Histone Methyltransferase

TNG908 is a MTAP (methylthioadenosine phosphorylase)-synergistic inhibitor of PRMT5 (protein arginine methyltransferase 5). It is orally active and capable of crossing the blood–brain barrier, making it suitable for targeting both systemic and central nervous system tumors. TNG908 selectively exploits MTAP deletion—a common alteration in cancers—to enhance its antitumor efficacy, making it a promising agent for cancer research and precision oncology.

Navlimetostat is a potent, orally active, and selective inhibitor of the PRMT5-MTA complex. It exhibits IC₅₀ values of 3.6 nM for the PRMT5-MTA complex and 20.5 nM for PRMT5 alone. Navlimetostat binds to the PRMT5-MTA complex with exceptionally high affinity (K\_D = 0.14 pM). It demonstrates strong antineoplastic activity both in vitro and in vivo, making it a promising candidate for cancer research and therapeutic development targeting PRMT5-driven malignancies.

AMI-1 free acid is a potent, cell-permeable, and reversible inhibitor of protein arginine N-methyltransferases (PRMTs). It inhibits human PRMT1 and yeast Hmt1p with IC₅₀ values of 8.8 μM and 3.0 μM, respectively. AMI-1 functions by blocking the binding of peptide substrates to PRMTs, making it a useful tool for studying arginine methylation and its role in gene regulation, signal transduction, and disease.

MS023 dihydrochloride is a potent, selective, and cell-permeable inhibitor of type I protein arginine methyltransferases (PRMTs). It exhibits strong inhibitory activity with IC₅₀ values of 30 nM for PRMT1, 119 nM for PRMT3, 83 nM for PRMT4, 4 nM for PRMT6, and 5 nM for PRMT8. MS023 is a valuable tool for studying PRMT-dependent epigenetic regulation and has potential applications in cancer and other PRMT-associated diseases.

LLY-284 is the diastereomer of LLY-283 and exhibits significantly reduced activity compared to LLY-283. While LLY-283 is a potent inhibitor of protein arginine methyltransferase 5 (PRMT5) with strong anticancer potential, LLY-284 serves primarily as a less active control compound in studies evaluating PRMT5-targeted cancer therapeutics.

BRD0639 is a first-in-class inhibitor that disrupts the interaction between protein arginine methyltransferase 5 (PRMT5) and its substrate adaptor proteins. It functions as a PRMT5 binding motif (PBM)-competitive agent, selectively interfering with PBM-dependent PRMT5 activities. BRD0639 is a valuable chemical probe for studying PRMT5-mediated methylation and its role in epigenetic regulation and disease.

Tulmimetostat (CPI-0209) is an orally active, dual inhibitor of EZH1 and EZH2, key enzymatic components of the polycomb repressive complex 2 (PRC2) involved in histone methylation and gene silencing. By targeting EZH2, Tulmimetostat effectively suppresses aberrant gene repression associated with tumorigenesis. It exhibits antitumor activity and is currently being investigated in studies involving a variety of solid tumors and hematologic malignancies.

Bleximenib (JNJ-75276617) is an orally active and highly selective menin–KMT2A (MLL) interaction inhibitor, with IC50 values of 0.1 nM in humans, 0.045 nM in mice, and ≤0.066 nM in dogs. It effectively inhibits the proliferation of tumor cells and induces apoptosis and differentiation, particularly in malignancies driven by KMT2A rearrangements. Bleximenib is a promising therapeutic candidate for the study and treatment of leukemia and other menin-dependent cancers.

Bleximenib (JNJ-75276617) oxalate is an orally active and highly selective inhibitor of the menin–KMT2A (MLL) interaction, with IC50 values of 0.1 nM in humans, 0.045 nM in mice, and ≤0.066 nM in dogs. It effectively inhibits tumor cell proliferation and induces apoptosis and differentiation, particularly in cancers driven by KMT2A rearrangements. Bleximenib oxalate is a promising candidate for research in leukemia and other menin–KMT2A-dependent malignancies.

RK-701 is a highly selective and non-genotoxic inhibitor of G9a histone methyltransferase, with an IC₅₀ of 23–27 nM. It selectively upregulates fetal hemoglobin (HbF), γ-globin, and *BGLT3* expression, while downregulating H3K9me2 levels. RK-701 also exhibits inhibitory effects on the transcriptional repressors BCL11A and ZBTB7A, making it a promising candidate for the treatment of hemoglobinopathies such as sickle cell disease and β-thalassemia.

