Histone Methyltransferase Inhibitor

Tazemetostat (EPZ-6438) is a potent, selective and orally available EZH2 inhibitor. Tazemetostat inhibits the activity of human polycomb repressive complex 2 (PRC2)-containing wild-type EZH2 with a K_i value of 2.5 nM. Tazemetostat inhibits EZH2 with IC₅₀s of 11 and 16 nM in peptide assay and nucleosome assay, respectively. Tazemetostat inhibits rat EZH2 with an IC₅₀ of 4 nM. Tazemetostat also inhibits EZH1 with an IC₅₀ of 392 nM. Tazemetostat induces apoptosis and differentiation specifically in SMARCB1-deleted MRT cells.

GSK126 (GSK2816126A) is a potent, highly selective inhibitor of EZH2 methyltransferase with an IC₅₀ of 9.9 nM.

Pinometostat (EPZ-5676) is a potent DOT1L histone methyltransferase inhibitor with a K_i of 80 pM.

GSK3326595 is a protein arginine methyltransferase 5 (PRMT5) inhibitor. GSK3326595 decreases SARS-CoV-2 infection, inhibits cancer cell proliferation and induces pro-inflammatory macrophage polarization and increases hepatic triglyceride levels without affecting atherosclerosis. GSK3326595 can be used for research of relapsed/refractory mantle cell lymphoma.

Navlimetostat is a potent, orally active, selective PRMT5-MTA complex inhibitor, with IC₅₀ of 3.6 and 20.5 nM for PRMT5-MTA and PRMT5. Navlimetostat binds to the PRMT5-MTA complex, with KD value of 0.14 pM. Navlimetostat shows antineoplastic activity in vitro and in vivo, and can be used for cancer study.

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.

WX2-43 is a PRMT5-KLF4 inhibitor (K_d of 11.0 nM). WX2-43 binds to the region between amino acids L400-M500 on PRMT5. WX2-43 efficiently intercepts the interaction between KLF4 and PRMT5, and blocks KLF4 methylation. WX2-43 decreases p21 levels and increases Bax levels. WX2-43 suppresses triple negative breast tumor progression. WX2-43 can be used in the research of triple-negative breast cancer and colorectal cancer.

GSK343, a chemical probe, is a highly potent and selective EZH2 inhibitor with an IC₅₀ of 4 nM.

EZM0414 (SETD2-IN-1) TFA is the TFA salt form of EZM0414 (HY-144858). EZM0414 TFA is a potent, selective, orally active inhibitor of SETD2 (IC₅₀=18 nM in SETD2 biochemical assay; IC₅₀=34 nM in cellular assay). EZM0414 TFA can be used for the research of relapsed or refractory multiple myeloma and diffuse large B-cell lymphoma.

3-Deazaneplanocin A (DZNep) is a potent histone methyltransferase EZH2 inhibitor. 3-Deazaneplanocin A is a potent S-adenosylhomocysteine hydrolase (AHCY) inhibitor. 3-Deazaneplanocin A shows anti-orthopoxvirus activity.

Valemetostat (DS-3201), a first-in-class EZH1/2 dual inhibitor with IC₅₀ values ＜10 nM. Valemetostat can be used for the research of relapsed/refractory peripheral T-cell lymphoma.

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.

AMG 193 is an orally active MTA-cooperative PRMT5 inhibitor with antitumor activity. AMG 193, when complexed with MTA, preferentially inhibits the growth of MTAP-deficient tumor cells by inhibiting PRMT5 (IC₅₀=0.107 μM), thereby protecting normal cells with wild-type MTAP.

Chaetocin is a specific inhibitor of the histone methyltransferase (HMT) SU(VAR)3-9 with an IC₅₀ of 0.6 μM for SU(VAR)3-9. It also inhibits thioredoxin reductase (TrxR) with an IC₅₀ of 4 μM.

3-Deazaneplanocin A hydrochloride (DZNep hydrochloride) is a potent histone methyltransferase EZH2 inhibitor. 3-Deazaneplanocin A hydrochlorideis a potent S-adenosylhomocysteine hydrolase (AHCY) inhibitor. 3-Deazaneplanocin A hydrochloride also has anti-orthopoxvirus and anti-variola activities.

EED226 is a polycomb repressive complex 2 (PRC2) inhibitor, which binds to the K27me3-pocket on embryonic ectoderm development (EED) and shows strong antitumor activity in xenograft mice model. EED226 is a potent, selective, and orally bioavailable EED inhibitor. EED226 inhibits PRC2 with an IC₅₀ of 23.4 nM when the H3K27me0 peptide is used as a substrate in the in vitro enzymatic assays.

MS023, a chemical probe, is a potent, selective, and cell-active inhibitor of human type I protein arginine methyltransferases (PRMTs) inhibitor, with IC₅₀s of 30, 119, 83, 4 and 5 nM for PRMT1, PRMT3, PRMT4, PRMT6, and PRMT8, respectively.

EPZ004777 is an effective and selective DOT1L inhibitor, with IC₅₀ being 0.4 nM. EPZ004777 reduces the levels of H3K79me2 and H3K79me1, significantly down-regulating the expression of HOXA9 and MEIS1. EPZ004777 selectively inhibits the proliferation of MLL rearrangement cells and promotes the differentiation and subsequent apoptosis (apoptosis) of leukemia cells. EPZ004777 can be used for the study of leukemia.

UNC1999, a chemical probe, is a SAM-competitive, potent and selective inhibitor of EZH2/1 with IC₅₀s of <10 nM and 45 nM, repectively.