Discovery of imidazopyridazinecarbonitriles as potent, selective inhibitors of CK2.

Casein kinase 2 (CK2) is a serine/threonine kinase that has been implicated in the regulation of a number of oncogenic or tumor suppressor proteins. CK2 activity has been shown to be elevated in numerous studies in a variety of cancer types. CK2 has been shown to phosphorylate numerous cellular proteins. Among the proteins regulated directly or indirectly by CK2 phosphorylation are oncogenes and tumor suppressor proteins including beta-catenin, c-Myc, PML, and PTEN as well as proteins directly involved in cell cycle, apoptosis, and transcriptional regulation. The plethora of CK2 substrates and their participation in various cellular processes is a major confounding factor in understanding the role of CK2 in oncogenesis. Unlike other kinase targets that participate in relatively linear growth factor signaling pathways, CK2 appears to function more “laterally,” across many important signaling pathways to promote growth and survival of cancer cells. It is clear from numerous studies using siRNA as well as small molecule CK2 inhibitors that cancer cells are highly dependent upon CK2 for growth and survival. As a result, new small molecule inhibitors of CK2 may provide useful tools for probing CK2 biology and may also provide therapeutic benefits against several cancer types. Herein, we report our efforts toward the identification of CK2 inhibitors based on an imidazopyridazine carbonitrile scaffold. Lead compounds from this series demonstrate low nanomolar CK2 biochemical potency, while achieving excellent selectivity versus the majority of kinases in the human kinome. The development of structure-activity relationships and the establishment of a strong correlation between biochemical potency, inhibition of cellular protein target phosphorylation and anti-proliferative effects in targeted cancer cell lines will be presented. In addition, the optimization of pharmacokinetic properties resulting in compounds with excellent in vivo exposure has allowed for the investigation of CK2 inhibition in a pharmacodynamic model. Finally, our efforts to elucidate pathway effects mediated by CK2 in model colon cancer cell lines, including gene expression profiling using advanced small molecules leads, will be disclosed. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B284. Citation Format: Brian Fink, Ashvinikumar Gavai, Soong-Hoon Kim, Yufen Zhao, Ashok Purandare, Gregory Vite, John Tokarski, Chiang Yu, Benjamin Henley, Joseph Fargnoli, Heshani Desilva, Petra Ross-MacDonald, Brent Rupnow, Tai W. Wong. Discovery of imidazopyridazinecarbonitriles as potent, selective inhibitors of CK2. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B284.