Epigenetic-based therapy: From single- to multi-target approaches

Benedetti, Rosaria; Conte, Mariarosaria; Iside, Concetta; Altucci, Lucia

doi:10.1016/j.biocel.2015.10.016

Cited by 44 publications

(31 citation statements)

References 120 publications

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“…First, such therapeutic interventions delivered at an early developmentally-appropriate time period may be very effective for simultaneous prevention of multiple aging-related diseases in adults and even across generations (as discussed above). In addition, one important trend for drug discovery is the ongoing shift from single-target-oriented molecules to network- or biological system-active compounds and to “epi-drugs” [67–69]. Epigenetic targets typically regulate a large number of genes through epigenetic modifications [70], and individual inhibitors or activators may achieve network-active purpose on their own.…”

Section: Discussionmentioning

confidence: 99%

Transgenerational programming of longevity through E(z)-mediated histone H3K27 trimethylation in Drosophila

Xia

Gerstin²,

Schones

et al. 2016

Aging

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Transgenerational effects on health and development of early-life nutrition have gained increased attention recently. However, the underlying mechanisms of transgenerational transmission are only starting to emerge, with epigenetics as perhaps the most important mechanism. We recently reported the first animal model to study transgenerational programming of longevity after early-life dietary manipulations, enabling investigations to identify underlying epigenetic mechanisms. We report here that post-eclosion dietary manipulation (PDM) with a low-protein (LP) diet upregulates the protein level of E(z), an H3K27 specific methyltransferase, leading to higher levels of H3K27 trimethylation (H3K27me3). This PDM-mediated change in H3K27me3 corresponded with a shortened longevity of F0 flies as well as their F2 offspring. Specific RNAi-mediated post-eclosion knockdown of E(z) or pharmacological inhibition of its enzymatic function with EPZ-6438 in the F0 parents improved longevity while rendering H3K27me3 low across generations. Importantly, addition of EPZ-6438 to the LP diet fully alleviated the longevity-reducing effect of the LP PDM, supporting the increased level of E(z)-dependent H3K27me3 as the primary cause and immediate early-life period as the critical time to program longevity through epigenetic regulation. These observations establish E(z)-mediated H3K27me3 as one epigenetic mechanism underlying nutritional programming of longevity and support the use of EPZ-6438 to extend lifespan.

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Section: Discussionmentioning

confidence: 99%

Transgenerational programming of longevity through E(z)-mediated histone H3K27 trimethylation in Drosophila

Xia

Gerstin²,

Schones

et al. 2016

Aging

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“…In case of failure of the so‐called “magic bullets,” three different and alternative strategies may be followed: the multiple‐medication therapy (MMT, drug combination), the multicompound medication (MCM, which consists in the association of multiple active principles in the same pharmaceutical formulation) or the new, promising multitarget‐directed ligands (MTDLs, using single multitargeting compounds) . The polypharmacology approach was born with the aim to overcome the limitations of the single‐targeted therapy, such as the potential mechanism(s) of resistance caused by redundancy and robustness of biological pathways . Polypharmacology has the aim to simultaneously hit different targets, all related to the onset and development of a certain disease, although at different levels .…”

Section: Introductionmentioning

confidence: 99%

“…During the last years, several research groups questioned the possibility to identify structural and not structural features emerging from statistically significant correlation studies (such as lipophilicity, positive or negative charges, basic centers, binding site similarity, flexibility, etc) common to these promiscuous molecules, to identify them as early as possible during the drug discovery process, thus reducing the risk of failure . Just to give an example, the clinical application of the antiallergy drug astemizole was terminated because, in addition to the desired antagonism of H1 receptors, it inhibits h ERG heart potassium channels leading to serious arrhythmia events.…”

Section: Introductionmentioning

confidence: 99%

“…This is the reason why multifactorial diseases like cancer may require more complex therapeutic approaches, able to simultaneously interact with various signaling pathways and various cross‐talks existing between epigenetic and not epigenetic players. Thus, effective anticancer therapy should not consider a single pharmacological target, but the biological system as a whole . Some of the most important challenges of the polypharmacology strategy are the identification of the most appropriate targets and of the relative hit compound(s), as well as the optimization of its (their) structure‐activity relationship (SAR).…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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“…Furthermore new therapeutic approaches that are currently being developed to circumvent the effectiveness of the current arsenal of anticancer agents may definitely lead to discover novel drugs having low toxicity and resistance. For example the search for a putative anticancer drug could involve a multiple-target approach to overcome potential mechanism(s) of resistance caused in part by redundancy and robustness of biological pathways and to afford compounds able to modulate multiple aspects of pathologies [24,25]. All these considerations prompt to us to continue the research based on the imidazo[2,1-b]thiazole core as a tool to discover small molecules that could be lead compound for anticancer therapy.…”

Section: Introductionmentioning

confidence: 99%