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

Casein Kinase II / antagonists & inhibitors Drug Design Humans Jurkat Cells Molecular Docking Simulation Protein Conformation Protein Kinase Inhibitors / chemistry Pyrimidinones / chemistry Structure-Activity Relationship Thiadiazoles / chemistry
Chemical synthesis and structural characterization Endocellular assay and mechanism of action Protein kinase CK2 X-ray crystallography

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
01 Jun 2020
Historique:
received: 30 09 2019
revised: 02 02 2020
accepted: 20 03 2020
pubmed: 14 4 2020
medline: 30 12 2020
entrez: 14 4 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ejmech.2020.112267 PMID: 32283296
pubmed: 32283296
pii: S0223-5234(20)30234-8
doi: 10.1016/j.ejmech.2020.112267
pii:
doi:

Substances chimiques

Protein Kinase Inhibitors 0
Pyrimidinones 0
SRPIN803 0
Thiadiazoles 0
Casein Kinase II EC 2.7.11.1

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

112267

Informations de copyright

Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Auteurs

Andrea Dalle Vedove (A)

Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Via Sommarive 9, 38123, Trento, Italy.

Francesca Zonta (F)

Department of Biomedical Sciences and CNR Institute of Neuroscience, University of Padua, Via U. Bassi 58/B, 35131, Padua, Italy.

Enrico Zanforlin (E)

Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131, Padua, Italy.

Nicola Demitri (N)

Elettra-Sincrotrone Trieste, S.S. 14 Km 163.5 in Area Science Park, 34149, Basovizza-Trieste, Italy.

Giovanni Ribaudo (G)

Department of Molecular and Translational Medicine, Division of Pharmacology, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.

Giulia Cazzanelli (G)

Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Via Sommarive 9, 38123, Trento, Italy.

Alberto Ongaro (A)

Department of Molecular and Translational Medicine, Division of Pharmacology, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.

Stefania Sarno (S)

Department of Biomedical Sciences and CNR Institute of Neuroscience, University of Padua, Via U. Bassi 58/B, 35131, Padua, Italy.

Giuseppe Zagotto (G)

Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131, Padua, Italy. Electronic address: giuseppe.zagotto@unipd.it.

Roberto Battistutta (R)

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.

Maria Ruzzene (M)

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.

Graziano Lolli (G)

Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Via Sommarive 9, 38123, Trento, Italy. Electronic address: graziano.lolli@unitn.it.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Casein Kinases › Casein Kinase II › A novel class of selective CK2 inhibitors...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Conception de médicament › A novel class of selective CK2 inhibitors...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A novel class of selective CK2 inhibitors...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › Cellules Jurkat › A novel class of selective CK2 inhibitors...
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de docking moléculaire › A novel class of selective CK2 inhibitors...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › A novel class of selective CK2 inhibitors...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › A novel class of selective CK2 inhibitors...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › Pyrimidinones › A novel class of selective CK2 inhibitors...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › A novel class of selective CK2 inhibitors...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Thiazoles › Thiadiazoles › A novel class of selective CK2 inhibitors...