Heat shock protein 90 (Hsp90) and B-Raf are validated targets for anticancer drug discovery. Although there is strong evidence that concomitant inhibition of Hsp90 and B-Raf may provide significant therapeutic benefits, molecules endowed with dual activity against the two targets have not been reported. For the first time, we show that Hsp90 and B-Raf inhibitors have overlapping chemical space and we disclose the first-in-class dual inhibitors. The compounds were identified through a computational strategy especially devised for detecting ligands with dual-target activity. Although the two targets had only remote binding site similarity, we were able to identify dual inhibitors with well-balanced in vitro potencies and relatively low molecular weight. Remarkably, they also inhibited the V600E mutant form of B-Raf with similar potency. This study provides the first direct proof that designing dual ligands of Hsp90 and a kinase is possible, thus opening the way to new interesting possibilities in drug discovery.

Heat shock protein 90 and serine/threonine kinase B-Raf inhibitors have overlapping chemical space / Anighoro, A.; Pinzi, Luca; Marverti, Gaetano; Bajorath, J; Rastelli, Giulio. - In: RSC ADVANCES. - ISSN 2046-2069. - 7:49(2017), pp. 31069-31074. [10.1039/c7ra05889f]

Heat shock protein 90 and serine/threonine kinase B-Raf inhibitors have overlapping chemical space

PINZI, LUCA;MARVERTI, Gaetano;RASTELLI, Giulio
2017

Abstract

Heat shock protein 90 (Hsp90) and B-Raf are validated targets for anticancer drug discovery. Although there is strong evidence that concomitant inhibition of Hsp90 and B-Raf may provide significant therapeutic benefits, molecules endowed with dual activity against the two targets have not been reported. For the first time, we show that Hsp90 and B-Raf inhibitors have overlapping chemical space and we disclose the first-in-class dual inhibitors. The compounds were identified through a computational strategy especially devised for detecting ligands with dual-target activity. Although the two targets had only remote binding site similarity, we were able to identify dual inhibitors with well-balanced in vitro potencies and relatively low molecular weight. Remarkably, they also inhibited the V600E mutant form of B-Raf with similar potency. This study provides the first direct proof that designing dual ligands of Hsp90 and a kinase is possible, thus opening the way to new interesting possibilities in drug discovery.
7
49
31069
31074
Heat shock protein 90 and serine/threonine kinase B-Raf inhibitors have overlapping chemical space / Anighoro, A.; Pinzi, Luca; Marverti, Gaetano; Bajorath, J; Rastelli, Giulio. - In: RSC ADVANCES. - ISSN 2046-2069. - 7:49(2017), pp. 31069-31074. [10.1039/c7ra05889f]
Anighoro, A.; Pinzi, Luca; Marverti, Gaetano; Bajorath, J; Rastelli, Giulio
File in questo prodotto:
File Dimensione Formato  
Hsp90 Braf overlappping chemical space RSC Adv 2017.pdf

accesso aperto

Tipologia: Versione dell'editore (versione pubblicata)
Dimensione 1.16 MB
Formato Adobe PDF
1.16 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1143391
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 11
  • ???jsp.display-item.citation.isi??? 8
social impact