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Updated: Aug 26, 2025
High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
Published on: March 3, 2015
Synthesis and evaluation of small molecule inhibitors of LSD1 for use against MYCN-expressing neuroblastoma
Catherine M Mills1, Jonathan Turner1, Ivett C Piña1
1Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 70 President St, Charleston, SC, 29425, USA.
Abstract:
The epigenetic regulator lysine specific demethylase 1 (LSD1), a MYCN cofactor, cooperatively silences MYCN suppressor genes. Furthermore, LSD1 has been correlated with adverse effects in neuroblastic tumors by propagating an undifferentiated, malignant phenotype. We observed that high LSD1 mRNA expression in MYCN-expressing neuroblastoma (NB) correlated with poor prognosis, implicating LSD1 as an oncogenic accomplice in high-grade NB. Thus, LSD1 inhibition is a potential strategy for targeting treatment-resistant MYCN-expressing NB. Tranylcypromine-based covalent LSD1 inhibitors have demonstrated anti-tumor activity but are associated with undesirable off-target effects, such that only 2 non-covalent LSD1 inhibitors are in clinical trials. We now report 3 novel scaffolds for reversible LSD1 inhibition: 2-(arylsulfonamido)benzoic acid, N-(2-(1H-tetrazol-5-yl)phenyl)benzenesulfonamide and 2-(arylcarboxamido)benzoic acid analogues. The most active of these analogues, compound 48, exhibited potent and selective mixed reversible inhibition of LSD1 (IC50 = 0.58 μM) and significantly increased global H3K4me2 in NB cells. In addition, combination treatment with 48 and bortezomib in NB cells results in a synergistic effect.
Insights
New reversible inhibitors targeting lysine specific demethylase 1 (LSD1) show promise for treating aggressive neuroblastoma. Compound 48 demonstrates potent inhibition and synergistic effects with bortezomib, offering a potential new therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Lysine specific demethylase 1 (LSD1) is an epigenetic regulator and MYCN cofactor implicated in neuroblastoma malignancy.
- High LSD1 expression correlates with poor prognosis in MYCN-expressing neuroblastoma, suggesting it as a therapeutic target.
Purpose of the Study:
- To identify novel, reversible LSD1 inhibitors for treating MYCN-expressing neuroblastoma.
- To evaluate the efficacy and safety of new LSD1 inhibitor scaffolds.
Main Methods:
- Synthesis and characterization of novel LSD1 inhibitor scaffolds: 2-(arylsulfonamido)benzoic acid, N-(2-(1H-tetrazol-5-yl)phenyl)benzenesulfonamide, and 2-(arylcarboxamido)benzoic acid analogues.
- In vitro evaluation of inhibitory activity and selectivity against LSD1.
- Assessment of compound effects on global H3K4me2 levels in neuroblastoma cells.
- Combination treatment studies with bortezomib.
Main Results:
- Three novel scaffolds for reversible LSD1 inhibition were identified.
- Compound 48 demonstrated potent and selective mixed reversible inhibition of LSD1 (IC50 = 0.58 μM).
- Compound 48 treatment increased global H3K4me2 in neuroblastoma cells and showed synergistic effects when combined with bortezomib.
Conclusions:
- Novel reversible LSD1 inhibitors represent a promising therapeutic strategy for treatment-resistant MYCN-expressing neuroblastoma.
- Compound 48 is a potent and selective LSD1 inhibitor with potential for combination therapy.