UNC8153 is a potent and selective degrader targeting nuclear receptor-binding SET domain-containing protein 2 (NSD2), with a binding affinity (Kd) of 24 nM. It induces proteasome-dependent degradation of NSD2 by incorporating a simple warhead, leading to a reduction in both NSD2 protein levels and the associated H3K36me2 chromatin mark in cells. UNC8153 is a valuable chemical tool for investigating NSD2 function and epigenetic regulation.

UNC6934 is a potent and selective chemical probe targeting the N-terminal PWWP1 domain of NSD2 (nuclear receptor-binding SET domain protein 2). It binds NSD2-PWWP1 with a Kd of 80 nM (measured by SPR) and exhibits high selectivity over 14 other PWWP domains, including NSD3-PWWP1. In U2OS cells, UNC6934 disrupts the interaction between NSD2-PWWP1 and H3K36me2-marked nucleosomes, with an IC₅₀ of 1.09 μM as determined by NanoBRET assay. It is a valuable tool for studying NSD2 chromatin interactions and epigenetic regulation.

TP-064 is a potent and selective inhibitor of protein arginine methyltransferase 4 (PRMT4/CARM1), with an IC50 of less than 10 nM. It effectively inhibits the dimethylation of BAF155 and MED12 with IC50 values of 340 nM and 43 nM, respectively. TP-064 shows minimal activity against other PRMT family members, except for PRMT6 (IC50 = 1.3 μM). It exhibits anticancer activity, making it a valuable tool for studying PRMT4-related epigenetic regulation and cancer therapy.

AM-9747 (PRMT5-IN-25) is a highly potent PRMT5 inhibitor with a Ki value of 0.06 nM. It exhibits strong antiproliferative activity, making it a valuable candidate for research in PRMT5-driven cancers and epigenetic regulation.

AS1411 (AGRO-100) is a G-rich oligonucleotide aptamer that selectively targets nucleolin, a nucleoprotein overexpressed on the surface and within the nucleus of many cancer cells. It inhibits tumor cell proliferation by disrupting nucleolin-containing complexes, thereby affecting key oncogenic processes. AS1411 has been shown to reduce PRMT5 expression and inhibit tumor growth in DU145 prostate cancer cells, and to block the interaction between nucleolin and *bcl-2* mRNA in MCF-7 breast cancer cells, leading to decreased Bcl-2 protein levels and enhanced apoptosis. Beyond its intrinsic anticancer activity, AS1411 serves as a precision-targeting carrier for the delivery of nanoparticles, oligonucleotides, and small molecules to cancer cells. AS1411-conjugated gold nanospheres have demonstrated effective inhibition of breast cancer cell proliferation in vitro and in vivo, with the added advantage of crossing the blood-brain barrier and exhibiting low tissue toxicity, making AS1411 a versatile platform for targeted cancer therapy and drug delivery.

MS8709 (compound 10) is a first-in-class PROTAC degrader targeting the histone methyltransferases G9a and GLP, with potential anticancer activity. Engineered from the G9a/GLP inhibitor UNC0642, MS8709 recruits the von Hippel–Lindau (VHL) E3 ubiquitin ligase to promote the selective ubiquitination and proteasomal degradation of G9a/GLP proteins. This targeted degradation approach offers a novel therapeutic strategy for disrupting epigenetic dysregulation in cancer.

CMP-5 is a potent and highly selective inhibitor of PRMT5, exhibiting no inhibitory activity against related enzymes PRMT1, PRMT4, or PRMT7. It specifically blocks the symmetric dimethylation of histone H4 at arginine 3 (H4R3me2s) by targeting PRMT5-mediated methyltransferase activity. CMP-5 effectively prevents Epstein-Barr virus (EBV)-induced transformation of B lymphocytes while sparing normal B cells, highlighting its potential as a selective epigenetic modulator in virus-associated malignancies.

EZM0414 is a potent, selective, and orally bioavailable inhibitor of the histone methyltransferase SETD2, exhibiting an IC₅₀ of 18 nM in biochemical assays and 34 nM in cellular assays. It is being investigated for its therapeutic potential in relapsed or refractory multiple myeloma and diffuse large B-cell lymphoma (DLBCL), making it a valuable tool for studying SETD2-mediated epigenetic regulation in hematologic malignancies.

