2. Academic Validation
  3. Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors

Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors

  • Bioorg Med Chem. 2014 Aug 1;22(15):4135-50. doi: 10.1016/j.bmc.2014.05.056.
Elena Casale 1,  Nadia Amboldi 2,  Maria Gabriella Brasca 2,  Dannica Caronni 2,  Nicoletta Colombo 2,  Claudio Dalvit 2,  Eduard R Felder 2,  Gianpaolo Fogliatto 2,  Arturo Galvani 2,  Antonella Isacchi 2,  Paolo Polucci 2,  Laura Riceputi 2,  Francesco Sola 2,  Carlo Visco 2,  Fabio Zuccotto 2,  Francesco Casuscelli 3
Affiliations

Affiliations

  • 1 Oncology, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI), Italy. Electronic address: elena.casale@nervianoms.com.
  • 2 Oncology, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
  • 3 Oncology, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI), Italy. Electronic address: francesco.casuscelli@nervianoms.com.
PMID: 24980703 DOI: 10.1016/j.bmc.2014.05.056
Abstract

In the last decade the heat shock protein 90 (HSP90) has emerged as a major therapeutic target and many efforts have been dedicated to the discovery of HSP90 inhibitors as new potent Anticancer agents. Here we report the identification of a novel class of HSP90 inhibitors by means of a biophysical FAXS-NMR based screening of a library of fragments. The use of X-ray structure information combined with modeling studies enabled the fragment evolution of the initial triazoloquinazoline hit to a class of compounds with nanomolar potency and drug-like properties suited for further lead optimization.

Keywords

Anti-cancer agents; FAXS-NMR screening; Fragment based hit discovery; Hsp90 inhibitors; Structure-based design.

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