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Updated: Dec 29, 2025
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Tranylcypromine-Based LSD1 Inhibitors: Structure-Activity Relationships, Antiproliferative Effects in Leukemia, and
Rossella Fioravanti1, Annalisa Romanelli1, Nicola Mautone1
1Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy.
Abstract:
LSD1 is a lysine demethylase highly involved in initiation and development of cancer. To design highly effective covalent inhibitors, a strategy is to fill its large catalytic cleft by designing tranylcypromine (TCP) analogs decorated with long, hindered substituents. We prepared three series of TCP analogs, carrying aroyl- and arylacetylamino (1 a-h), Z-amino acylamino (2 a-o), or double-substituted benzamide (3 a-n) residues at the C4 or C3 position of the phenyl ring. Further fragments obtained by chemical manipulation applied on the TCP scaffold (compounds 4 a-i) were also prepared. When tested against LSD1, most of 1 and 3 exhibited IC50 values in the low nanomolar range, with 1 e and 3 a,d,f,g being also the most selective respect to monoamine oxidases. In MV4-11 AML and NB4 APL cells compounds 3 were the most potent, displaying up to sub-micromolar cell growth inhibition against both cell lines (3 a) or against NB4 cells (3 c). The most potent compounds in cellular assays were also able to induce the expression of LSD1 target genes, such as GFI-1b, ITGAM, and KCTD12, as functional read-out for LSD1 inhibition. Mouse and human intrinsic clearance data highlighted the high metabolic stability of compounds 3 a, 3 d and 3 g. Further studies will be performed on the new compounds 3 a and 3 c to assess their anticancer potential in different cancer contexts.
Insights
Researchers designed novel tranylcypromine (TCP) analogs as covalent inhibitors targeting lysine-specific demethylase 1 (LSD1) for cancer therapy. Compounds showed potent inhibition and selectivity, with promising results in leukemia cell lines and good metabolic stability.
Area of Science:
- Medicinal Chemistry
- Oncology
- Biochemistry
Background:
- Lysine-specific demethylase 1 (LSD1) is a key epigenetic regulator implicated in cancer initiation and progression.
- Developing effective covalent inhibitors requires strategies to target the enzyme's catalytic cleft, such as using tranylcypromine (TCP) analogs with specific substituents.
Purpose of the Study:
- To design and synthesize novel tranylcypromine (TCP) analogs as potent and selective covalent inhibitors of LSD1.
- To evaluate the in vitro anticancer activity and metabolic stability of these novel compounds.
Main Methods:
- Synthesis of three series of TCP analogs (1a-h, 2a-o, 3a-n) and scaffold-modified fragments (4a-i).
- In vitro enzymatic assays to determine IC50 values against LSD1 and selectivity against monoamine oxidases.
- Cell-based assays using MV4-11 AML and NB4 APL cell lines to assess growth inhibition and LSD1 target gene expression.
Main Results:
- Compounds 1 and 3 demonstrated low nanomolar IC50 values against LSD1, with compounds 1e and 3a,d,f,g showing high selectivity.
- Compounds 3a and 3c exhibited potent sub-micromolar cell growth inhibition in MV4-11 and NB4 cells, respectively.
- Inhibition of LSD1 activity was confirmed by observing increased expression of target genes (GFI-1b, ITGAM, KCTD12). Compounds 3a, 3d, and 3g displayed high metabolic stability in mouse and human intrinsic clearance assays.
Conclusions:
- Novel TCP analogs, particularly series 3, are potent and selective covalent inhibitors of LSD1 with significant anticancer potential.
- Compounds 3a and 3c warrant further investigation for their therapeutic efficacy in various cancer types.
- The designed compounds represent promising leads for developing new epigenetic therapies against cancer.
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