TNG-462 is an orally active and selective inhibitor of PRMT5, designed to exploit vulnerabilities in cancers characterized by methylthioadenosine phosphorylase (MTAP) deficiency and/or elevated methylthioadenosine (MTA) levels. By targeting MTA-sensitized PRMT5 activity, TNG-462 demonstrates potent antitumor efficacy in preclinical models of MTAP-deleted cancers.

AMG 193 is an orally bioavailable, MTA-cooperative inhibitor of protein arginine methyltransferase 5 (PRMT5), exhibiting potent antitumor activity. By leveraging the accumulation of methylthioadenosine (MTA) in MTAP-deficient cells, AMG 193 selectively inhibits PRMT5 with an IC₅₀ of 0.107 μM, leading to preferential suppression of tumor cell growth while sparing normal cells with intact MTAP function.

SGC3027 is a potent, selective, and cell-permeable inhibitor of the protein arginine methyltransferase PRMT7, serving as the first validated chemical probe for this target. As a histone methyltransferase inhibitor, SGC3027 enables the functional study of PRMT7-mediated arginine methylation and its role in epigenetic regulation.

F5446 (Compound 1) is a selective small-molecule inhibitor of the histone methyltransferase SUV39H1. By reducing H3K9 trimethylation (H3K9me3) at the Fas promoter, F5446 upregulates Fas expression and enhances the sensitivity of colorectal carcinoma cells to Fas ligand (FasL)-induced apoptosis in vitro. In vivo, F5446 effectively suppresses the growth of human colorectal tumor xenografts, highlighting its potential as an epigenetic therapeutic agent in cancer treatment.

AR420626 is a selective agonist of free fatty acid receptor 3 (FFAR3, also known as GPR41), with an IC₅₀ of 117 nM. It demonstrates anti-inflammatory, antitumor, and antidiabetic activities. AR420626 improves neurogenic diarrhea by modulating neural pathways mediated by nicotinic acetylcholine receptors (nAChRs). In cancer models, it suppresses the growth of HepG2 xenografts and inhibits hepatoma cell proliferation through apoptosis induction. Additionally, AR420626 mitigates allergic asthma and eczema and enhances glucose uptake by activating FFAR3-mediated Ca²⁺ signaling, offering potential therapeutic benefits in metabolic disorders such as diabetes.

MRK-740 is a potent and selective small-molecule inhibitor of the histone methyltransferase PRDM9, acting in a substrate-competitive manner with an IC₅₀ of 80 nM. It exhibits high selectivity for PRDM9 over other histone methyltransferases and non-epigenetic targets. MRK-740 effectively inhibits PRDM9-mediated trimethylation of histone H3 at lysine 4 (H3K4me3), with an IC₅₀ of 0.8 µM in cellular assays.

MS181 (Compound 1) is a potent PROTAC degrader that targets components of the polycomb repressive complex 1 (PRC1) by recruiting cereblon (CRBN) and binding EED. It effectively reduces the expression of key PRC1 and PRC2 components, including EED, EZH2, SUZ12, BMI1, and RING1B. MS181 exhibits significant antiproliferative activity, making it a valuable tool for studying epigenetic regulation and potential cancer therapeutics.

MS9715 is a potent and selective PROTAC degrader targeting NSD3, designed by conjugating the NSD3 PWWP1 domain binder BI-9321 to a von Hippel-Lindau (VHL) E3 ligase ligand. It effectively induces degradation of NSD3 and holds significant potential for research in NSD3-dependent cancers, offering a novel approach to target epigenetic drivers in oncology.

PROTAC EZH2 Degrader-2 (Compound E-3P-MDM2) is a PROTAC molecule designed by linking the EZH2 inhibitor Tazemetostat (EPZ6438) to an E3 ligase ligand. It induces dose-dependent degradation of EZH2 in SU-DHL-6 cells, suppresses H3K27me3 expression, and concurrently degrades PRC2 components EED and SUZ12 without altering their mRNA levels. PROTAC EZH2 Degrader-2 exhibits strong anti-cancer and anti-proliferative activity, making it a valuable tool for epigenetic and oncology research.

LLC0424 is a potent and selective cereblon-based PROTAC that targets NSD2 for degradation. It induces NSD2 degradation in a cereblon- and proteasome-dependent manner, with a DC₅₀ of 20 nM in RPMI-8402 cells.

UNC6852 is a selective PROTAC degrader of the polycomb repressive complex 2 (PRC2), incorporating ligands for EED (embryonic ectoderm development) and von Hippel-Lindau (VHL). It targets EED with an IC₅₀ of 247 nM, enabling PRC2 degradation and serving as a valuable tool for epigenetic and cancer research.

