Abstract B47: Potent and selective CK2 kinase inhibitors with effects on Wnt pathway signaling in vivo

Abstract

Abstract The serine/threonine protein kinase CK2, which exists as a constitutively active, hetero-tetrameric complex consisting of two catalytic (α or α') and two regulatory (β) subunits, has emerged as an attractive drug discovery target in oncology. Among its diverse functions, CK2 modulates cellular signaling pathways that are frequently activated in cancer, including PI3K/AKT, NFκB and Wnt. In order to explore the reported links between CK2 kinase activity and Wnt pathway signaling we sought to identify a potent, selective inhibitor of CK2 kinase with suitable physicochemical properties and pharmacokinetics for hypothesis testing in vivo. Starting from a pyrazolo[1,5-a]pyrimidine lead (1), we identified compound 2, a potent CK2 inhibitor with picomolar affinity (CK2a KD = 10 pM) that is highly selective against other kinase family enzymes and inhibits Wnt pathway signaling (Wnt luciferase reporter IC50 = 50 nM) in DLD-1 cells. Compound 2 has demonstrated good pharmacokinetics in preclinical species, depletes β-catenin in vivo and exhibits a high level of activity (TGI > 90%) as a monotherapy in HCT-116 xenografts at tolerated doses. Citation Format: James E. Dowling. Potent and selective CK2 kinase inhibitors with effects on Wnt pathway signaling in vivo. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B47.