2. Academic Validation
  3. Discovery of XL413, a potent and selective CDC7 inhibitor

Discovery of XL413, a potent and selective CDC7 inhibitor

  • Bioorg Med Chem Lett. 2012 Jun 1;22(11):3727-31. doi: 10.1016/j.bmcl.2012.04.024.
Elena S Koltun 1,  Amy Lew Tsuhako,  David S Brown,  Naing Aay,  Arlyn Arcalas,  Vicky Chan,  Hongwang Du,  Stefan Engst,  Kim Ferguson,  Maurizio Franzini,  Adam Galan,  Charles R Holst,  Ping Huang,  Brian Kane,  Moon H Kim,  Jia Li,  David Markby,  Manisha Mohan,  Kevin Noson,  Arthur Plonowski,  Steven J Richards,  Scott Robertson,  Kenneth Shaw,  Gordon Stott,  Thomas J Stout,  Jenny Young,  Peiwen Yu,  Cristiana A Zaharia,  Wentao Zhang,  Peiwen Zhou,  John M Nuss,  Wei Xu,  Patrick C Kearney
Affiliations

Affiliation

  • 1 Exelixis, Department of Drug Discovery, South San Francisco, CA 94080, USA. [email protected]
PMID: 22560567 DOI: 10.1016/j.bmcl.2012.04.024
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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