title: Design of Allosteric Stimulators of the Hsp90 ATPase as New Anticancer Leads.
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.
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, CNR, via Mario Bianco, 9, 20131, Milan, Italy.
authors.forename: Ilda
authors.initials: I
authors.lastname: D'Annessa
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano, via Golgi, 19, 20133, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Sattin
authors.affiliation: Howard Hughes Medical Institute and Dept. of Biochemistry & Biophysics, University of California, 600 16thStreet, San Francisco, CA, 94158, USA.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Tao
authors.affiliation: Dept. Experimental Oncology & Molecular Medicine, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo, 42, 20133, Milano, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Pennati
authors.affiliation: Dipartimento di Scienze Biomediche-DSB, Università di Padova, Via Ugo Bassi 58/B, 35131, Padova, Italy.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sànchez-Martìn
authors.affiliation: IRCCS Multimedica, via Fantoli 16/15, 20138, Milano, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Moroni
authors.affiliation: Dipartimento di Scienze Biomediche-DSB, Università di Padova, Via Ugo Bassi 58/B, 35131, Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rasola
authors.affiliation: Dept. Experimental Oncology & Molecular Medicine, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo, 42, 20133, Milano, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: Howard Hughes Medical Institute and Dept. of Biochemistry & Biophysics, University of California, 600 16thStreet, San Francisco, CA, 94158, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Agard
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano, via Golgi, 19, 20133, Milan, Italy.
authors.forename: Anna
authors.identifier: http://orcid.org/0000-0002-1258-2007
authors.initials: A
authors.lastname: Bernardi
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, CNR, via Mario Bianco, 9, 20131, Milan, Italy.
authors.forename: Giorgio
authors.identifier: http://orcid.org/0000-0002-1318-668X
authors.initials: G
authors.lastname: Colombo
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism*; D000494:Allosteric Regulation; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D011485:Protein Binding
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D000251:Adenosine Triphosphatases
keywords: allostery; drug design; hsp90; modulators; molecular dynamics