Activation of Hsp90 Enzymatic Activity and Conformational Dynamics through Rationally Designed Allosteric Ligands

Sattin, Sara; Tao, Jiahui; Vettoretti, Gerolamo; Moroni, Elisabetta; Pennati, Marzia; Lopergolo, Alessia; Morelli, Laura; Bugatti, Antonella; Zuehlke, Abbey D.; Moses, Mike; Prince, Thomas; Kijima, Toshiki; Beebe, Kristin; Rusnati, Marco; Neckers, Len; Zaffaroni, Nadia; Agard, David A.; Bernardi, Anna; Colombo, Giorgio

doi:10.1002/chem.201502211

Cited by 66 publications

(114 citation statements)

References 60 publications

(89 reference statements)

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“…In the context of allosteric perturbation of PPIs, we characterized the effects of allosteric Hsp90 activators on its interactions in vitro, and on the stability of a number of its clients in cellular models: consistent with observations from other groups, administration of these accelerators induced a marked decrease in levels and viability of stringent client proteins of Hsp90 (for whose production Hsp90 is essential). This supports the concept that acceleration of conformational dynamics may in fact represent a new way of perturbing the chaperoning mechanisms that underlie cell viability: indeed, some of our allosteric compounds inhibit the proliferative potential of tumor cells, including those resistant to Hsp90 ATP‐competitive inhibitors …”

Section: Modulating Biological Functions By Targeting Protein–proteinmentioning

confidence: 95%

Designing Molecular Spanners to Throw in the Protein Networks

Serapian

Colombo

2020

Chemistry A European J

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Proteins govern most aspects of cellular life and, through specific interfaces, are typically involved in intricate protein–protein interaction (PPI) networks and signaling pathways. Subtle up‐ or downregulation of key protein functions and PPIs results in disease; still, the preferred option to contrast the role of a protein in disease and healthy conditions alike remains its outright shutdown through orthosteric ligands that block its active site. Here, we explore subtler alternatives to modulate proteins and PPIs. Driven by a view of proteins as dynamic entities, we discuss ways to identify allosteric binding sites, which, when targeted by tailored ligands, can induce significant changes in the active site of a protein, and lead to agonistic or antagonistic effects. We also summarize the selective regulation of specific PPIs—either direct or allosteric—and show that effects can be stabilizing as well as destabilizing, depending on how the conformational equilibrium of a protein is shifted.

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Section: Modulating Biological Functions By Targeting Protein–proteinmentioning

confidence: 95%

Designing Molecular Spanners to Throw in the Protein Networks

Serapian

Colombo

2020

Chemistry A European J

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“…Such approach has already proven effective in the design of allosteric anticancer leads against HSP90 (102, 107). Allosteric sites are located in the M-domain and in the CTD of TRAP1 (Figure 4) and their stereoelectronic properties can be used to design a new class of small molecule inhibitors.…”

Section: Targeting Trap1 As a Strategy For Cancer Treatmentmentioning

confidence: 99%

The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells

et al. 2017

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Mitochondria can receive, integrate, and transmit a variety of signals to shape many biochemical activities of the cell. In the process of tumor onset and growth, mitochondria contribute to the capability of cells of escaping death insults, handling changes in ROS levels, rewiring metabolism, and reprograming gene expression. Therefore, mitochondria can tune the bioenergetic and anabolic needs of neoplastic cells in a rapid and flexible way, and these adaptations are required for cell survival and proliferation in the fluctuating environment of a rapidly growing tumor mass. The molecular bases of pro-neoplastic mitochondrial adaptations are complex and only partially understood. Recently, the mitochondrial molecular chaperone TRAP1 (tumor necrosis factor receptor associated protein 1) was identified as a key regulator of mitochondrial bioenergetics in tumor cells, with a profound impact on neoplastic growth. In this review, we analyze these findings and discuss the possibility that targeting TRAP1 constitutes a new antitumor approach.

