Discovery of XL413, a potent and selective CDC7 inhibitor

CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-06, Vol.22 (11), p.3727-3731
Main Authors: Koltun, Elena S., Tsuhako, Amy Lew, Brown, David S., Aay, Naing, Arcalas, Arlyn, Chan, Vicky, Du, Hongwang, Engst, Stefan, Ferguson, Kim, Franzini, Maurizio, Galan, Adam, Holst, Charles R., Huang, Ping, Kane, Brian, Kim, Moon H., Li, Jia, Markby, David, Mohan, Manisha, Noson, Kevin, Plonowski, Arthur, Richards, Steven J., Robertson, Scott, Shaw, Kenneth, Stott, Gordon, Stout, Thomas J., Young, Jenny, Yu, Peiwen, Zaharia, Cristiana A., Zhang, Wentao, Zhou, Peiwen, Nuss, John M., Xu, Wei, Kearney, Patrick C.
Format: Article
Language:English
Subjects:
Animals
Benzofuropyrimidinone
Binding Sites
Biological and medical sciences
CDC7 kinase inhibitor
Cell cycle
Cell cycle arrest
Cell Cycle Checkpoints - drug effects
Cell Cycle Proteins - antagonists & inhibitors
Cell Cycle Proteins - metabolism
Cell interactions
Cell Line, Tumor
chemistry
CK2 inhibitors
Clinical trials
Computer Simulation
DNA biosynthesis
DNA replication
growth retardation
Humans
Medical sciences
Mice
Neoplasms - drug therapy
Pharmacology. Drug treatments
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacokinetics
Protein Kinase Inhibitors - therapeutic use
Protein Structure, Tertiary
protein-serine-threonine kinases
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - metabolism
Protein-serine/threonine kinase
Pyrimidinones - chemistry
Pyrimidinones - pharmacokinetics
Pyrimidinones - therapeutic use
Rats
Replication
Replication initiation
serine
Structure-Activity Relationship
threonine
Transplantation, Heterologous
Tumor cell lines
Tumors
Up-Regulation
Xenografts
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Description
Summary:CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.04.024