PROTAC EZH2 Degrader-1 (Compound 150d) is a potent PROTAC molecule targeting EZH2, with an IC₅₀ of 2.7 nM for inhibition of its methyltransferase activity. By degrading EZH2, it provides a valuable tool for studying its role in tumorigenesis and cancer progression.

MS177 is a fast-acting and effective PROTAC degrader targeting EZH2. It comprises a cereblon (CRBN) ligand, a linker, and the potent EZH2 enzymatic inhibitor C24 (IC₅₀: 12 nM). MS177 efficiently depletes both canonical EZH2–PRC2 and noncanonical EZH2–cMyc complexes, leading to inhibition of leukemia cell proliferation, induction of apoptosis, and cell cycle arrest. It is a valuable tool for epigenetic and cancer research.

MS1943 is an orally active, PROTAC-based selective degrader of EZH2 that effectively reduces cellular EZH2 levels. It exhibits strong anticancer activity, showing cytotoxic effects in various triple-negative breast cancer (TNBC) cell lines while sparing normal cells. MS1943 maintains high potency in inhibiting EZH2 methyltransferase activity (IC₅₀ = 120 nM) and demonstrates high selectivity for EZH2, making it a promising candidate for epigenetic and cancer research.

EPZ015666 is a potent inhibitor of the protein arginine methyltransferase 5 (PRMT5), exhibiting an IC50 of 22 nM. This compound is utilized in research focused on epigenetic regulation and has potential applications in the study of cancer and other diseases associated with aberrant PRMT5 activity. Its selective mode of action makes it a valuable tool for understanding the role of arginine methylation in various biological processes.

LSD1/HDAC-IN-1 is a potent inhibitor of histone deacetylases (HDACs) and lysine-specific demethylase 1 (LSD1), demonstrating impressive inhibitory activity with IC50 values of 0.125 nM for HDAC1, 0.373 nM for HDAC2, 0.0118 nM for HDAC6, 0.103 nM for HDAC8, and 0.571 μM for LSD1. This compound is significant in cancer research, as it influences gene expression and histone modification, making it a valuable tool for studies addressing epigenetic regulation and potential therapeutic interventions.

LSD1/HDAC6-IN-1 is a dual inhibitor targeting lysine-specific demethylase 1 (LSD1) and histone deacetylase 6 (HDAC6), demonstrating significant anti-tumor activity. This compound is particularly relevant for research into multiple myeloma (MM), providing insights into epigenetic regulation and potential therapeutic strategies. Its oral bioavailability makes it suitable for in vivo studies in cancer research.

PROTAC EZH2 Degrader-44 is a selective degrader targeting the EZH2-PRC2 complex through the recruitment of the CRBN E3 ligase, facilitating proteasome-mediated degradation of EZH2, SUZ12, and EED. This process leads to a marked reduction in H3K27me3 and CARM1 levels, resulting in potent antiproliferative effects. It induces mitochondrial dysfunction and promotes apoptosis by modulating Bcl-2 family proteins, demonstrating minimal cytotoxicity in normal human mammary epithelial, liver, and kidney cells. PROTAC EZH2 Degrader-44 serves as an effective research tool for investigating targeted therapies in triple-negative breast cancer.

LSD1/HDAC6-IN-2 is a potent inhibitor targeting LSD1, HDAC6, and MAO-A, with IC50 values of 5 nM, 11 nM, and 5 nM, respectively. It demonstrates significant inhibitory effects on the growth of multiple myeloma cell lines, including MM.1S, MM.1R, and RPMI-8226. This compound is suitable for research applications focused on acute myeloid leukemia and lymphoma, providing insights into potential therapeutic mechanisms.

CMP-5 dihydrochloride is a specific and selective inhibitor of PRMT5, effectively blocking its methyltransferase activity without affecting PRMT1, PRMT4, or PRMT7. This compound inhibits the methylation of S2Me-H4R3 on histones, making it a valuable tool for studying PRMT5's role in cellular processes. Additionally, CMP-5 dihydrochloride has been shown to prevent EBV-driven transformation of B-lymphocytes while sparing normal B cells, highlighting its potential applications in cancer research and therapeutic development.

CPI-905 is a potent and selective inhibitor of Enhancer of Zeste Homolog 2 (EZH2), a key enzyme involved in histone methylation and gene silencing. This compound effectively disrupts the methyltransferase activity of EZH2, leading to reactivation of tumor suppressor genes. CPI-905 is primarily utilized in cancer research, particularly in studies focusing on malignancies driven by EZH2 mutations or overexpression.

