Novel SAR for quinazoline inhibitors of EHMT1 and EHMT2

Leenders, Ruben G.G.; Zijlmans, Remco; Bree, Bart van; Sande, M. Van; Trivarelli, F.; Damen, Eddy; Wegert, Anita; Müller, Daniel S.; Ehlert, Jan E.; Feger, Daniel; Heidemann-Dinger, Carolin; Kubbutat, Michael H.G.; Schächtele, Christoph; Lenstra, Danny C.; Mecinović, Jasmin; Müller, Gerhard

doi:10.1016/j.bmcl.2019.06.012

Cited by 2 publications

(1 citation statement)

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“…To date, a number of G9a/GLP dual inhibitors have been developed by targeting either the SAM binding site or the substrate binding pocket. − Among them, our substrate-competitive G9a/GLP dual inhibitors, UNC0638 and UNC0642, have been widely used by the research community as cellular and in vivo chemical probes, respectively. , We also developed a highly selective GLP inhibitor, MS012. , The cocrystal structures of UNC0638 and MS012 in complex with G9a or GLP revealed that both G9a and GLP have a cysteine residue (Cys1098 in G9a, Cys1186 in GLP) at the inhibitor binding site (Figure and Figure S1). , We hypothesized that this unexploited cysteine residue could be targeted to generate covalent inhibitors that may offer potential advantages over noncovalent inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Discovery of the First-in-Class G9a/GLP Covalent Inhibitors

et al. 2022

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The highly homologous protein lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), have been implicated in various human diseases. To investigate functions of G9a and GLP in human diseases, we and others reported several noncovalent reversible small-molecule inhibitors of G9a and GLP. Here, we report the discovery of the first-in-class G9a/GLP covalent irreversible inhibitors, 1 and 8 (MS8511), by targeting a cysteine residue at the substrate binding site. We characterized these covalent inhibitors in enzymatic, mass spectrometry based and cellular assays and using X-ray crystallography. Compared to the noncovalent G9a/GLP inhibitor UNC0642, covalent inhibitor 8 displayed improved potency in enzymatic and cellular assays. Interestingly, compound 8 also displayed potential kinetic preference for covalently modifying G9a over GLP. Collectively, compound 8 could be a useful chemical tool for studying the functional roles of G9a and GLP by covalently modifying and inhibiting these methyltransferases.

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