Design of a selective peptide inhibitor targeting KDM5C demethylase activity

Post-translational modifications, particularly protein lysine demethylation, intricately regulate diverse cellular processes. Dysregulation of this modification often precipitates human pathologies by perturbing substrate protein functions, stability, and interactions. Lysine demethylases (KDMs), such as the KDM5 family, are crucial in removing methyl marks. In particular, KDM5C has gained prominence for its role in cancer biology and drug resistance. These enzymes, specializing in erasing lysine methylation marks—especially from histone H3 lysine 4 (H3K4)—directly influence gene transcription. This study pioneers the design of a peptide inhibitor of KDM5C demethylase activity. This novel inhibitor displays remarkable selectivity for KDM5C over other family members. Intriguingly, in vivo experiments demonstrate that this inhibitor significantly reduces tumor growth. These findings highlight the potential of targeting KDM5C inhibition as a strategy for colon cancer treatment. Moreover, these findings underscore the promise of peptide inhibitors as targeted therapies, emphasizing their potential in altering the trajectory of cancer therapeutics.