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 Riceputi

Francesco Sola, Carlo Visco, Fabio Zuccotto, Gianpaolo Fogliatto

Drug Discovery Unit

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

35 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

UN SDGs

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

SDG 3 Good Health and Well-being

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

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

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",

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

language = "English",

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journal = "Bioorganic \& Medicinal Chemistry",

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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

TY - JOUR

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

N2 - 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.

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

UR - https://www.scopus.com/pages/publications/84885857466

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EP - 7063

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 22

ER -

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

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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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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