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Recent advances of LSD1/KDM1A inhibitors for disease therapy

Lysine-specific demethylase 1 (LSD1/KDM1A) dysregulation is closely associated with the pathological processes of various diseases, especially hematologic malignancies. Significant progresses have been made in the field of LSD1-targeted drug discovery. Nine LSD1 inhibitors including tranylcypromine, ORY-1001, ORY-2001, GSK-2879552, IMG-7289, INCB059872, TAK-418, CC-90011 and SP-2577 have entered clinical stage for disease treatment as either mono- or combinational therapy. This review updates LSD1 inhibitors reported during 2022. Design strategies, structure-activity relationship studies, binding model analysis and modes of action are highlighted. In particular, the unique multiple-copies binding mode of quinazoline derivatives paves new ways for the development of reversible LSD1 inhibitors by blocking the substrate entrance. The design strategy of clinical candidate TAK-418 also provides directions for further optimization of novel irreversible LSD1 inhibitors with low hematological side effects. The influence of the stereochemistry on the potency against LSD1 and its homolog LSD2 is briefly discussed. Finally, the challenges and prospects of LSD1-targeted drug discovery are also given.

 

Comments：

It is interesting to note that LSD1 dysregulation has been implicated in various diseases, particularly hematologic malignancies, and that several LSD1 inhibitors have entered clinical trials for disease treatment.

The focus on design strategies, structure-activity relationship studies, binding model analysis, and modes of action of LSD1 inhibitors in the review provides valuable insights into the development of novel LSD1 inhibitors with improved efficacy and reduced side effects.

The unique multiple-copies binding mode of quinazoline derivatives is a promising approach for the development of reversible LSD1 inhibitors by blocking the substrate entrance. Additionally, the design strategy of clinical candidate TAK-418 offers directions for the optimization of novel irreversible LSD1 inhibitors with low hematological side effects.

It is also interesting to note the influence of stereochemistry on the potency against LSD1 and its homolog LSD2. This provides important considerations for the development of LSD1 inhibitors with selectivity and improved therapeutic index.

Overall, the review provides a comprehensive overview of recent advances in LSD1-targeted drug discovery and highlights the challenges and prospects of developing effective LSD1 inhibitors for the treatment of various diseases.

Related Products

Cat.No. Product Name Information
S6722 Seclidemstat (SP-2577) Seclidemstat (SP-2577) is a potent and orally bioavailable inhibitor of lysine-specific demethylase 1 (LSD1/KDM1A) with IC50 of 13 nM. Seclidemstat (SP-2577) has potential antineoplastic activity.

Related Targets

LSD1