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

• Published in: Bioorganic & medicinal chemistry 2013-11, Vol.21 (22), p.7047-7063
• Main Authors: Brasca, Maria Gabriella, Mantegani, Sergio, Amboldi, Nadia, Bindi, Simona, Caronni, Dannica, Casale, Elena, Ceccarelli, Walter, Colombo, Nicoletta, De Ponti, Anna, Donati, Daniele, Ermoli, Antonella, Fachin, Gabriele, Felder, Eduard R., Ferguson, Ronald D., Fiorelli, Claudio, Guanci, Marco, Isacchi, Antonella, Pesenti, Enrico, Polucci, Paolo, Riceputi, Laura, Sola, Francesco, Visco, Carlo, Zuccotto, Fabio, Fogliatto, Gianpaolo
• Format: Article
• Language: English
• Subjects: Animals; Anti-cancer agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Binding Sites; Biomarkers, Tumor - metabolism; Catalytic Domain; Cell Line, Tumor; Cell Survival - drug effects; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical; drugs; Female; Fragment based drug discovery; heat shock proteins; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Isoxazoles - chemistry; Isoxazoles - pharmacology; Isoxazoles - therapeutic use; mechanism of action; medicinal properties; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; pharmacokinetics; Protein Binding - drug effects; Structure-Activity Relationship; Transplantation, Heterologous; Tumor cell proliferation inhibition
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.09.018

Fragment based approach and subsequent optimization of the fragment 1 led to the identification of the heat shock protein 90 (Hsp90) inhibitor 18 (NMS-E973), with favourable pharmacokinetic and safety profile and efficacy in human ovarian A2780 xenograft tumor model. 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.