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. 2021 Apr 10;2(4):370–387. doi: 10.1158/2643-3230.BCD-20-0108

Figure 2.

Figure 2.

JQKD82 is a cell-permeable KDM5-selective inhibitor. A, Chemical structures of the prodrug esters JQKD82 and KDM5-C70, and their active metabolite KDM5-C49. B, The crystal structure of JQKD82 bound to KDM5B was resolved after soaking the prodrug ester JQKD82 with KDM5B. This resulted in a crystal resolved for the acid derivative KDM5-C49 derived from JQKD82 under crystallization conditions, demonstrating that KDM5-C49 interacts with Glu501 to chelate with metal and with Lysine 517 on the backbone for selectivity against KDM5 in the demethylase catalytic domain.C, Intracellular concentrations of compounds (both parent compounds and metabolite KDM5-C49) were determined using LC/MS after treatment withKDM5-C70 or JQKD82 at 10 μmol/L for 2 hours in Caco2 cells. Data are shown as average ± SD of duplicate testing. *, P < 0.05; unpaired Student t test.D, Immunoblot analysis for H3K4me3 using H3 as loading control after treatment with KDM5-C49, KDM5-C70, or JQKD82 at 0.3 μmol/L or DMSO for 24 hours in MM.1S cells. E, Immunoblot analysis for H3K4me3, H3K9me3, H3K27me3, H3K36me3, and H3K79me3 using H3 as loading control after treatment with JQKD82 (0.3 or 1 μmol/L) or DMSO for 24 hours in MM.1S and MOLP-8 cells. Densitometry analysis displayed on the right (numbers are levels of methylation as a percentage of DMSO control).