Exploiting the repertoire of CK2 inhibitors to target DYRK and PIM kinases.
Advantage has been taken of the relative promiscuity of commonly used inhibitors of protein kinase CK2 to develop compounds that can be exploited for the selective inhibition of druggable kinases other than CK2 itself. Here we summarize data obtained by altering the scaffold of CK2 inhibitors to give rise to novel selective inhibitors of DYRK1A and to a powerful cell permeable dual inhibitor of PIM1 and CK2. In the former case one of the new compounds, C624 (naphto [1,2-b]benzofuran-5,9-diol) displays a potency comparable to that of the first-in-class DYRK1A inhibitor, harmine, lacking however the drawback of drastically inhibiting monoamine oxidase-A (MAO-A) as harmine does. On the other hand the promiscuous CK2 inhibitor 4,5,6,7-tetrabromo-1H-benzimidazole (TBI,TBBz) has been derivatized with a sugar moiety to generate a 1-(β-D-2'-deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazole (TDB) compound which inhibits PIM1 and CK2 with comparably high efficacy (IC50 values<100nM) and remarkable selectivity. TDB, unlike other dual PIM1/CK2 inhibitors described in the literature is readily cell permeable and displays a cytotoxic effect on cancer cells consistent with concomitant inhibition of both its onco-kinase targets. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).
Department of Biomedical Sciences and CNR, Institute of Neuroscience, University of Padua, Viale G. Colombo 3 35131, Padova, Italy.
Giorgio
G
Cozza
Stefania
S
Sarno
Maria
M
Ruzzene
Cristina
C
Girardi
Andrzej
A
Orzeszko
Zygmunt
Z
Kazimierczuk
Giuseppe
G
Zagotto
Emanuela
E
Bonaiuto
Maria Luisa
ML
Di Paolo
Lorenzo A
LA
Pinna
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017667:Adipocytes / Q000201:enzymology; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006247:Harmine / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000097603:Dyrk Kinases
D000255:Adenosine Triphosphate; D001562:Benzimidazoles; D047390:Casein Kinase II; D006247:Harmine; D008995:Monoamine Oxidase; D008996:Monoamine Oxidase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; D000097603:Dyrk Kinases; C475924:4,5,6,7-tetrabromobenzimidazole; C496634:PIM1 protein, human