Oligo-aspartic acid conjugates with benzo[c][2,6]naphthyridine-8carboxylic acid scaffold as picomolar inhibitors of CK2

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 7; pp. 2277 - 2284
• Main Authors: Vahter, Juergen, Viht, Kaido, Uri, Asko, Enkvist, Erki
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 01.04.2017
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; ASSAY; Protein kinase; AFFINITY; PROTEIN-KINASE CK2; Fluorescence probe; CK2; Bisubstrate inhibitor; Biligand; Fluorescence anisotropy
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.02.055

Structurally diverse inhibitors of the protein kinase CK2 are required for regulation of this ubiquitous protein to establish biological roles of the enzyme which catalyzes the phosphorylation of a vast number of substrate proteins. In this article we disclose a series of new bisubstrate inhibitors of CK2 that are structurally represented by the oligo(L-Asp) peptide conjugates of benzo[c][2,6]naphthyridine-8-carboxylic acid. This fragment originated from CX-4945, the first in class inhibitor taken to clinical trials. The most potent conjugates possessed two-digit picomolar affinity and clear selectivity for CK2 alpha in a panel of 140 protein kinases. Labeling of the inhibitors with a fluorescent dye yielded probes for a fluorescence anisotropy-based binding/displacement assay which can be used for analysis of CK2 and precise determination of affinity of the highly potent (tight-binding) CK2-targeting inhibitors. (C) 2017 Elsevier Ltd. All rights reserved.