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Design, Synthesis, and Biological Activity of 5,10-Dihydro-dibenzo[ b , e ][1,4]diazepin-11-one-Based Potent and Selective Chk-1 Inhibitors

2007; American Chemical Society; Volume: 50; Issue: 17 Linguagem: Inglês

10.1021/jm070105d

1520-4804

Le Wang, Gerard M. Sullivan, Laura A. Hexamer, Lisa Hasvold, Reema K. Thalji, Magdalena Przytulinska, Zhi‐Fu Tao, Gaoquan Li, Zehan Chen, Zhan Xiao, Wen‐Zhen Gu, John Xue, Mai-Ha Bui, Philip J. Merta, Peter Kovar, Jennifer J. Bouska, Haiying Zhang, Chang Park, Kent D. Stewart, Hing L. Sham, Thomas J. Sowin, Saul H. Rosenberg, Nan‐Horng Lin,

Microtubule and mitosis dynamics

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.