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“…Such analysis unveiled an allosteric pocket at 65 Å from the active site, located at the MD:CTD (MD=middle domain; CTD=C‐terminal domain) border in a region that is in close proximity to the client binding site . This method facilitated the design of modulators showing promising anticancer activities and a novel molecular mechanism of perturbation of Hsp90 functions: the ligands, in fact, were synthesized and experimentally proved to be activators of closure kinetics and ATPase activity of the chaperone in vitro, to induce cancer cell death, and to interfere with client maturation . We developed a first quantitative structure–dynamics–activity–relationship (QSDAR) model correlating the structures of an initial set of modulators to observed activation effects …”

Section: Structures Stimulatory Potencies and Cytotoxic Activities mentioning

confidence: 99%

“…This model led to redesigning 1 into 18 and 19 (Table ), in which the sugar moiety was replaced by an N , N ‐dimethyil‐ethylamino or a propylamino group. Substitution of the propenyl group by a Cl atom was initially explored for synthetic convenience and proved to be beneficial for the compound's solubility and activity, therefore, it was maintained for 18 and 19 . Such modification resulted in an improved anticancer cytotoxicity of the ligands.…”

Section: Structures Stimulatory Potencies and Cytotoxic Activities mentioning

confidence: 99%

“…Such modification resulted in an improved anticancer cytotoxicity of the ligands. A new round of MD simulations and allosteric coordination analysis supported the importance of interactions with E477 and D503 . Here, to establish structure–dynamics–activity relationships, in the absence of crystal structures difficult to obtain due to the flexibility of the system, we directed design efforts towards obtaining different amine substitutions on the phenyl‐benzofuran scaffold.…”

Section: Structures Stimulatory Potencies and Cytotoxic Activities mentioning

confidence: 99%

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

D’Annessa

Sattin

Tao

et al. 2017

Chemistry A European J

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We rationally designed allosteric compounds that stimulate Hsp90 ATPase activity and show anticancer potencies in the low micromolar to nanomolar range. In parallel, we clarified their mode of action and developed a quantitative model that links the dynamic ligand-protein cross-talk to observed cellular and in vitro activities. Our results support the potential of using dynamicsbased approaches to develop original mechanism-based cancer therapeutics.Heat Shock Protein 90 (Hsp90) is a chaperone that controls the folding of more than 200 client proteins and constitutes a central node in many signaling pathways [1] . Overexpression and dysregulation of Hsp90 have been linked with cancer and neurodegeneration. It is thus not surprising that this chaperone has become an important drug-target: in principle its inhibition can result in the simultaneous degradation of multiple clients associated with different pathological hallmarks [2] . Inhibitors targeting the N-terminal ATP-binding site have been developed and some reached clinical trials [3] . However, they all showed problems due to the induction of the HSF1 mediated heat shock response and of Hsp70 overexpression, leading to drug resistance and toxicity [3a-c, 4] .A viable alternative to interfering with Hsp90 is represented by allosteric ligands, which perturb the chaperone by targeting sites alternative to the ATP-site. Novobiocin was shown to inhibit Hsp90 by binding the C-terminal region without inducing the heat shock response. Based on this observation, a number of new derivatives with promising activities against a variety of cancers were developed [5] .Correspondence to: Giorgio Colombo. HHMI Author Manuscript HHMI Author Manuscript HHMI Author ManuscriptIn this context, we have developed a method for the identification of allosteric pockets via the analysis of residue-pair distance fluctuations in the structural ensemble around the active state of the chaperone. Such analysis unveiled an allosteric pocket at 65Å from the active site, located at the MD:CTD border in a region overlapping with the client binding site [6] . This facilitated the design of modulators showing promising anticancer activities and a novel molecular mechanism of perturbation of Hsp90 functions: the ligands in fact proved to be activators of closure kinetics and ATPase of the chaperone in vitro, induce cancer cell death, and interfere with client maturation. We developed a first Quantitative-Structure-DynamicsActivity-Relationship (QSDAR) model correlating the structures of an initial set of modulators to observed activation effects [6c] .Here, based on this initial model, we report the rational design of new allosteric ligands, reaching low micromolar to nanomolar anticancer activities, which supports their potential in the development of anticancer therapeutics. On the computational side, we further develop a model to evaluate the potency of allosteric modulators by taking into account the dynamic cross-talk that exists between the protein and the ligand.The conform...

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Activation of Hsp90 Enzymatic Activity and Conformational Dynamics through Rationally Designed Allosteric Ligands

Cited by 66 publications

References 60 publications

Designing Molecular Spanners to Throw in the Protein Networks

Designing Molecular Spanners to Throw in the Protein Networks

The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells

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

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