Discovery of NMS-E973 as novel, selective and potent inhibitor of heat shock protein 90 (Hsp90)

Maria Gabriella Brasca (Lead / Corresponding author), Sergio Mantegani, Nadia Amboldi, Simona Bindi, Dannica Caronni, Elena Casale, Walter Ceccarelli, Nicoletta Colombo, Anna De Ponti, Daniele Donati, Antonella Ermoli, Gabriele Fachin, Eduard R. Felder, Ronald D. Ferguson, Claudio Fiorelli, Marco Guanci, Antonella Isacchi, Enrico Pesenti, Paolo Polucci, Laura RiceputiFrancesco Sola, Carlo Visco, Fabio Zuccotto, Gianpaolo Fogliatto

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Novel small molecule inhibitors of heat shock protein 90 (Hsp90) were discovered with the help of a fragment based drug discovery approach (FBDD) and subsequent optimization with a combination of structure guided design, parallel synthesis and application of medicinal chemistry principles. These efforts led to the identification of compound 18 (NMS-E973), which displayed significant efficacy in a human ovarian A2780 xenograft tumor model, with a mechanism of action confirmed in vivo by typical modulation of known Hsp90 client proteins, and with a favorable pharmacokinetic and safety profile.

Original languageEnglish
Pages (from-to)7047-7063
Number of pages17
JournalBioorganic & Medicinal Chemistry
Volume21
Issue number22
Early online date19 Sep 2013
DOIs
Publication statusPublished - 15 Nov 2013

Keywords

  • Anti-cancer agents
  • Fragment based drug discovery
  • Tumor cell proliferation inhibition

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    • 17 Citations
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    Corrigendum to “Discovery of NMS-E973 as novel, selective and potent inhibitor of heat shock protein 90 (Hsp90)” [Bioorg. Med. Chem. 21 (2013) 7047–7063]

    Brasca, M. G., Mantegani, S., Amboldi, N., Bindi, S., Caronni, D., Casale, E., Ceccarelli, W., Colombo, N., De Ponti, A., Donati, D., Ermoli, A., Fachin, G., Felder, E. R., Ferguson, R. D., Fiorelli, C., Guanci, M., Isacchi, A., Pesenti, E., Polucci, P., Riceputi, L. & 4 others, Sola, F., Visco, C., Zuccotto, F. & Fogliatto, G., 1 Jan 2014, In : Bioorganic & Medicinal Chemistry. 22, 1, p. 662 1 p.

    Research output: Contribution to journalArticle

    Cite this

    Brasca, M. G., Mantegani, S., Amboldi, N., Bindi, S., Caronni, D., Casale, E., Ceccarelli, W., Colombo, N., De Ponti, A., Donati, D., Ermoli, A., Fachin, G., Felder, E. R., Ferguson, R. D., Fiorelli, C., Guanci, M., Isacchi, A., Pesenti, E., Polucci, P., ... Fogliatto, G. (2013). Discovery of NMS-E973 as novel, selective and potent inhibitor of heat shock protein 90 (Hsp90). Bioorganic & Medicinal Chemistry, 21(22), 7047-7063. https://doi.org/10.1016/j.bmc.2013.09.018