Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Via Sommarive 9, 38123, Trento, Italy.
Department of Biomedical Sciences and CNR Institute of Neuroscience, University of Padua, Via U. Bassi 58/B, 35131, Padua, Italy.
Eur J Med Chem. 2020 Jun 1;195:112267. doi: 10.1016/j.ejmech.2020.112267. Epub 2020 Mar 25.
Protein kinase CK2 sustains cancer growth, especially in hematological malignancies. Its inhibitor SRPIN803, based on a 6-methylene-5-imino-1,3,4-thiadiazolopyrimidin-7-one scaffold, showed notable specificity. Our synthesis of the initially proposed SRPIN803 resulted in its constitutional isomer SRPIN803-revised, where the 2-cyano-2-propenamide group does not cyclise and fuse to the thiadiazole ring. Its crystallographic structure in complex with CK2α identifies the structural determinants of the reported specificity. SRPIN803-revised explores the CK2 open hinge conformation, extremely rare among kinases, also interacting with side chains from this region. Its optimization lead to the more potent compound 4, which inhibits endocellular CK2, significantly affects viability of tumour cells and shows remarkable selectivity on a panel of 320 kinases.
蛋白激酶 CK2 维持着癌症的生长，尤其是在血液恶性肿瘤中。其抑制剂 SRPIN803 基于 6-亚甲基-5-亚氨基-1,3,4-噻二唑并嘧啶-7-酮骨架，表现出显著的特异性。我们最初提出的 SRPIN803 的合成导致了其结构异构体 SRPIN803-修订版的产生，其中 2-氰基-2-丙烯酰胺基团不环化并与噻二唑环融合。其与 CK2α 的复合物的晶体结构确定了报道特异性的结构决定因素。SRPIN803-修订版探索了 CK2 的开放铰链构象，这种构象在激酶中极为罕见，也与该区域的侧链相互作用。其优化导致了更有效的化合物 4，它抑制细胞内 CK2，显著影响肿瘤细胞的活力，并在 320 种激酶的面板上表现出显著的选择性。
