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Bioorg Med Chem. 2014 Aug 1;22(15):4135-50. doi: 10.1016/j.bmc.2014.05.056. Epub 2014 Jun 14.

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

Author information

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.

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

PMID:
24980703
DOI:
10.1016/j.bmc.2014.05.056
[Indexed for MEDLINE]

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