Research surrounding the epigenetic regulation of gene expression is gaining momentum, and deservedly so. There are many examples of disease states, including cancers, which are associated with aberrant epigenetic markers, including erroneous protein post-translational modifications (PTMs) of the histones of chromatin. A particularly attractive area of study is histone lysine methylation, as this is one of the most stable and widely-studied PTMs. The enzyme family responsible for this PTM - the histone lysine methyltransferases (HKMTs) – are highly homologous, and therefore difficult to target selectively. Initial research has been applied to the HKMT, DOT1L, as this enzyme is structurally distinct from other HKMTs. A new proteomic technology has been designed using analogues of the co-factor, S-adenosyl-L-methionine (SAM): one of which, is selective for DOT1L. The turnover of the co-factor probes is detectable by mass spectrometry. This work demonstrates validation of the approach, with a view to expanding the technology to seek out potential non-histone targets of DOT1L.