Design and synthesis of tranylcypromine derivatives as novel LSD1/HDACs dual inhibitors for cancer treatment

Duan, Ying-Chao; Ma, Yongcheng; Qin, Wenping; Ding, Ling; Zheng, Yi-Chao; Zhu, Yin; Zhai, Xiaoyu; Yang, Jing; Ma, Chao-Ya; Guan, Yu

doi:10.1016/j.ejmech.2017.09.038

Cited by 72 publications

(45 citation statements)

References 69 publications

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“…During the drafting of this manuscript, two papers reporting about novel dual HDAC-LSD1 inhibitors appeared. 23,24 However, these compounds turned out to be structurally slightly different than those reported in the present manuscript.…”

Section: Dual-binding Agents Epigenetics Histone Deacetylase Inhibitocontrasting

confidence: 70%

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

Milelli

Marchetti

Turrini

et al. 2018

Bioorganic & Medicinal Chemistry Letters

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Epigenetic modulators Histone deacetylases (HDACs) and Lysine demethylase (LSD1) are validated targets for anticancer therapy. Both HDAC1/2 and LSD1 are found in association with the repressor protein CoREST in a transcriptional co-repressor complex, which is responsible for gene silencing. Combined modulation of both targets results in a synergistic antiproliferative activity. In the present investigation, we report about the design and synthesis of a series of polyamine-based HDACs-LSD1 dual binding inhibitors obtained by coupling Vorinostat and Tranylcypromine. Compound 4 emerged as the most promising of the synthesized series, showing good inhibitory activity towards HDAC1 and LSD1 either in vitro and in cell-based assay (Ki = 42.52 ± 8.94 nM and IC = 3.85 μM, respectively). Furthermore, at 70.0 µM compound 4 induced a more pronounced cytotoxic effect than Vorinostat (68.6% vs 56.6% of dead cells) in MCF7 cancer cell line.

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Section: Dual-binding Agents Epigenetics Histone Deacetylase Inhibitocontrasting

confidence: 70%

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

Milelli

Marchetti

Turrini

et al. 2018

Bioorganic & Medicinal Chemistry Letters

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“…For example, numerous novel inhibitors (called chimeric or hybrid) have been designed, so that single molecules can be directed against multiple targets [133]. This new class of epigenetic inhibitors includes the LSD1/HDAC hybrid inhibitors that target simultaneously LSD1 and HDAC1 or HDAC1/2 [134][135][136]. Such drugs guarantee the combined effect at multiple targets in the very same cell, apart from the more favorable pharmacokinetic or pharmacodynamic parameters or their more predictable and less complex metabolism [133].…”

Section: Lsd1 As a Therapeutic Target In Cancer Treatmentmentioning

confidence: 99%

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Karakaidos

Verigos

Magklara

2019

Cancers

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A new exciting area in cancer research is the study of cancer stem cells (CSCs) and the translational implications for putative epigenetic therapies targeted against them. Accumulating evidence of the effects of epigenetic modulating agents has revealed their dramatic consequences on cellular reprogramming and, particularly, reversing cancer stemness characteristics, such as self-renewal and chemoresistance. Lysine specific demethylase 1 (LSD1/KDM1A) plays a well-established role in the normal hematopoietic and neuronal stem cells. Overexpression of LSD1 has been documented in a variety of cancers, where the enzyme is, usually, associated with the more aggressive types of the disease. Interestingly, recent studies have implicated LSD1 in the regulation of the pool of CSCs in different leukemias and solid tumors. However, the precise mechanisms that LSD1 uses to mediate its effects on cancer stemness are largely unknown. Herein, we review the literature on LSD1’s role in normal and cancer stem cells, highlighting the analogies of its mode of action in the two biological settings. Given its potential as a pharmacological target, we, also, discuss current advances in the design of novel therapeutic regimes in cancer that incorporate LSD1 inhibitors, as well as their future perspectives.

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“…Compound 113 inhibited LSD1 at micromolar and HDAC1/2 at nanomolar levels and showed antiproliferative activities higher than vorinostat 3 against A549 lung, MCF‐7 breast, MGC‐803 gastric, and SW‐620 colorectal cancer cells. Target engagement was demonstrated in MGC‐803 cells, where 113 increased methyl‐H3K4/methyl‐H3K9 together with acetyl‐H3 levels, decreased the mitochondrial membrane potential, and induced apoptosis …”

Section: The Mtdl Approachmentioning

confidence: 99%

“…Target engagement was demonstrated in MGC-803 cells, where 113 increased methyl-H3K4/methyl-H3K9 together with acetyl-H3 levels, decreased the mitochondrial membrane potential, and induced apoptosis. 395 Our contribution in this field was to prepare novel LSD1/HDAC dual inhibitors by the introduction of the HDAC inhibiting hydroxamate or benzamide side chain at the phenyl ring of tranylcypromine 24, where we previously inserted various amide or amino acid substituents that highly improved the LSD1 inhibitory potency of 24 itself. 30,[396][397][398][399][400] Size exclusion chromatography revealed a stable association of the HDAC1:LSD1:CoREST ternary complex with 1:1:1 stoichiometry.…”

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confidence: 99%

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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Design and synthesis of tranylcypromine derivatives as novel LSD1/HDACs dual inhibitors for cancer treatment

Cited by 72 publications

References 69 publications

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

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

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

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