6cg2
Crystal Structure of KDM4A with Compound 8Crystal Structure of KDM4A with Compound 8
Structural highlights
FunctionKDM4A_HUMAN Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate. Participates in transcriptional repression of ASCL2 and E2F-responsive promoters via the recruitment of histone deacetylases and NCOR1, respectively.[1] [2] [3] Isoform 2: Crucial for muscle differentiation, promotes transcriptional activation of the Myog gene by directing the removal of repressive chromatin marks at its promoter. Lacks the N-terminal demethylase domain.[4] [5] [6] Publication Abstract from PubMedHistone lysine demethylases (KDMs) play a key role in epigenetic regulation and KDM5A and KDM5B have been identified as potential anti-cancer drug targets. Using structural information from known KDM4 and KDM5 inhibitors, a potent series of pyrazolylpyridines was designed. Structure-activity relationship (SAR) exploration resulted in the identification of compound 33, an orally available, potent inhibitor of KDM5A/5B with promising selectivity. Potent cellular inhibition as measured by levels of tri-methylated H3K4 was demonstrated with compound 33 in the breast cancer cell line ZR-75-1. Structure-based design and discovery of potent and selective KDM5 inhibitors.,Nie Z, Shi L, Lai C, O'Connell SM, Xu J, Stansfield RK, Hosfield DJ, Veal JM, Stafford JA Bioorg Med Chem Lett. 2018 Mar 30. pii: S0960-894X(18)30288-9. doi:, 10.1016/j.bmcl.2018.03.083. PMID:29627262[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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