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A novel class of selective CK2 inhibitors targeting its open hinge conformation.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-03-25 , DOI: 10.1016/j.ejmech.2020.112267 Andrea Dalle Vedove 1 , Francesca Zonta 2 , Enrico Zanforlin 3 , Nicola Demitri 4 , Giovanni Ribaudo 5 , Giulia Cazzanelli 1 , Alberto Ongaro 5 , Stefania Sarno 2 , Giuseppe Zagotto 3 , Roberto Battistutta 6 , Maria Ruzzene 2 , Graziano Lolli 1
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-03-25 , DOI: 10.1016/j.ejmech.2020.112267 Andrea Dalle Vedove 1 , Francesca Zonta 2 , Enrico Zanforlin 3 , Nicola Demitri 4 , Giovanni Ribaudo 5 , Giulia Cazzanelli 1 , Alberto Ongaro 5 , Stefania Sarno 2 , Giuseppe Zagotto 3 , Roberto Battistutta 6 , Maria Ruzzene 2 , Graziano Lolli 1
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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.
中文翻译：
靶向其开放铰链构象的新型一类选择性CK2抑制剂。
蛋白激酶CK2维持癌症的生长，特别是在血液系统恶性肿瘤中。其抑制剂SRPIN803基于6-亚甲基-5-亚氨基-1,3,4-噻二唑并吡啶亚胺-7-7骨架，表现出显着的特异性。我们最初提出的SRPIN803的合成导致其结构异构体SRPIN803进行了修订，其中2-氰基-2-丙烯酰胺基团不环化并与噻二唑环融合。与CK2α配合形成的晶体结构确定了报道的特异性的结构决定因素。SRPIN803修订版探讨了CK2开放铰链构象，这种结构在激酶中极为罕见，并且也与该区域的侧链相互作用。它的优化产生了更有效的化合物4，该化合物抑制细胞内CK2，显着影响肿瘤细胞的活力，并在一组320种激酶上显示出显着的选择性。
更新日期：2020-03-26
中文翻译：
靶向其开放铰链构象的新型一类选择性CK2抑制剂。
蛋白激酶CK2维持癌症的生长，特别是在血液系统恶性肿瘤中。其抑制剂SRPIN803基于6-亚甲基-5-亚氨基-1,3,4-噻二唑并吡啶亚胺-7-7骨架，表现出显着的特异性。我们最初提出的SRPIN803的合成导致其结构异构体SRPIN803进行了修订，其中2-氰基-2-丙烯酰胺基团不环化并与噻二唑环融合。与CK2α配合形成的晶体结构确定了报道的特异性的结构决定因素。SRPIN803修订版探讨了CK2开放铰链构象，这种结构在激酶中极为罕见，并且也与该区域的侧链相互作用。它的优化产生了更有效的化合物4，该化合物抑制细胞内CK2，显着影响肿瘤细胞的活力，并在一组320种激酶上显示出显着的选择性。
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