6spx

Publication Abstract from PubMed

Protein kinase CK2, a heterotetrameric holoenzyme composed of two catalytic chains (CK2alpha) attached to a homodimer of regulatory subunits (CK2beta), is a target for drug development for cancer therapy. Here, we describe the tetraiodobenzimidazole derivative ARC-3140, a bisubstrate inhibitor addressing the ATP site and the substrate-binding site of CK2 with extraordinary affinity (Ki = 84 pM). In a crystal structure of ARC-3140 in complex with CK2alpha, three copies of the inhibitor are visible, one of them at the CK2beta interface of CK2alpha. Subsequent interaction studies based on microscale thermophoresis and fluorescence anisotropy changes revealed a significant impact of ARC-3140 and of its tetrabromo equivalent ARC-1502 on the CK2alpha/CK2beta interaction. A structural inspection revealed that ARC-3140, unlike CK2beta antagonists described so far, interferes with both sub-interfaces of the bipartite CK2alpha/CK2beta interaction. Thus, ARC-3140 is a lead for the further development of highly effective compounds perturbating the quaternary structure of the CK2alpha2beta2 holoenzyme.

Unexpected CK2beta-antagonistic functionality of bisubstrate inhibitors targeting protein kinase CK2.,Pietsch M, Viht K, Schnitzler A, Ekambaram R, Steinkruger M, Enkvist E, Nienberg C, Nickelsen A, Lauwers M, Jose J, Uri A, Niefind K Bioorg Chem. 2020 Jan 23;96:103608. doi: 10.1016/j.bioorg.2020.103608. PMID:32058103^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.