2. Academic Validation
  3. A novel class of selective CK2 inhibitors targeting its open hinge conformation

A novel class of selective CK2 inhibitors targeting its open hinge conformation

  • Eur J Med Chem. 2020 Jun 1;195:112267. 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 6,  Roberto Battistutta 7,  Maria Ruzzene 8,  Graziano Lolli 9
Affiliations

Affiliations

  • 1 Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Via Sommarive 9, 38123, Trento, Italy.
  • 2 Department of Biomedical Sciences and CNR Institute of Neuroscience, University of Padua, Via U. Bassi 58/B, 35131, Padua, Italy.
  • 3 Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131, Padua, Italy.
  • 4 Elettra-Sincrotrone Trieste, S.S. 14 Km 163.5 in Area Science Park, 34149, Basovizza-Trieste, Italy.
  • 5 Department of Molecular and Translational Medicine, Division of Pharmacology, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
  • 6 Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131, Padua, Italy. Electronic address: giuseppe.zagotto@unipd.it.
  • 7 Department of Chemical Sciences and CNR Institute of Biomolecular Chemistry, University of Padua, Via F. Marzolo 1, 35131, Padua, Italy. Electronic address: roberto.battistutta@unipd.it.
  • 8 Department of Biomedical Sciences and CNR Institute of Neuroscience, University of Padua, Via U. Bassi 58/B, 35131, Padua, Italy. Electronic address: maria.ruzzene@unipd.it.
  • 9 Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Via Sommarive 9, 38123, Trento, Italy. Electronic address: graziano.lolli@unitn.it.
PMID: 32283296 DOI: 10.1016/j.ejmech.2020.112267
Abstract

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.

Keywords

Chemical synthesis and structural characterization; Endocellular assay and mechanism of action; Protein kinase CK2; X-ray crystallography.

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