GSK926 is a selective inhibitor of the histone lysine methyltransferase EZH2, exhibiting an IC50 of 0.02 μM and a Ki of 7.9 nM. This compound demonstrates SAM-competitive behavior and is active in cellular systems. GSK926 serves as a valuable tool in cancer research, particularly in studies targeting epigenetic regulation and the oncogenic functions of EZH2.

GSK591 hydrochloride is a potent and selective inhibitor of protein methyltransferase 5 (PRMT5), exhibiting an IC50 of 4 nM. This compound is primarily utilized in research related to epigenetic regulation, particularly in the context of cancer biology. Its ability to modulate methylation processes makes it a valuable tool for studying the role of PRMT5 in various cellular functions and disease mechanisms.

DCE_42 is a potent inhibitor of Enhancer of Zeste Homolog 2 (EZH2) with an IC50 value of 22.6 µM. This compound effectively inhibits cell proliferation, making it a valuable tool for investigating EZH2-related pathways in lymphoma research. Its specificity for EZH2 presents opportunities for studying the role of epigenetic regulation in cancer biology.

Fagaronine chloride is an alkaloid that acts as an inhibitor of histone methyltransferases. It possesses significant anti-tumor activity and has been shown to inhibit the reverse transcriptase of RSii tumor virus within a concentration range of 6-60 μg/mL. By interacting with the template primer, Fagaronine chloride disrupts DNA synthesis, making it a valuable tool for research into retroviral infections and cancer biology.

PRMT1-IN-2 is a selective inhibitor of protein arginine methyltransferase 1 (PRMT1), exhibiting an IC50 of 55.4 μM. This compound induces histone hypomethylation in HepG2 cells, highlighting its potential role in epigenetic regulation. PRMT1-IN-2 is suitable for investigating the biological functions of PRMT1 and its implications in various cellular processes and diseases.

MS453 is a potent and selective inhibitor of the histone methyltransferase SETD8, exhibiting an IC50 of 804 nM. It preferentially targets a cysteine residue adjacent to the binding site, demonstrating specificity over 28 other methyltransferases. The crystal structure elucidates the binding mode of MS453 to SETD8, offering valuable insights for the design of advanced chemical probes aimed at this important target in epigenetic regulation.

(1-Nitroethene-1,2-diyl)dibenzene is a potent inhibitor of protein arginine methyltransferase 1 (PRMT1), exhibiting an IC50 of 11 μM in histone H4 methylation assays. This compound also effectively inhibits histone H4 methylation by PRMT8 at concentrations of 10 and 100 μM, while showing no effect on histone H3.1 methylation mediated by CARM1 or Set7/9. Its specificity and potency make it a valuable tool for studying histone methylation processes and their implications in epigenetics and gene regulation.

EPZ030456 is a potent and selective inhibitor of SMYD3, exhibiting an IC50 of 48 nM. This compound is primarily utilized in cancer research due to its role in targeting histone methylation processes associated with tumorigenesis. Its specificity for SMYD3 makes it a valuable tool for elucidating the mechanisms underlying cancer progression and for potential therapeutic applications.

MC3629 is a selective inhibitor of the histone methyltransferase EZH2, demonstrating significant anti-tumor activity. It effectively inhibits the proliferation and self-renewal of SHH MB cancer cells while also inducing apoptosis. MC3629 serves as a valuable tool for investigating drug resistance mechanisms and the aggressiveness of tumors in cancer research.

4-Methoxycinnamyl alcohol targets histone methyltransferases and exhibits significant anticancer properties. It demonstrates cytotoxic activity against MCF-7, HeLa, and DU145 cancer cell lines, with IC50 values of 14.24, 7.82, and 22.10 μg/mL, respectively. Notably, 4-Methoxycinnamyl alcohol induces cell necrosis rather than apoptosis, as evidenced by a 48-hour DNA fragmentation assay. This compound is derived from Foeniculum vulgare, highlighting its potential relevance in cancer research applications.

(R)-BAY-598 is a potent inhibitor of the protein-lysine methyltransferase SMYD2, exhibiting an IC50 value of 1.7 μM. This compound selectively interferes with SMYD2 activity, making it a valuable tool for studying the role of lysine methylation in various biological processes. It is applicable in research focused on cancer biology and epigenetic regulation, facilitating the understanding of disease mechanisms and the development of potential therapeutic strategies.