EHMT2/G9a/KMT1C Inhibitor

BIX-01294 is a reversible and highly selective G9a and GLP Histone Methyltransferase inhibitor, with IC₅₀s of of 1.7 μM and 0.9 μM, respectively. BIX-01294 inhibits G9a/GLP by competing for binding with the amino acids N-terminal of the substrate lysine residue. BIX-01294, a (1H-1,4-diazepin-1-yl)-quinazolin-4-yl amine derivative, induces necroptosis and autophagy. BIX-01294 has antitumor activity in recurrent tumor cells.

UNC0642, a chemical probe, is a potent and selective lysine methyltransferases G9a and GLP inhibitor, with an IC₅₀ of <2.5 nM for G9a.

UNC0638, a chemical probe, selectively inhibits G9a and GLP histone methyltransferases with IC₅₀ of 15 nM and 19 nM, respectively. UNC0638 inhibits TNBC cell invasion and migration in vitro. UNC0638 is also an inhibitor of EHMT1/2 and induces fetal hemoglobin (HbF) expression in human erythroid progenitor cell culture. In addition, UNC0638 has anti-FMDV (foot-and-mouth disease virus) and anti-VSV (vesicular stomatitis virus) activities, with excellent potency and selectivity against multiple epigenetic and non-epigenetic targets.

A-366, a chemical probe, is a potent, highly selective, peptide-competitive histone methyltransferase G9a inhibitor with IC₅₀s of 3.3 and 38 nM for G9a and GLP (EHMT1), respectively. A-366 shows >1000-fold selectivity over 21 other methyltransferases. A-366 is also a potent, nanomolar inhibitor of the Spindlin1-H3K4me3-interaction (IC₅₀=182.6 nM). A-366 displays high affinity at human histamine H3 receptor (K_i=17 nM) and shows subtype selectivity among subsets of the histaminergic and dopaminergic receptor families.

CM-272 is a first-in-class, potent, selective, substrate-competitive and reversible dual G9a/DNA methyltransferases (DNMTs) inhibitor with antitumor activities. CM-272 inhibits G9a, DNMT1, DNMT3A, DNMT3B and GLP with IC₅₀s of 8 nM, 382 nM, 85 nM, 1200 nM and 2 nM, respectively. CM-272 inhibits cell proliferation and promotes apoptosis, inducing IFN-stimulated genes and immunogenic cell death.

EZM8266 is an orally active and selective G9a (EHMT2) histone methyltransferase inhibitor with a human EHMT2 IC₅₀ of 1 pM. EZM8266 reduces repressive H3K9me2 marks at immune-stimulatory gene and endogenous retroviral element promoters. EZM8266 reduces colony formation, migration, and invasion of cancer cells. EZM8266 enhances IFN-γ response, increases MHC class I expression, and enhances CXCL10-mediated T cell recruitment in cancer cells. EZM8266 can be used for the research of hepatocellular carcinoma.

UNC0224 is a potent and selective histone methyltransferase G9a inhibitor with a K_i of 2.6 nM, an IC₅₀ of 15 nM and a K_d of 23 nM. UNC0224 also potently inhibits b>GLP with assay-dependent IC₅₀ values of 20-58 nM. UNC0224 is inactive against SET7/9, SET8/PreSET7, PRMT3 and JMJD2E.

BRD4770 is a histone methyltransferase G9a inhibitor. BRD4770 reduces di- and trimethylation of lysine 9 on histone H3 (H3K9) with an EC₅₀ of 5 μM, and has less or little effect toward H3K27me3, H3K36me3, H3K4me3, and H3K79me3. BRD4770 can activate the ataxia telangiectasia mutated (ATM) pathway and induce cell senescence.

UNC 0631 is a potent histone methyltransferase G9a inhibitor with an IC₅₀ of 4 nM. UNC 0631 potently reduces H3K9me2 levels in MDA-MB-231 cells with an IC₅₀ of 25 nM.

RK-701 is an highly selective and non-genotoxic inhibitor of G9a with IC₅₀ value of 23-27 nM. RK-701 selectively up-regulates HbF, γ- Globin, BGLT3 expression, down-regulates H3K9me2 expression. RK-701 also has inhibition for BCL11A and ZBTB7A.

UNC0321 is a potent and selective histone methyltransferase G9a inhibitor with a K_i of 63 pM and with assay-dependent IC₅₀ values of 6-9 nM. UNC0321 also inhibits GLP with assay-dependent IC₅₀ values of 15-23 nM. UNC0321 has anti-apoptotic activity and has potential application in diabetic vascular complications.

EHMT2-IN-1 is a potent EHMT inhibitor, with IC₅₀s of all <100 nM for EHMT1 peptide, EHMT2 peptide and cellular EHMT2. Used in the research of blood disorder or cancer.

UNC0646 is a potent and selective histone methyltransferase G9a inhibitor with an IC₅₀ of 6 nM. UNC0646 is also a potent GLP inhibitor (IC₅₀ <15 nM) and highly selective for G9a/GLP over SETD7, SUV39H2, SETD8 and PRMT3. UNC0646 reduces H3K9me2 levels in MDA-MB-231 cells with an IC₅₀ of 26 nM.

MS152 is an orally active, blood-brain barrier penetrant inhibitor of EHMT2/G9a and EHMT1/GLP, with IC₅₀s of 76 nM and 126 nM, repsectively. MS152 reduces H3K9me2 levels and reactivates maternally silenced Prader-Willi syndrome (PWS) genes. MS152 significantly improves perinatal lethality and growth retardation in mouse models, and is applicable to research related to Prader-Willi syndrome.

EHMT2-IN-2 is a potent EHMT inhibitor, with IC₅₀s of all <100 nM for EHMT1 peptide, EHMT2 peptide and cellular EHMT2. Used in the research of blood disease or cancer.

DC-S239 is a selective histone methyltransferase SET7 inhibitor with an IC₅₀ value of 4.59 μM. DC-S239 also displays selectivity for DNMT1, DOT1L, EZH2, NSD1, SETD8 and G9a. DC-S239 has anticancer activity.

BRD9539 is a histone methyltransferase G9a inhibitor with an IC₅₀ of 6.3 μM. BRD9539 also inhibits PRC2 activity and is inactive against SUV39H1, NSD2 and DNMT1.

ZZM-1220 is a histone lysine methyltransferase G9a/GLP covalent inhibitor with IC₅₀s of of 458 nM and 924 nM, respectively. ZZM-1220 inhibits H3K9me2 in cells and significantly induces apoptosis of triple-negative breast cancer (TNBC) cells and blocks the cell cycle in the G2/M phase.

CPUY074020 is a potent and oral bioavailable inhibitor of histone methyltransferase G9a, with an IC₅₀ of 2.18 μM. CPUY074020 possesses anti-proliferative activity.

MS8511 is a selective G9a/GLP covalent irreversible inhibitor by targeting a cysteine residue at the substrate binding site, with IC₅₀ values of 100 nM (G9a) and 140 nM (GLP), and K_d values of 44 nM (G9a) and 46 nM (GLP). MS8511 reduces the cellular H3K9me2 level and enhances antiproliferation activity. MS8511 can be used for the research of several types of cancers including brain, breast, ovarian, lung, bladder, melanoma, colorectal cancer, and other disease such as Alzheimer’s disease (AD), sickle cell disease, Prader−Willi syndrome (PWS).