2-Oxoglutarate-dependent nucleic acid demethylases areof biologicalinterest because of their roles in nucleic acid repair and modification.Although some of these enzymes are linked to physiology, their regulatoryroles are unclear. Hence, there is a desire to develop selective inhibitorsfor them; we report studies on AlkB, which reveal it as being amenableto selective inhibition by small molecules. Dynamic combinatorialchemistry linked to mass spectrometric analyses (DCMS) led to theidentification of lead compounds, one of which was analyzed by crystallography.Subsequent structure-guided studies led to the identification of inhibitorsof improved potency, some of which were shown to be selective overtwo other 2OG oxygenases. The work further validates the use of theDCMS method and will help to enable the development of inhibitorsof nucleic acid modifying 2OG oxygenases both for use as functionalprobes and, in the longer term, for potential therapeutic use. [ABSTRACT FROM AUTHOR]