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
  • 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.