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. © 2020 Elsevier Masson SAS. All rights reserved

A novel class of selective CK2 inhibitors targeting its open hinge conformation / Dalle Vedove, A.; Zonta, F.; Zanforlin, E.; Demitri, N.; Ribaudo, G.; Cazzanelli, G.; Ongaro, A.; Sarno, S.; Zagotto, G.; Battistutta, R.; Ruzzene, M.; Lolli, G.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 195:(2020), pp. 112267.1-112267.9. [10.1016/j.ejmech.2020.112267]

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

Dalle Vedove A.;Zonta F.;Cazzanelli G.;Lolli G.
2020-01-01

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. © 2020 Elsevier Masson SAS. All rights reserved
2020
Dalle Vedove, A.; Zonta, F.; Zanforlin, E.; Demitri, N.; Ribaudo, G.; Cazzanelli, G.; Ongaro, A.; Sarno, S.; Zagotto, G.; Battistutta, R.; Ruzzene, M....espandi
A novel class of selective CK2 inhibitors targeting its open hinge conformation / Dalle Vedove, A.; Zonta, F.; Zanforlin, E.; Demitri, N.; Ribaudo, G.; Cazzanelli, G.; Ongaro, A.; Sarno, S.; Zagotto, G.; Battistutta, R.; Ruzzene, M.; Lolli, G.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 195:(2020), pp. 112267.1-112267.9. [10.1016/j.ejmech.2020.112267]
File in questo prodotto:
File Dimensione Formato  
srpin_Mar19_final_preprint.pdf

accesso aperto

Tipologia: Pre-print non referato (Non-refereed preprint)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 2.43 MB
Formato Adobe PDF
2.43 MB Adobe PDF Visualizza/Apri
1-s2.0-S0223523420302348-main.pdf

Solo gestori archivio

Tipologia: Versione editoriale (Publisher’s layout)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 1.58 MB
Formato Adobe PDF
1.58 MB Adobe PDF   Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/275324
Citazioni
  • ???jsp.display-item.citation.pmc??? 9
  • Scopus 17
  • ???jsp.display-item.citation.isi??? 15
  • OpenAlex ND
social impact