4ANM

Discovery of Xl413, a Potent and Selective Cdc7 Inhibitor.

Koltun, E.S., Tsuhako, A.L., Brown, D.S., Aay, N., Arcalas, A., Chan, V., Du, H., Engst, S., Ferguson, K., Franzini, M., Galan, A., Holst, C.R., Huang, P., Kane, B., Kim, M.H., Li, J., Markby, D., Mohan, M., Noson, K., Plonowski, A., Richards, S.J., Robertson, S., Shaw, K., Stott, G., Stout, T.J., Young, J., Yu, P., Zaharia, C.A., Zhang, W., Zhou, P., Nuss, J.M., Xu, W., Kearney, P.C.

(2012) Bioorg Med Chem Lett 22: 3727

• PubMed: 22560567 Search on PubMed
• DOI: https://doi.org/10.1016/j.bmcl.2012.04.024
• Primary Citation of Related Structures:  
  4ANM


• PubMed Abstract: 
  

  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.

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Organizational Affiliation: 

Exelixis, Department of Drug Discovery, South San Francisco, CA 94080, USA. elena@numerate.com