The selectivity of inhibitors of protein kinase CK2. An update.

Mario A Pagano , Jenny Bain , Zygmunt Kazimierczuk , Stefania Sarno , Maria Ruzzene , Giovanni Di Maira , Matthew Elliott , Andrzej Orzeszko , Giorgio Cozza , Flavio Meggio , Lorenzo A Pinna (1)

1 Dipartimento di Chimica Biologica

CK2 is a very pleiotropic Ser/Thr protein kinase whose abnormally high constitutive activity has been often correlated to pathological conditions with special reference to neoplasia. The two most widely used cell permeable CK2 inhibitors, 4,5,6,7-tetrabromo-1H-benzotriazole (TBB) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), are marketed as quite specific CK2 blockers. Here we show by using a panel of about 80 protein kinases that DMAT and its parent compound 4,5,6,7-tetrabromo-1H-benzimidazole (TBI or TBBz) are potent inhibitors of several other kinases, with special reference to PIM1, PIM2, PIM3, PKD1, HIPK2 and DYRK1a. In contrast TBB is significantly more selective toward CK2, although it also inhibits PIM1 and PIM3. In an attempt to improve selectivity toward CK2 a library of 68 TBB/TBI related compounds have been tested for their ability to discriminate among CK2, PIM1, HIPK2 and DYRK1a, ending up with 7 compounds whose efficacy toward CK2 is markedly higher than that toward the second most inhibited kinase. Two of these, 3,4,5,6,7–pentabromo–1H-indazole (K64) and 1-carboxymethyl-2-dimethylamino-4,5,6,7-tetrabromo-benzimidazole (K66), display an overall selectivity much higher than TBB and DMAT when tested on an 80 kinases panel and display similar efficacy as inducers of apoptosis.

Mots clés: Life Sciences

Mario A Pagano, Jenny Bain, Zygmunt Kazimierczuk, Stefania Sarno, Maria Ruzzene, et al.. The selectivity of inhibitors of protein kinase CK2. An update.. Biochemical Journal, 2008, 415 (3), pp.353-365. ⟨10.1042/BJ20080309⟩. ⟨hal-00478973⟩