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
  • 1. Oncology, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI), Italy. Electronic address: [email protected].
  • 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: [email protected].
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.