Enzyme kinetic studies of histone demethylases KDM4C and KDM6A: Towards understanding selectivity of inhibitors targeting oncogenic histone demethylases

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Jan B L Kristensen, Anders L Nielsen, Lars Jørgensen, Line Hyltoft Kristensen, Charlotte Helgstrand, Lina Juknaite, Jesper Langgaard Kristensen, Jette Sandholm Kastrup, Rasmus Prætorius Clausen, Lars Olsen, Michael Gajhede

To investigate ligand selectivity between the oncogenic KDM4C and tumor repressor protein KDM6A histone demethylases, KDM4C and KDM6A were enzymatically characterized, and subsequently, four compounds were tested for inhibitory effects. 2,4-dicarboxypyridine and (R)-N-oxalyl-O-benzyltyrosine (3) are both known to bind to a close KDM4C homolog and 3 binds in the part of the cavity that accommodates the side chain in position 11 of histone 3. The inhibition measurements showed significant selectivity between KDM4C and KDM6A. This demonstrates that despite very similar active site topologies, selectivity between Jumonji family histone demethylases can be obtained even with small molecule ligands.
Original languageEnglish
JournalF E B S Letters
Volume585
Issue number12
Pages (from-to)1951-1956
ISSN0014-5793
DOIs
Publication statusPublished - 23 Jun 2011

ID: 33688211