Design, validation and efficacy of bisubstrate inhibitors specifically affecting ecto-CK2 kinase activity

The Biochemical Journal
Giorgio CozzaLorenzo A Pinna

Abstract

By derivatizing the purely competitive CK2 inhibitor N1-(4,5,6,7-tetrabromo-1H-benzimidazol-2-yl)-propane-1,3-diamine (K137) at its 3-amino position with a peptidic fragment composed of three or four glutamic or aspartic acid residues, a new family of bisubstrate inhibitors has been generated whose ability to simultaneously interact with both the ATP and the phosphoacceptor substrate-binding sites has been probed by running mixed competition kinetics and by mutational mapping of the kinase residues implicated in substrate recognition. The most effective bisubstrate inhibitor, K137-E4, interacts with three functional regions of the kinase: the hydrophobic pocket close to the ATP-binding site, the basic residues of the p+1 loop that recognizes the acidic determinant at position n+1 and the basic residues of α-helixC that recognize the acidic determinant at position n+3. Compared with the parent inhibitor (K137), K137-E4 is severalfold more potent (IC50 25 compared with 130 nM) and more selective, failing to inhibit any other kinase as drastically as CK2 out of 140 enzymes, whereas 35 kinases are inhibited more potently than CK2 by K137. K137-E4 is unable to penetrate the cell and to inhibit endogenous CK2, its pro-apoptotic effic...Continue Reading

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Citations

Feb 5, 2016·Advances in Hematology·Alessandro MorottiGiuseppe Saglio
Nov 18, 2015·BioMed Research International·Sandra MarmiroliMaria Ruzzene
Feb 24, 2017·Pharmaceuticals·Janeen H TrembleyKhalil Ahmed
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Jan 10, 2017·Pharmaceuticals·Julia CastelloHeike Rebholz
Mar 18, 2021·European Journal of Medicinal Chemistry·Seungbeom LeeHwayoung Yun
Jun 11, 2020·Structure·Samual D DickPeter Cherepanov
May 27, 2021·Organic & Biomolecular Chemistry·Jessica IegreDavid R Spring
May 18, 2021·Signal Transduction and Targeted Therapy·Christian BorgoMaria Ruzzene

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