Novel polyamine-based Histone deacetylases-Lysine demethylase 1 dual binding inhibitors

Milelli, Andrea; Marchetti, Chiara; Turrini, Eleonora; Catanzaro, Elena; Mazzone, Roberta; Tomaselli, Daniela; Fimognari, Carmela; Tumiatti, Vincenzo; Minarini, Anna

doi:10.1016/j.bmcl.2018.02.034

Cited by 24 publications

(16 citation statements)

References 26 publications

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“…Notably, due to the functional interplay of LSD1 and HDAC1/2 in the CoREST complex, it has been suggested that combined targeting of HDACs and LSD1 might be superior with respect to cancer-specific cytotoxicity compared to individual inhibition of histone acetylation or methylation [39]. Indeed, synergistic effects of combined LSD1/HDAC inhibition could be demonstrated, and several single drugs inhibiting HDACs as well as LSD1 have been developed [39–42]. One such compound which has been reported to target class I HDACs as well as LSD1 is domatinostat (4SC-202) [43], which is currently investigated in a phase I clinical trial in hematological neoplasms with up to now excellent tolerability and good efficacy [44].…”

Section: Introductionmentioning

confidence: 99%

Elucidating the mechanism of action of domatinostat (4SC-202) in cutaneous T cell lymphoma cells

et al. 2019

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BackgroundTargeting epigenetic modifiers is effective in cutaneous T cell lymphoma (CTCL). However, there is a need for further improvement of this therapeutic approach. Here, we compared the mode of action of romidepsin (FK228), an established class I histone deacetylase inhibitor, and domatinostat (4SC-202), a novel inhibitor of class I HDACs, which has been reported to also target the lysine-specific histone demethylase 1A (LSD1).MethodsWe performed MTS assays and flow cytometric analyses of propidium iodide or annexin V-stained cells to assess drug impact on cellular proliferation, cell cycle distribution, and survival. Histone acetylation and methylation as well as caspase activation was analyzed by immunoblot. Gene expression analysis was performed using NanosString technology. Knockdown and knockout of LSD1 was achieved with shRNA and CRISPR/Cas9, respectively, while the CRISPR/Cas9 synergistic activation mediator system was used to induce expression of endogenous HDACs and LSD1. Furthermore, time-lapse fluorescence microscopy and an in vitro tubulin polymerization assay were applied.ResultsWhile FK228 as well as 4SC-202 potently induced cell death in six different CTCL cell lines, only in the case of 4SC-202 death was preceded by an accumulation of cells in the G2/M phase of the cell cycle. Surprisingly, apoptosis and accumulation of cells with double DNA content occurred already at 4SC-202 concentrations hardly affecting histone acetylation and methylation, and provoking significantly less changes in gene expression compared to biologically equivalent doses of FK228. Indeed, we provide evidence that the 4SC-202-induced G2/M arrest in CTCL cells is independent of de novo transcription. Furthermore, neither enforced expression of HDAC1 nor knockdown or knockout of LSD1 affected the 4SC-202-induced effects. Since time-lapse microscopy revealed that 4SC-202 could affect mitotic spindle formation, we performed an in vitro tubulin polymerization assay revealing that 4SC-202 can directly inhibit microtubule formation.ConclusionsWe demonstrate that 4SC-202, a drug currently tested in clinical trials, effectively inhibits growth of CTCL cells. The anti-cancer cell activity of 4SC-202 is however not limited to LSD1-inhibition, modulation of histone modifications, and consecutive alteration of gene expression. Indeed, the compound is also a potent microtubule-destabilizing agent.Electronic supplementary materialThe online version of this article (10.1186/s13045-019-0719-4) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Elucidating the mechanism of action of domatinostat (4SC-202) in cutaneous T cell lymphoma cells

et al. 2019

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“…Recently, targeting LSD1‐containing complexes by one molecule, such as pan‐KDM inhibitors, and dual LSD1‐HDAC inhibitors has been shown to be effective for targeting cancers and other diseases, because they are expected to show synergistic or additive pharmacological activities. In addition, the strategy of using PDCs ( 21 ) to target cancers overexpressing LSD1 can be applied to other drugs such as cytotoxic drugs and other epigenetic drugs targeting nuclear complexes including LSD1 …”

Section: Discussionmentioning

confidence: 99%

Drug Design Concepts for LSD1‐Selective Inhibitors

Ota

Suzuki

2018

The Chemical Record

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Lysine‐specific demethylase 1 (LSD1) is one of the flavin‐dependent oxidases and is involved in many cellular processes by controlling the methylation of histone H3. Recently, it has been reported that LSD1 is associated with several diseases such as cancer, metabolic disorders, and psychiatric diseases. Thus, LSD1 is an attractive molecular target for the treatment of these diseases, and its inhibitors are predicted as therapeutic agents. Although a variety of LSD1 inhibitors have been reported to date, many of them show insufficient activities and selectivity toward LSD1. Meanwhile, we identified several LSD1‐selective inhibitors using target‐guided synthesis strategies based on our original ideas. Our LSD1 inhibitors show not only potent LSD1‐selective inhibitory activities, but also unique bioactivities both in vitro and in vivo. This account highlights our drug design concepts for and identification of LSD1‐selective inhibitors.

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“…Milelli et al developed a series of polyamine‐based hybrid compounds, from which emerged 115 (Figure ), showing interesting inhibitory activity against LSD1 (IC 50 LSD1‐CoREST3 = 3.8 μM) and HDAC1 (Ki HDAC1‐CoREST3 = 42.5 nM) in vitro as well as in cellular assays. In 115 , the two anti‐HDAC and ‐LSD1 pharmacophoric portions were connected using a polyamine‐type chain, since the polyamine moiety can interact with both LSD1 and HDAC enzymes due to protonated nitrogen atoms allowing electrostatic interactions with negatively charge amino acid residues .…”

Section: The Mtdl Approachmentioning

confidence: 99%

“…Among the different polyamine linkers used, the spermine (3‐4‐3), typical of 115 , produced the best enzymatic results. When tested against MCF7 breast cancer cell line, 115 resulted more effective (at high concentration) than vorinostat 3 in inducing cytotoxicity (68.6% vs 56.6% of dead cells) …”

Section: The Mtdl Approachmentioning

confidence: 99%

“…When tested against MCF7 breast cancer cell line, 115 resulted more effective (at high concentration) than vorinostat 3 in inducing cytotoxicity (68.6% vs 56.6% of dead cells). 402 Design and synthesis of dual inhibitors of BRDs and HDACs arises from the evidence that both these families of proteins take part in the acetylation process, and the independent inhibition of each single target is connected with similar genetic and biological effects. 408,409 The 9H-purine scaffold has been reported to bind with different strength the BRD proteins, 410 and some N 6 -benzoyladenine derivatives have been described as BRD4 inhibitors.…”

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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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Novel polyamine-based Histone deacetylases-Lysine demethylase 1 dual binding inhibitors

Cited by 24 publications

References 26 publications

Elucidating the mechanism of action of domatinostat (4SC-202) in cutaneous T cell lymphoma cells

Elucidating the mechanism of action of domatinostat (4SC-202) in cutaneous T cell lymphoma cells

Drug Design Concepts for LSD1‐Selective Inhibitors

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

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