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Chemistry. 2017 Apr 19;23(22):5188-5192. doi: 10.1002/chem.201700169. Epub 2017 Mar 22.

Design of Allosteric Stimulators of the Hsp90 ATPase as New Anticancer Leads.

Author information

1
Istituto di Chimica del Riconoscimento Molecolare, CNR, via Mario Bianco, 9, 20131, Milan, Italy.
2
Dipartimento di Chimica, Università degli Studi di Milano, via Golgi, 19, 20133, Milan, Italy.
3
Howard Hughes Medical Institute and Dept. of Biochemistry & Biophysics, University of California, 600 16thStreet, San Francisco, CA, 94158, USA.
4
Dept. Experimental Oncology & Molecular Medicine, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo, 42, 20133, Milano, Italy.
5
Dipartimento di Scienze Biomediche-DSB, Università di Padova, Via Ugo Bassi 58/B, 35131, Padova, Italy.
6
IRCCS Multimedica, via Fantoli 16/15, 20138, Milano, Italy.

Abstract

Allosteric compounds that stimulate Hsp90 adenosine triphosphatase (ATPase) activity were rationally designed, showing anticancer potencies in the low micromolar to nanomolar range. In parallel, the mode of action of these compounds was clarified and a quantitative model that links the dynamic ligand-protein cross-talk to observed cellular and in vitro activities was developed. The results support the potential of using dynamics-based approaches to develop original mechanism-based cancer therapeutics.

KEYWORDS:

allostery; drug design; hsp90; modulators; molecular dynamics

PMID:
28207175
PMCID:
PMC5927549
DOI:
10.1002/chem.201700169
[Indexed for MEDLINE]
Free PMC Article

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