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Innovation is always an important focus for Mercachem. Together with our partner ProQinase, we embarked on a mission to turn literature-reported histone lysine methyltransferase (HKMT) inhibitors into drug-like starting points. This was achieved by exploring the structure–activity relationship (SAR) around two of these reported compounds.

Euchromatic histone methyltransferase (EHMT) 1 and EHMT2 are responsible for transferring methyl groups to lysine residues in histone tails. Dysregulation of these methylations has been implicated in cancers and other diseases, making these HKMTs interesting targets for drug development.

"Most reported compounds have three very basic sites, which are disadvantageous for cell permeability and limit cellular activity," explains Dr Ruben Leenders, the group leader overseeing this research. "To improve this activity, we explored the SAR around these compounds." By focusing on replacing the lysine-mimicking tail with more drug-like side chains, Mercachem succeeded in finding compounds that were more active in cellular assays. The assay results indicated an improvement in permeability and confirmed recent reports that it was possible to find compounds with significant selectivity towards EHMT1. These findings create an interesting starting point for a drug development program.

Leenders, Ruben et. al., Bioorganic & Medicinal Chemistry Letters, 2019 (17), 2516, Novel SAR for quinazoline inhibitors of EHMT1 and EHMT2


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