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

  • Bioorg Med Chem. 2013 Nov 15;21(22):7047-63. doi: 10.1016/j.bmc.2013.09.018.
Maria Gabriella Brasca  1 ,  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 Riceputi ,  Francesco Sola ,  Carlo Visco ,  Fabio Zuccotto ,  Gianpaolo Fogliatto
Affiliations
  • 1. Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano, MI, Italy. Electronic address: [email protected].
PMID: 24100158 DOI: 10.1016/j.bmc.2013.09.018
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.

Keywords
Anti-cancer agents; Fragment based drug discovery; Tumor cell proliferation inhibition.