Targeting histone lysine demethylases - progress, challenges, and the future

Area of Science:

• Biochemistry
• Epigenetics
• Molecular Biology

Background:

• N-methylation of lysine and arginine residues is a key mechanism for transcriptional regulation in eukaryotes.
• Histone methylation status is critical for epigenetic regulation, impacting diseases such as cancer and genetic disorders.
• Lysine demethylases (KDMs) catalyze N(ε)-methyllysine residue demethylation via oxidative mechanisms.

Purpose of the Study:

• To introduce the enzymology of lysine demethylases (KDMs).
• To review the therapeutic potential and challenges of targeting KDMs.
• To provide a comprehensive review of reported KDM inhibitors, including their mechanisms of action from kinetic and structural viewpoints.

Main Methods:

• Review of existing literature on KDM enzymology.
• Analysis of kinetic and structural data for KDM inhibitors.
• Exploration of therapeutic strategies targeting KDMs.

Main Results:

• Two distinct KDM subfamilies (KDM1 and JmjC) utilize oxidative mechanisms for demethylation.
• Modulating histone methylation presents significant therapeutic opportunities.
• Various KDM inhibitors have been reported with diverse mechanisms of action.

Conclusions:

• KDMs are critical regulators of epigenetic processes with substantial medicinal potential.
• Targeting KDMs presents both opportunities and challenges for disease treatment.
• Understanding KDM inhibitor mechanisms is key for developing effective therapies.