Structural and Functional Landscape of FAD-Dependent Histone Lysine Demethylases for New Drug Discovery

Small molecules targeting the flavin adenine dinucleotide (FAD)-dependent histone lysine demethylase LSD family have displayed therapeutic promise against various diseases. Nine clinical candidates targeting the classic demethylase-dependent functions of the LSD family are currently being investigated for treating cancers, neurodegenerative diseases, etc. Moreover, targeting noncatalytic functions of LSDs also represents an emerging strategy for treating human diseases. In this Perspective, we provide full structural and functional landscape of the LSD family and action modes of different types of LSD inhibitors including natural products, peptides, and synthetic compounds, aiming to reveal new druggable space for the design of new LSD inhibitors. Particularly, we first classify these inhibitors into three types based on their unique binding modes. Additionally, the strategies targeting the demethylase-independent functions of LSDs are also briefly discussed. This Perspective may benefit the discovery of new LSD inhibitors for probing LSD biology and/or treating human diseases.

Automated summary

Small molecules targeting the FAD-dependent LSD family have shown promise as therapeutic candidates for various diseases. Nine clinical candidates are currently being investigated for their ability to treat cancers and neurodegenerative diseases. In addition, noncatalytic functions of LSDs are being explored as a new strategy for disease treatment. This Perspective provides a comprehensive analysis of the LSD family, including its structure, function, and different types of inhibitors, with the aim of identifying new druggable targets for LSD inhibitors. The strategies for targeting LSD's demethylase-independent functions are also briefly discussed.