Department of General, Visceral and Transplantation Surgery, Surgery Centre, University of Ulm, Steinhövel Str. 9, 89075, Ulm, Germany.
Amino Acids. 2012 Oct;43(4):1577-91. doi: 10.1007/s00726-012-1234-x. Epub 2012 Feb 14.
In this study we identified two heterocyclic compounds (5 and 6) as potent and specific inhibitors of CK1δ (IC(50) = 0.040 and 0.042 μM, respectively). Whereas compound 5 exhibited fivefold higher affinity towards CK1δ than to CK1ε (IC(50) CK1ε = 0.199 μM), compound 6 also inhibited CK1ε (IC(50) = 0.0326 μM) in the same range as CK1δ. Selected compound 5 was screened over 442 kinases identifying 5 as a highly potent and selective inhibitor of CK1δ. X-ray analysis of 5 bound to CK1δ demonstrated its binding mode. In addition, characterization of 5 and 6 in a cell biological approach revealed the ability of both compounds to inhibit proliferation of tumor cell lines in a dose and cell line specific manner. In summary, our optimizations lead to the development of new highly selective CK1δ and ε specific inhibitors with biological activity.
在这项研究中，我们鉴定出两种杂环化合物（5 和 6），它们是 CK1δ 的有效且特异的抑制剂（IC50 值分别为 0.040 和 0.042 μM）。化合物 5 对 CK1δ 的亲和力比对 CK1ε 高五倍（IC50 CK1ε = 0.199 μM），而化合物 6 也抑制 CK1ε（IC50 = 0.0326 μM），其活性与 CK1δ 相当。对选定的化合物 5 进行了 442 种激酶的筛选，结果表明其为 CK1δ 的高活性和选择性抑制剂。X 射线分析表明 5 与 CK1δ 结合的方式。此外，在细胞生物学方法中对 5 和 6 的特性研究表明，这两种化合物都能够以剂量和细胞系特异性的方式抑制肿瘤细胞系的增殖。总之，我们的优化导致了新的高选择性 CK1δ 和 ε 特异性抑制剂的开发，它们具有生物活性。
