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

Maria Gabriella Brasca; 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

doi:10.1016/j.bmc.2013.09.018

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

Drug Discovery Unit

Research output: Contribution to journal › Article › peer-review

28 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 language	English
Pages (from-to)	7047-7063
Number of pages	17
Journal	Bioorganic & Medicinal Chemistry
Volume	21
Issue number	22
Early online date	19 Sept 2013
DOIs	https://doi.org/10.1016/j.bmc.2013.09.018
Publication status	Published - 15 Nov 2013

Keywords

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

ASJC Scopus subject areas

Pharmaceutical Science
Drug Discovery
Organic Chemistry
Molecular Medicine
Molecular Biology
Clinical Biochemistry
Biochemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2013.09.018

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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

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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.",

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doi = "10.1016/j.bmc.2013.09.018",

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Brasca, MG, Mantegani, S, Amboldi, N, Bindi, S, Caronni, D, Casale, E, Ceccarelli, W, Colombo, N, De Ponti, A, Donati, D, Ermoli, A, Fachin, G, Felder, ER, Ferguson, RD, Fiorelli, C, Guanci, M, Isacchi, A, Pesenti, E, Polucci, P, Riceputi, L, Sola, F, Visco, C, Zuccotto, F & Fogliatto, G 2013, 'Discovery of NMS-E973 as novel, selective and potent inhibitor of heat shock protein 90 (Hsp90)', Bioorganic & Medicinal Chemistry, vol. 21, no. 22, pp. 7047-7063. https://doi.org/10.1016/j.bmc.2013.09.018

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T1 - Discovery of NMS-E973 as novel, selective and potent inhibitor of heat shock protein 90 (Hsp90)

AU - Brasca, Maria Gabriella

AU - Mantegani, Sergio

AU - Amboldi, Nadia

AU - Bindi, Simona

AU - Caronni, Dannica

AU - Casale, Elena

AU - Ceccarelli, Walter

AU - Colombo, Nicoletta

AU - De Ponti, Anna

AU - Donati, Daniele

AU - Ermoli, Antonella

AU - Fachin, Gabriele

AU - Felder, Eduard R.

AU - Ferguson, Ronald D.

AU - Fiorelli, Claudio

AU - Guanci, Marco

AU - Isacchi, Antonella

AU - Pesenti, Enrico

AU - Polucci, Paolo

AU - Riceputi, Laura

AU - Sola, Francesco

AU - Visco, Carlo

AU - Zuccotto, Fabio

AU - Fogliatto, Gianpaolo

PY - 2013/11/15

Y1 - 2013/11/15

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AB - 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.

KW - Anti-cancer agents

KW - Fragment based drug discovery

KW - Tumor cell proliferation inhibition

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EP - 7063

JO - Bioorganic & Medicinal Chemistry

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IS - 22

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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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]

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