Abstract 711: Small molecule compounds that target cell division cycle 7 (Cdc7) kinase inhibit cell proliferation and tumor growth.

Cdc7 is an essential, serine/threonine protein kinase that activates the initiation of DNA synthesis at replication origins. Cdc7 also promotes cell cycle checkpoint activation in response to replication stress. As a key regulator of S phase entry and progression, Cdc7 kinase is a potential target for cancer therapy, with a distinct mechanism of action from known drugs that inhibit DNA replication. Following a high throughput screen for inhibitors of Cdc7 kinase activity, we investigated structure-activity relationships of azole-based compounds and optimized the compounds for potency and pharmacokinetic properties. Here we present the characterization of one of these compounds as a potent, selective, bioavailable Cdc7 kinase inhibitor. In cells, Cdc7 inhibition decreases MCM2 phosphorylation and DNA synthesis, causes DNA damage, and slows S phase progression. Cdc7 inhibition also induces chromosome missegregation leading to cell lethality in vitro and tumor growth inhibition in vivo. Cdc7 inhibition provides a new approach to target cancers, either as a single agent or in combination with chemotherapy. Citation Format: Julie Bailis, Li Fang, Jessica Orf, Scott Heller, Tammy Bush, Matthew Bourbeau, Sonia Escobar, Michael Frohn, Paul Harrington, Faye Hsieh, Alexander Pickrell, Kelvin Sham, Aaron Siegmund, Helming Tan, Leeanne Zalameda, John Allen, Dineli Wickramasinghe. Small molecule compounds that target cell division cycle 7 (Cdc7) kinase inhibit cell proliferation and tumor growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 711. doi:10.1158/1538-7445.AM2013-711