Rational Design of Allosteric and Selective Inhibitors of the Molecular Chaperone TRAP1

Sánchez-Martín, Carlos; Moroni, Elisabetta; Ferraro, Mariarosaria; Laquatra, Claudio; Cannino, Giuseppe; Masgras, Ionica; Negro, Alessandro; Quadrelli, Paolo; Rasola, Andrea; Colombo, Giorgio

doi:10.1016/j.celrep.2020.107531

Cited by 71 publications

(93 citation statements)

References 59 publications

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“…The chaperone activity of TRAP1 is enhanced by its ERK-mediated phosphorylation (Masgras et al, 2017a), and dysregulated activation of Ras/ERK signalling is mandatory for the malignant growth of a variety of cancer types, including highly aggressive pancreatic adenocarcinoma and malignant peripheral nerve sheath tumors, where we show that TRAP1 has a dramatic inhibitory effect on SDH activity (this study and (Sanchez-Martin et al, 2020b). Hence, the possibility of targeting TRAP1 with great precision unlocks the doorway to the development of therapeutic approaches in neoplastic conditions where the metabolic rewiring that it orchestrates is critical for malignant cell viability.…”

Section: Discussionsupporting

confidence: 63%

“…Here we find that TRAP1 is highly expressed at the beginning of fish embryogenesis, when it exerts an important bioenergetic role. As previously reported in tumor models (Guzzo et al, 2014, Kowalik et al, 2016, Masgras et al, 2017a, Sanchez-Martin et al, 2020a, Sanchez-Martin et al, 2020b, Sciacovelli et al, 2013, TRAP1 inhibits SDH activity during early Zebrafish development, crucially contributing to a bioenergetic phenotype characterized by low levels of OXPHOS. Absence of TRAP1 causes a delay in early development; this defect is gradually lost during the passage from embryo to larva stages, when oxygen tension increases and TRAP1 levels progressively decline.…”

Section: Discussionmentioning

confidence: 53%

“…protein levels recorded in the same period ( Figure 1H). Treatment with the highly specific TRAP1 allosteric inhibitor compound 5 (Sanchez-Martin et al, 2020b) increased SDH activity at each developmental stage ( Figure 1I), strongly connecting TRAP1 activity with SDH inhibition.…”

Section: Trap1 Regulates Mitochondrial Bioenergetics During Zebrafishmentioning

confidence: 88%

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HIF1α-dependent induction of the mitochondrial chaperone TRAP1 regulates bioenergetic adaptations to hypoxia

Rasola

Laquatra

Sánchez-Martín

et al. 2020

Preprint

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The mitochondrial paralog of the Hsp90 chaperone family TRAP1 is often induced in tumors, but the mechanisms controlling its expression, as well as its physiological functions remain poorly understood. Here, we find that TRAP1 is highly expressed in the early stages of Zebrafish development, and its ablation delays embryogenesis while increasing mitochondrial respiration of fish larvae. TRAP1 expression is enhanced by hypoxic conditions both in developing embryos and in cancer models of Zebrafish and mammals. The TRAP1 promoter contains evolutionary conserved hypoxic responsive elements, and HIF1α stabilization increases TRAP1 levels. TRAP1 inhibition by selective compounds or by genetic knock-out maintains a high level of respiration in Zebrafish embryos after exposure to hypoxia.Our data identify TRAP1 as a primary regulator of mitochondrial bioenergetics in highly proliferating cells following reductions in oxygen tension and HIF1α stabilization.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 53%

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HIF1α-dependent induction of the mitochondrial chaperone TRAP1 regulates bioenergetic adaptations to hypoxia

Rasola

Laquatra

Sánchez-Martín

et al. 2020

Preprint

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“…7A). TRAP1 is the mitochondrial paralog of the heat shock protein 90 (HSP90) family and is widely recognized as a potential anti-cancer drug target across multiple human malignancies, including leukemia [43][44][45][46][47][48][49] . Given that ATPase activity is required for TRAP1 function 50 , we hypothesized that ETS inhibition in leukemic mitochondria exposed to ΔG ATP may be driven by acute activation of TRAP1.…”

Section: Resultsmentioning

confidence: 99%

Intrinsic oxidative phosphorylation limitations underlie cellular bioenergetics in leukemia.

Nelson

McLaughlin

Hagen

et al. 2020

Preprint

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Currently there is great interest in developing cytotoxic pharmacotherapies that disrupt mitochondrial energy transduction in cancer. Given that mitochondria are critical to mammalian energy homeostasis, clinical success of a given therapeutic will undoubtedly hinge upon its cancer cell selectivity. That said, how the mitochondrial network is intrinsically remodeled to drive/enable the cancer phenotype remains a biological black box, largely due to limitations in analytical approaches. Herein, we leveraged an in-house diagnostic biochemical workflow to comprehensively evaluate mitochondrial bioenergetic efficiency and capacity in human leukemia. Using this platform, we provide direct evidence that despite minimal changes in absolute respiratory kinetics, leukemic mitochondria are hallmarked by intrinsic limitations in oxidative phosphorylation (OXPHOS) that constrain the network’s ability to contribute to cellular ATP free energy (i.e, ΔGATP) charge. Together, these findings link accelerated oxidative metabolism in leukemia to intrinsic OXPHOS deficiency and provide proof-of-concept that restoring, rather than disrupting, OXPHOS across the leukemic mitochondrial network may represent an untapped, but highly feasible, therapeutic avenue.

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“…We have recently used a molecular dynamics-based strategy to identify an allosteric pocket distal to the ATPase site of TRAP1, which allowed the rational design and testing of small molecule compounds that target it (157). We have also found that the same allosteric domain can host the bis-dichloroacetate ester of the vegetal derivative honokiol DCA (HDCA) (158).…”

Section: Allosteric Inhibitorsmentioning

confidence: 99%

Dynamically Shaping Chaperones. Allosteric Modulators of HSP90 Family as Regulatory Tools of Cell Metabolism in Neoplastic Progression

et al. 2020

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Molecular chaperones have recently emerged as fundamental regulators of salient biological routines, including metabolic adaptations to environmental changes. Yet, many of the molecular mechanisms at the basis of their functions are still unknown or at least uncertain. This is in part due to the lack of chemical tools that can interact with the chaperones to induce measurable functional perturbations. In this context, the use of small molecules as modulators of protein functions has proven relevant for the investigation of a number of biomolecular systems. Herein, we focus on the functions, interactions and signaling pathways of the HSP90 family of molecular chaperones as possible targets for the discovery of new molecular entities aimed at tuning their activity and interactions. HSP90 and its mitochondrial paralog, TRAP1, regulate the activity of crucial metabolic circuitries, making cells capable of efficiently using available energy sources, with relevant implications both in healthy conditions and in a variety of disease states and especially cancer. The design of small-molecules targeting the chaperone cycle of HSP90 and able to inhibit or stimulate the activity of the protein can provide opportunities to finely dissect their biochemical activities and to obtain lead compounds to develop novel, mechanism-based drugs.

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Rational Design of Allosteric and Selective Inhibitors of the Molecular Chaperone TRAP1

Cited by 71 publications

References 59 publications

HIF1α-dependent induction of the mitochondrial chaperone TRAP1 regulates bioenergetic adaptations to hypoxia

HIF1α-dependent induction of the mitochondrial chaperone TRAP1 regulates bioenergetic adaptations to hypoxia

Intrinsic oxidative phosphorylation limitations underlie cellular bioenergetics in leukemia.

Dynamically Shaping Chaperones. Allosteric Modulators of HSP90 Family as Regulatory Tools of Cell Metabolism in Neoplastic Progression

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