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Enzyme kinetic studies of histone demethylases KDM4C and KDM6A: Towards understanding selectivity of inhibitors targeting oncogenic histone demethylases
Author(s) -
Kristensen Jan B.L.,
Nielsen Anders L.,
Jørgensen Lars,
Kristensen Line H.,
Helgstrand Charlotte,
Juknaite Lina,
Kristensen Jesper L.,
Kastrup Jette S.,
Clausen Rasmus P.,
Olsen Lars,
Gajhede Michael
Publication year - 2011
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2011.05.023
Subject(s) - histone , selectivity , enzyme , chemistry , biochemistry , biology , gene , catalysis
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.