A novel class of selective CK2 inhibitors targeting its open hinge conformation
| Autor: | Roberto Battistutta, Giovanni Ribaudo, Stefania Sarno, Andrea Dalle Vedove, Giuseppe Zagotto, Francesca Zonta, Graziano Lolli, Nicola Demitri, Alberto Ongaro, Maria Ruzzene, Giulia Cazzanelli, Enrico Zanforlin |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Protein Conformation
Stereochemistry Hinge Pyrimidinones Ring (chemistry) Jurkat Cells Structure-Activity Relationship Endocellular assay and mechanism of action Protein kinase CK2 Thiadiazoles Drug Discovery Structural isomer Side chain Humans Transferase Chemical synthesis and structural characterization Casein Kinase II Protein Kinase Inhibitors X-ray crystallography Pharmacology Kinase Chemistry Organic Chemistry General Medicine Molecular Docking Simulation Drug Design |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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