Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors

Elena Casale; Nadia Amboldi; Maria Gabriella Brasca; Dannica Caronni; Nicoletta Colombo; Claudio Dalvit; Eduard R. Felder; Gianpaolo Fogliatto; Arturo Galvani; Antonella Isacchi; Paolo Polucci; Laura Riceputi; Francesco Sola; C. Visco; Fabio Zuccotto; Francesco Casuscelli

doi:10.1016/j.bmc.2014.05.056

Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors

Elena Casale (Lead / Corresponding author), Nadia Amboldi, Maria Gabriella Brasca, Dannica Caronni, Nicoletta Colombo, Claudio Dalvit, Eduard R. Felder, Gianpaolo Fogliatto, Arturo Galvani, Antonella Isacchi, Paolo Polucci, Laura Riceputi, Francesco Sola, C. Visco, Fabio Zuccotto, Francesco Casuscelli (Lead / Corresponding author)

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

35 Citations (Scopus)

Abstract

In the last decade the heat shock protein 90 (Hsp90) has emerged as a major therapeutic target and many efforts have been dedicated to the discovery of Hsp90 inhibitors as new potent anticancer agents. Here we report the identification of a novel class of Hsp90 inhibitors by means of a biophysical FAXS-NMR based screening of a library of fragments. The use of X-ray structure information combined with modeling studies enabled the fragment evolution of the initial triazoloquinazoline hit to a class of compounds with nanomolar potency and drug-like properties suited for further lead optimization.

Original language	English
Pages (from-to)	4135-4150
Number of pages	16
Journal	Bioorganic & Medicinal Chemistry
Volume	22
Issue number	15
Early online date	14 Jun 2014
DOIs	https://doi.org/10.1016/j.bmc.2014.05.056
Publication status	Published - 1 Aug 2014

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Casale, E., Amboldi, N., Brasca, M. G., Caronni, D., Colombo, N., Dalvit, C., Felder, E. R., Fogliatto, G., Galvani, A., Isacchi, A., Polucci, P., Riceputi, L., Sola, F., Visco, C., Zuccotto, F., & Casuscelli, F. (2014). Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors. Bioorganic & Medicinal Chemistry, 22(15), 4135-4150. https://doi.org/10.1016/j.bmc.2014.05.056

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title = "Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors",

abstract = "In the last decade the heat shock protein 90 (Hsp90) has emerged as a major therapeutic target and many efforts have been dedicated to the discovery of Hsp90 inhibitors as new potent anticancer agents. Here we report the identification of a novel class of Hsp90 inhibitors by means of a biophysical FAXS-NMR based screening of a library of fragments. The use of X-ray structure information combined with modeling studies enabled the fragment evolution of the initial triazoloquinazoline hit to a class of compounds with nanomolar potency and drug-like properties suited for further lead optimization.",

author = "Elena Casale and Nadia Amboldi and Brasca, {Maria Gabriella} and Dannica Caronni and Nicoletta Colombo and Claudio Dalvit and Felder, {Eduard R.} and Gianpaolo Fogliatto and Arturo Galvani and Antonella Isacchi and Paolo Polucci and Laura Riceputi and Francesco Sola and C. Visco and Fabio Zuccotto and Francesco Casuscelli",

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doi = "10.1016/j.bmc.2014.05.056",

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Casale, E, Amboldi, N, Brasca, MG, Caronni, D, Colombo, N, Dalvit, C, Felder, ER, Fogliatto, G, Galvani, A, Isacchi, A, Polucci, P, Riceputi, L, Sola, F, Visco, C, Zuccotto, F & Casuscelli, F 2014, 'Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors', Bioorganic & Medicinal Chemistry, vol. 22, no. 15, pp. 4135-4150. https://doi.org/10.1016/j.bmc.2014.05.056

TY - JOUR

T1 - Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors

AU - Casale, Elena

AU - Amboldi, Nadia

AU - Brasca, Maria Gabriella

AU - Caronni, Dannica

AU - Colombo, Nicoletta

AU - Dalvit, Claudio

AU - Felder, Eduard R.

AU - Fogliatto, Gianpaolo

AU - Galvani, Arturo

AU - Isacchi, Antonella

AU - Polucci, Paolo

AU - Riceputi, Laura

AU - Sola, Francesco

AU - Visco, C.

AU - Zuccotto, Fabio

AU - Casuscelli, Francesco

PY - 2014/8/1

Y1 - 2014/8/1

N2 - In the last decade the heat shock protein 90 (Hsp90) has emerged as a major therapeutic target and many efforts have been dedicated to the discovery of Hsp90 inhibitors as new potent anticancer agents. Here we report the identification of a novel class of Hsp90 inhibitors by means of a biophysical FAXS-NMR based screening of a library of fragments. The use of X-ray structure information combined with modeling studies enabled the fragment evolution of the initial triazoloquinazoline hit to a class of compounds with nanomolar potency and drug-like properties suited for further lead optimization.

AB - In the last decade the heat shock protein 90 (Hsp90) has emerged as a major therapeutic target and many efforts have been dedicated to the discovery of Hsp90 inhibitors as new potent anticancer agents. Here we report the identification of a novel class of Hsp90 inhibitors by means of a biophysical FAXS-NMR based screening of a library of fragments. The use of X-ray structure information combined with modeling studies enabled the fragment evolution of the initial triazoloquinazoline hit to a class of compounds with nanomolar potency and drug-like properties suited for further lead optimization.

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U2 - 10.1016/j.bmc.2014.05.056

DO - 10.1016/j.bmc.2014.05.056

M3 - Article

C2 - 24980703

AN - SCOPUS:84905111606

SN - 0968-0896

VL - 22

SP - 4135

EP - 4150

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 15

ER -

Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors

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