity of camptothecin by 19-fold against SW620 cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two important binding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, were hydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bond between the methoxy group and Lys38 of the protein.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Azepines / chemical synthesis*
-
Azepines / chemistry
-
Azepines / pharmacology
-
Benzodiazepinones / chemical synthesis*
-
Benzodiazepinones / chemistry
-
Benzodiazepinones / pharmacology
-
Biological Availability
-
Camptothecin / pharmacology
-
Cell Line, Tumor
-
Checkpoint Kinase 1
-
Crystallography, X-Ray
-
Doxorubicin / pharmacology
-
Drug Design
-
Drug Synergism
-
Humans
-
Mice
-
Models, Molecular
-
Protein Binding
-
Protein Kinase Inhibitors / chemical synthesis*
-
Protein Kinase Inhibitors / chemistry
-
Protein Kinase Inhibitors / pharmacology
-
Protein Kinases / chemistry
-
Protein Kinases / metabolism*
-
Structure-Activity Relationship
Substances
-
2-(3-(3-methoxy-4-nitrophenyl)-11-oxo-10,11-dihydro-5H-dibenzo(b,e)(1,4)diazepin-8-yl)-N,N-dimethylacetamide
-
Antineoplastic Agents
-
Azepines
-
Benzodiazepinones
-
Protein Kinase Inhibitors
-
Doxorubicin
-
Protein Kinases
-
CHEK1 protein, human
-
Checkpoint Kinase 1
-
Chek1 protein, mouse
-
Camptothecin