Related Experiment Video
Updated: Oct 9, 2025
Direct Measurement of KDM1A Target Engagement Using Chemoprobe-based Immunoassays
Published on: June 13, 2019
Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology
Natalia Sacilotto1, Paola Dessanti1, Michele M P Lufino1
1Oryzon Genomics S.A., Carrer Sant Ferran 74, Cornellà de Llobregat, 08940 Barcelona, Spain.
Abstract:
Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the demethylation of histones and nonhistone substrates. In addition to its enzymatic activity, LSD1 plays a fundamental scaffolding role as part of transcription silencing complexes such as rest co-repressor (CoREST) and nucleosome remodeling and deacetylase (NuRD). A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies. Additionally, several optimized new chemical entities have reached clinical trials in oncology such as ORY-1001 (iadademstat), GSK2879552, SP-2577 (seclidemstat), IMG-7289 (bomedemstat), INCB059872, and CC-90011 (pulrodemstat). Despite this, no single study exists that characterizes them all under the same experimental conditions, preventing a clear interpretation of published results. Herein, we characterize the whole LSD1 small molecule compound class as inhibitors of LSD1 catalytic activity, disruptors of SNAIL/GFI1 (SNAG)-scaffolding protein-protein interactions, inducers of cell differentiation, and potential anticancer treatments for hematological and solid tumors to yield an updated, unified perspective of this field. Our results highlight significant differences in potency and selectivity among the clinical compounds with iadademstat being the most potent and reveal that most of the tool compounds have very low activity and selectivity, suggesting some conclusions derived from their use should be taken with caution.
Insights
This study evaluates LSD1 inhibitors for cancer treatment, finding significant differences in potency and selectivity among clinical compounds. Most tool compounds showed low activity, cautioning against prior conclusions based on their use.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Lysine-specific demethylase 1 (LSD1/KDM1A) is a key chromatin modifier involved in cell cycle, differentiation, and proliferation.
- LSD1 functions both enzymatically and as a scaffold in transcriptional silencing complexes like CoREST and NuRD.
- Numerous LSD1 inhibitors, including clinical candidates, have been developed for cancer research.
Purpose of the Study:
- To comprehensively characterize the class of LSD1 small molecule inhibitors.
- To evaluate their efficacy as catalytic inhibitors, disruptors of protein-protein interactions, and inducers of cell differentiation.
- To provide a unified perspective on their potential as anticancer treatments for hematological and solid tumors.
Main Methods:
- Characterization of LSD1 small molecule compounds under unified experimental conditions.
- Assessment of catalytic inhibition of LSD1.
- Evaluation of disruption of SNAIL/GFI1 (SNAG) protein-protein interactions.
- Analysis of induction of cell differentiation and anticancer potential.
Main Results:
- Significant variations in potency and selectivity were observed among clinical LSD1 inhibitors.
- Iadademstat emerged as the most potent clinical compound.
- Most tool compounds exhibited low activity and selectivity, questioning previous findings.
- LSD1 inhibitors demonstrate potential as anticancer agents by modulating catalytic activity and protein interactions.
Conclusions:
- Clinical LSD1 inhibitors display diverse pharmacological profiles, with iadademstat showing superior potency.
- The low activity of many tool compounds necessitates cautious interpretation of past research.
- This unified characterization provides a clearer perspective on LSD1 inhibitors for hematological and solid tumors.
