Lysine-specific demethylase 5 (KDM5) (KDM5)

Lysine-specific demethylase 5 (KDM5), also known as the JARID1 family, is a group of histone demethylases (KDM5A, KDM5B, KDM5C, and KDM5D) that specifically catalyze the removal of methyl groups from tri- and di-methylated lysine 4 on histone H3 (H3K4me2/3). These enzymes are members of the Jumonji C (JmjC) domain-containing family and function as 2-oxoglutarate-dependent dioxygenases, requiring iron and alpha-ketoglutarate as cofactors. KDM5 proteins primarily act as transcriptional repressors by reducing the levels of H3K4 methylation, a mark typically associated with active gene transcription, and play essential roles in cell cycle regulation, DNA damage repair, and cellular differentiation. In the context of disease, KDM5 members are frequently overexpressed in multiple cancers, such as breast, prostate, and lung cancer, where they promote tumor growth, metastasis, and the development of drug tolerance. For instance, KDM5A has been linked to the maintenance of drug-tolerant persister cells, while KDM5B is often overexpressed in breast cancer and melanoma. Beyond oncology, mutations in KDM5C are associated with X-linked intellectual disability. Therapeutic strategies targeting KDM5 involve small-molecule inhibitors that bind to the JmjC domain, often by chelating the active-site iron or competing with the 2-oxoglutarate cofactor. While several potent inhibitors like CPI-455 and KDOAM-25 have shown efficacy in preclinical models, no KDM5-specific inhibitors have yet reached clinical trials, and achieving isoform selectivity remains a significant challenge.

Other names

JARID1 familyJumonji/ARID domain-containing protein 1H3K4 demethylaseRetinoblastoma-binding protein 2 (RBP2)Protein PLU-1SmcX proteinSmcY protein

KDM5 inhibitors primarily function by competitively binding to the Jumonji C (JmjC) catalytic domain or by chelating the essential Fe(II) cofactor, thereby preventing the demethylation of H3K4me2/3 and restoring the expression of genes typically repressed by KDM5 activity.