Fluorinated tranylcypromine analogues as inhibitors of lysine-specific demethylase 1 (LSD1, KDM1A)

Borrello, María Teresa; Schinor, Benjamin; Bartels, K.; Benelkebir, Hanae; Pereira, Sara; Al-Jamal, Wafa' T; Douglas, Leon; Duriez, Patrick J.; Packham, Graham; Haufe, Günter; Ganesan, A.

doi:10.1016/j.bmcl.2017.03.081

Cited by 23 publications

(10 citation statements)

References 28 publications

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“…To enhance the understanding of the pharmacological properties of TCP derivatives and to obtain insights into the mechanism-based inhibition caused by the formation of the covalent TCP–FAD adduct, introduction of substituents at the α- or β-position of TCP was carried out to develop more potent LSD1 inhibitors in recent years. − In 2014, Vianello et al developed a series of single enantiomers of α-substituted TCP derivatives as LSD1 inhibitors . It is worth mentioning that the inhibitory activity of these novel synthesized compounds was strongly dependent on the substitutions on the cyclopropyl ring, and hydrophobic groups (alkyl, phenyl, and benzyl) were also introduced to enhance the LSD1 inhibitory activity.…”

Section: Tcp-based Lsd1 Inhibitorsmentioning

confidence: 99%

Tranylcypromine Based Lysine-Specific Demethylase 1 Inhibitor: Summary and Perspective

et al. 2020

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Histone lysine-specific demethylase 1 (LSD1/KDM1A) has become an important and promising anticancer target since it was first identified in 2004 and specially demethylates lysine residues of histone H3K4me1/2 and H3K9me1/2. LSD1 is ubiquitously overexpressed in diverse cancers, and abrogation of LSD1 results in inhibition of proliferation, invasion, and migration in cancer cells. Over the past decade, a number of biologically active small-molecule LSD1 inhibitors have been developed. To date, six trans-2-phenylcyclopropylamine (TCP)-based LSD1 inhibitors (including TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, and ORY-2001) that covalently bind to the flavin adenine dinucleotide (FAD) within the LSD1 catalytic cavity have already entered into clinical trials. Here, we provide an overview about the structures, activities, and structure–activity relationship (SAR) of TCP-based LSD1 inhibitors that mainly covers the literature from 2008 to date. The opportunities, challenges, and future research directions in this emerging and promising field are also discussed.

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Section: Tcp-based Lsd1 Inhibitorsmentioning

confidence: 99%

Tranylcypromine Based Lysine-Specific Demethylase 1 Inhibitor: Summary and Perspective

et al. 2020

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“…Briefly, the assay uses a synthetic dimethylated histone H3K4me2 peptide as substrate and AmplexRed® detection of the H 2 O 2 byproduct. [19,20] While tranylcypromine itself had a IC 50 of 21.0 μM in this assay, the analogues were significantly more potent LSD1 inhibitors with the exception of 5 h and 5 i (Table 1). Compounds 5 a-c containing an aryl or heteroaryl substituent linked by a one or two carbon spacer to the carboxamide were sub-micromolar inhibitors of the enzyme.…”

Section: Biology: Lsd1 Inhibition and Antiproliferative Activity Agaimentioning

confidence: 91%

Synthesis of Carboxamide‐Containing Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors Targeting Acute Myeloid Leukemia

et al. 2021

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In memory of the late Professor Maurizio Botta 1950-2019 for his generous friendship and his many outstanding scientific contributions to medicinal chemistry.Lysine-specific demethylase 1 (LSD1/KDM1A) oxidatively removes methyl groups from histone proteins, and its aberrant activity has been correlated with cancers including acute myeloid leukemia (AML). We report a novel series of tranylcypromine analogues with a carboxamide at the 4-position of the aryl ring. These compounds, such as 5 a and 5 b with benzyl and phenethylamide substituents, respectively, had potent submicromolar IC 50 values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose-dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The tert-butyl and ethyl carbamate derivatives of these tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell-based assays with a more rapid onset of action. This suggests that carbamates can act as metabolically labile tranylcypromine prodrugs with superior pharmacokinetics.

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“…Dithiocarbamate 9 as a LSD1 inhibitor potently inhibited the growth of LSD1 overexpressing gastric tumour in vivo 8 . In addition, several LSD1 inhibitors ( CC-90011 , ORY-1001 , GSK-2879552 , ORY-2001 and TCP ) presently undergo clinical assessment for cancer therapy ( Figure 2 ) 8 , 9 .…”

Section: Introductionmentioning

confidence: 99%

Tertiary sulphonamide derivatives as dual acting small molecules that inhibit LSD1 and suppress tubulin polymerisation against liver cancer

Ding

Wei

Wang

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of tertiary sulphonamide derivatives were synthesised and evaluated for their antiproliferative activity against liver cancer cell lines . Among these tertiary sulphonamides, compound 17a displayed the best anti-liver cancer activity against Bel-7402 cells with an IC 50 value of 0.32 lM. Compound 17a could effectively inhibit tubulin polymerisation with an IC 50 value of 1.27 lM. Meanwhile, it selectively suppressed LSD1 with an IC 50 value of 63 nM. It also concentration-dependently inhibited migration against Bel-7402 cells. Importantly, tertiary sulphonamide 17a exhibited the potent antitumor activity in vivo. All these findings revealed that compound 17a might be a tertiary sulphonamide-based dual inhibitor of tubulin polymerisation and LSD1 to treat liver cancer.

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Fluorinated tranylcypromine analogues as inhibitors of lysine-specific demethylase 1 (LSD1, KDM1A)

Cited by 23 publications

References 28 publications

Tranylcypromine Based Lysine-Specific Demethylase 1 Inhibitor: Summary and Perspective

Tranylcypromine Based Lysine-Specific Demethylase 1 Inhibitor: Summary and Perspective

Synthesis of Carboxamide‐Containing Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors Targeting Acute Myeloid Leukemia

Tertiary sulphonamide derivatives as dual acting small molecules that inhibit LSD1 and suppress tubulin polymerisation against liver cancer

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