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

Elena Casale (Lead / Corresponding author), Nadia Amboldi, Maria Gabriella Brasca, Dannica Caronni, Nicoletta Colombo, Claudio Dalvit, Eduard R. Felder, Gianpaolo Fogliatto, Arturo Galvani, Antonella Isacchi, Paolo Polucci, Laura Riceputi, Francesco Sola, C. Visco, Fabio Zuccotto, Francesco Casuscelli (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    21 Citations (Scopus)

    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.
    Original languageEnglish
    Pages (from-to)4135-4150
    Number of pages16
    JournalBioorganic & Medicinal Chemistry
    Volume22
    Issue number15
    Early online date14 Jun 2014
    DOIs
    Publication statusPublished - 1 Aug 2014

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