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| | AlphaScreen Assay |
| Description: | We previously described 4-carboxy-2-triazolopyridines as selective KDM2 inhibitors (England et al., 2014). In efforts to find alternative scaffolds based on the 4-carboxypyridine core, a range of compounds with a 2-aminomethyl group were synthesized and tested for KDM inhibition. Aminomethylpyridines such as KDOAM-1 showed a preference for the KDM4 and KDM5 sub-families (Figure 1A), but we were unable to find analogs with a potency in cellular immunofluorescence (IF) assays of H3K36 and H3K4 demethylation. Hence, we were interested when a patent application described very similar compounds and reported potency in an almost identical cellular IF assay (Labelle et al., 2014). In our hands, two of the compounds described, named here KDOAM-20 and -21, showed low- and sub-micromolar potency, respectively, in an H3K4me3 IF assay overexpressing KDM5B, but also inhibited H3K9me3 demethylation in accordance with its in vitro KDM4 activity (Figures S1A and S1B). We considered it possible that KDOAM-21 may be acting as an ester pro-drug akin to the KDM5/6 inhibitor, GSK-J4 (Kruidenier et al., 2012). To our surprise, the ester KDOAM-21 itself showed potent inhibition of KDM5B in vitro (Figure 1A). However, KDOAM-20 was also a sub-micromolar inhibitor of KDM4C, and KDOAM-21 could potentially be hydrolyzed to KDOAM-20 in situ. Therefore, we sought to replace the ester of KDOAM-20 with a less labile group such as an amide to retain KDM5 potency and selectivity. There is some precedent for this, as compound 16 in Bavetsias et al. (2016) is a weak KDM4/5 inhibitor with some selectivity for KDM5A/B over KDM4A/B (5- to 50-fold). The amides KDOAM-25, -28, and -29 were synthesized, and KDOAM-25 was shown to be the most potent of the series with a KDM5B half maximal inhibitory concentration (IC50) of 19 nM and improved selectivity over KDM4C. |
| Affinity data for this assay | |
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