Histone modifications play critical roles in regulating both global and stage-specific gene expression. Methylation on histones H3K4, H3K36 and H3K79 is generally associated with gene activation, whereas methylation on histones H3K9 and H3K27 is generally associated with gene repression. Histone lysine methylation is dynamically regulated by site-specific methyltransferases and demethylases. EZH2 (the catalytic subunit of PRC2) is responsible for the methylation of H3K27 in cells.
DOT1L is a histone H3 lysine 79 methyltransferase whose inhibition increases the yield of induced pluripotent stem cells (iPSCs). EPZ-5676 is a potent and selective DOT1L inhibitor.
Crucial to PRC2 activity, the histone methyltransferase enhancer of zeste homolog 2 (EZH2) tri-methylates lysine 27 of histone 3 (H3K27me3), leading to chromatin condensation and transcriptional repression.
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A specific small molecule G9a histone methyltransferase inhibitor with IC50 of 1.7 uM; weakly inhibits the closely related GLP enzyme (IC50=38 uM), no inhibition of the other HMTases (>45 uM); reduces H3K9me2 of bulk histones in several cell lines, enables reprogramming of Oct4/Klf4-transduced mouse embryonic fibroblasts combined with BayK8644; also can reactivate expression of HIV-1 from latently infected cells.
A novel potent and selective protein arginine methyltransferase PRMT5 inhibitor; shows no inhibitory activity against the type I (PRMT1 and PRMT4) and type II (PRMT7) PRMT family members; exhibits effective inhibition of symmetric arginine dimethylation (me2) of histones H3 and H4 in AML samples, significantly increases expression of miR-29b and consequent suppression of Sp1 and FLT3 in AML cells; inhibits the proliferation of AML cell lines and primary blasts with IC50 of 7.21-21.46 uM.
MAK683 (MAK-683) is a novel inhibitor of embryonic ectoderm development protein (EED) and allosteric inhibitor of polycomb repressive complex 2 (PRC2), selectively binds to the domain of EED that interacts with H3K27me3; leads to a conformational change in the EED H3K27me3-binding pocket and prevents the interaction of EED with the histone methyltransferase enhancer zeste homolog 2 (EZH2), inhibits tumor cell proliferation in EZH2-mutated and PRC2-dependent cancer cells.
A novel potent, selective, SAM-competitive EZH2 inhibitor with IC50 of 80 nM (inhibition of enzymatic function of PRC2); demonstrates acutely reduced level of H3K27me3 without affecting mono- and di-methylation, suppresses the proliferation of EZH2-overexpression H661 and H522 cell lines, more effectively than GSK-126 and GSK-343; promotes the regression of EZH2-driven tumors in vivo.
A potent, selective PRC1 chromodomains antagonist that binds to CBX4 and CBX7 with Kd of 100 nM; displays 6- to 18-fold selectivity versus other CBX (CBX2/6/8) and CDY chromodomains, highly selectivity versus >250 other taergets in a Kme reader panel; inhibits PC3 cell proliferation with EC50 of 340 nM.
A highly potent and orally bioavailable small-molecule inhibitor of Menin-MLL interaction with Kd of 9.3 nM; effectively induces differentiation of MLL leukemia cells and and substantially increases expression of CD11b, also reduces expression of Hoxa9 and Meis1; induces marked anti-proliferative effects in MV4;11 cells with GI50 of 200 nM; blocks hematologic tumors in vivo and reduces MLL leukemia tumor burden in mouse models.
MI-538 is potent and selective menin–MLL interaction inhibitor (IC50=21 nM); shows the most potent binding affinity to menin (Kd = 6.5 nM) obtained for small molecule menin–MLL inhibitor reported to date; exhibits significantly increased activity, selectivity, polarity and pharmacokinetic profile over MI-136 and demonstrates a pronounced effect in a mouse model of MLL leukemia.
SGC-2085 is a potent, selective protein arginine methyltransferase PRMT4 (CARM1) inhibitor with IC50 of 50 nM, displays >100-fold selectivity over other PRMTs (PRMT6 IC50=5.3 uM); also shows complete selectivity against a panel of 21 human protein methyltransferases.
A potent, selective, small molecule SMYD3 inhibitor (Biochem IC50=3 nM; Cell IC50= 36 nM); displays <30% inhibition against 16 histone methyltransferase targets at 10 uM; shows good oral bioavailability and more favorable ADME profile than EPZ030456; orally active.
EPZ020411 is a potent, selective PRMT6 inhibitor with IC50 of 10 nM, displays 10-fold and 20-fold selectivity over PRMT1/8, and >100-fold over other histone methyltransferases (PRMT3/4/5/7); dose-dependently decreases H3R2 methylation A375 cell line with IC50 of 0.637 uM, with no affect levels of PRMT6 expression; exhibits good bioavailability following subcutaneous dosing in rats making it a suitable tool for potential in vivo target validation studies.
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