Pagano Mario A, Poletto Giorgia, Di Maira Giovanni, Cozza Giorgio, Ruzzene Maria, Sarno Stefania, Bain Jenny, Elliott Matthew, Moro Stefano, Zagotto Giuseppe, Meggio Flavio, Pinna Lorenzo A
Department of Biological Chemistry and CNR Institute of Neurosciences, University of Padova viale G. Colombo 3, 35121 Padova, Italy.
Chembiochem. 2007 Jan 2;8(1):129-39. doi: 10.1002/cbic.200600293.
Abnormally high constitutive activity of protein kinase CK2, levels of which are elevated in a variety of tumours, is suspected to underlie its pathogenic potential. The most widely employed CK2 inhibitor is 4,5,6,7-tetrabromobenzotriazole (TBB), which exhibits a comparable efficacy toward another kinase, DYRK1 a. Here we describe the development of a new class of CK2 inhibitors, conceptually derived from TBB, which have lost their potency toward DYRK1 a. In particular, tetrabromocinnamic acid (TBCA) inhibits CK2 five times more efficiently than TBB (IC50 values 0.11 and 0.56 microM, respectively), without having any comparable effect on DYRK1 a (IC50 24.5 microM) or on a panel of 28 protein kinases. The usefulness of TBCA for cellular studies has been validated by showing that it reduces the viability of Jurkat cells more efficiently than TBB through enhancement of apoptosis. Collectively taken, the reported data support the view that suitably derivatized tetrabromobenzene molecules may provide powerful reagents for dissecting the cellular functions of CK2 and counteracting its pathogenic potentials.
蛋白激酶CK2的组成型活性异常高,其水平在多种肿瘤中升高,人们怀疑这是其致病潜力的基础。应用最广泛的CK2抑制剂是4,5,6,7-四溴苯并三唑(TBB),它对另一种激酶DYRK1a也表现出类似的效力。在此,我们描述了一类新的CK2抑制剂的研发情况,这类抑制剂从概念上源自TBB,但对DYRK1a已失去效力。特别是,四溴肉桂酸(TBCA)抑制CK2的效率比TBB高五倍(IC50值分别为0.11和0.56微摩尔),而对DYRK1a(IC50为24.5微摩尔)或一组28种蛋白激酶没有任何类似影响。通过证明TBCA比TBB更有效地降低Jurkat细胞的活力(通过增强凋亡),验证了TBCA在细胞研究中的实用性。综合来看,所报道的数据支持这样一种观点,即适当衍生的四溴苯分子可能为剖析CK2的细胞功能并对抗其致病潜力提供有力的试剂。