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Purity: ≥98%
UNC1999 (UNC-1999) is an orally bioavailable, cell-permeable, selective, SAM-competitive and dual inhibitor of EZH2/EZH1 (Enhancer of zeste homolog) with antineoplastic activity. It inhibits EZH2/EZH1 with IC50s of 2 nM and 45 nM in cell-free assays, respectively, and shows >1000-fold selectivity for EZH2/EZH1 over a variety of epigenetic and non-epigenetic targets.
| Targets |
UNC1999 is a potent, selective, and orally bioavailable dual inhibitor of histone lysine methyltransferases EZH2 (IC50 = 45 nM) and EZH1 (IC50 = 2 nM), key components of the Polycomb Repressive Complex 2 (PRC2). It shows >1000-fold selectivity over other epigenetic enzymes (e.g., G9a, SUV39H1) and kinases (e.g., CDK2, EGFR) [1]
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| ln Vitro |
UNC1999 is a novel oral bioavailable inhibitor that exhibits strong in vitro potency against both wild-type and mutant EZH2. Additionally, it exhibits great potency against EZH1, a closely related H3K27 methyltransferase that shares 96% sequence identity with EZH2 in their respective catalytic domains. Over a wide spectrum of epigenetic and non-epigenetic targets, UNC1999 exhibits great selectivity for EZH2 and EZH1. It competes with the cofactor SAM but does not bind with peptide substrates. For sigma1, sigma2, histamine H3, and NET, the Ki values of UNC1999 are 4,700 nM, 65 nM, 300 nM, and 1,500 nM, in that order. DB cells, a DLBCL cell line carrying the EZH2 Y641N mutation, are specifically eliminated by NC1999. UNC1999 inhibits DB cell growth in a concentration- and time-dependent manner (EC50=633±101 nM (n=3))[1].
Enzyme inhibition: UNC1999 potently inhibits EZH2 and EZH1 enzymatic activity in cell-free assays, reducing histone H3 lysine 27 trimethylation (H3K27me3) in a dose-dependent manner. At 1 μM, it decreases EZH2-mediated H3K27me3 by 85±5% and EZH1-mediated H3K27me3 by 90±3% [1] - Antiproliferative activity: In lymphoma cell lines (e.g., Eμ-Myc, SU-DHL-4), UNC1999 (0.1–10 μM) inhibits proliferation with IC50 values of 0.3–0.8 μM. This is associated with downregulation of EZH2/EZH1 target genes (e.g., BCL2, MYC) and induction of apoptosis (Annexin V+ cells increase from 5±2% to 35±4% at 1 μM) [1] - Cell cycle arrest: Treatment with UNC1999 (1 μM) causes G1-phase arrest in Eμ-Myc lymphoma cells, accompanied by upregulation of cyclin-dependent kinase inhibitors p21CIP1 (2.5±0.3-fold) and p16INK4a (2.0±0.2-fold, qPCR) [1] |
| ln Vivo |
In male Swiss albino mice, a single intraperitoneal (IP) injection of UNC1999 at 15, 50, or 150 mg/kg produced a high Cmax (9,700-11,800 nM) and demonstrated dosage linearity. While the 15 mg/kg IP dose caused the plasma concentrations of UNC1999 to be above their cellular IC50 for about 12 hours, the 150 and 50 mg/kg IP doses caused the plasma concentrations of UNC1999 to be above their cellular IC50 for the full 24 hours. The oral bioavailability of UNC1999 was next investigated, and we are happy to report that in male Swiss albino mice, a single oral dosage of 50 mg/kg of UNC1999 produced a high Cmax (4,700 nM) and good exposure levels. After this single oral dose, UNC1999 plasma concentrations are sustained above its cellular IC50 for about 20 hours. It is noteworthy that the test animals exhibit good tolerance to all dosages, including the 150 mg/kg IP dose, and no side effects are noted [1].
Antitumor efficacy in lymphoma xenografts: Nude mice bearing Eμ-Myc lymphoma tumors receive oral UNC1999 (25 mg/kg/day for 14 days). Tumor growth is significantly inhibited (tumor volume: 120±20 mm³ vs. 350±40 mm³ in vehicle control), with reduced H3K27me3 levels in tumor tissues (IHC) and prolonged survival (median survival: 28±3 days vs. 20±2 days) [1] - Oral bioavailability: In CD-1 mice, oral UNC1999 (25 mg/kg) achieves a peak plasma concentration (Cmax = 2.1 μM) and area under the curve (AUC0-24h = 18 μM·h), with oral bioavailability of 35% [1] |
| Enzyme Assay |
EZH2/EZH1 inhibition assay: Recombinant EZH2 or EZH1 (catalytic domains) are incubated with 10 μM histone H3 peptide (residues 1–21), 2 μM S-adenosylmethionine (SAM), and UNC1999 (0.01–10 μM) in reaction buffer (50 mM Tris-HCl pH 8.0, 5 mM MgCl₂, 0.1 mM DTT). After 60 min at 37°C, H3K27me3 levels are quantified via ELISA using HTRF technology (excitation 320 nm, emission 665 nm). IC50 values are determined by nonlinear regression [1]
- Selectivity profiling: UNC1999 (10 μM) is tested against 40+ epigenetic enzymes and kinases using radiometric or fluorescence-based assays. No significant inhibition (>5%) is observed for non-target enzymes (e.g., DNMT1, HDAC1, CDK4) [1] |
| Cell Assay |
Proliferation and apoptosis: Eμ-Myc lymphoma cells (5×10⁴ cells/well) are treated with UNC1999 (0.1–10 μM) for 72 h. Cell viability is measured via MTT assay, and apoptosis is assessed by Annexin V/PI staining and flow cytometry. Western blot analysis detects reduced H3K27me3 (0.2±0.1-fold) and cleaved caspase-3 (3.0±0.5-fold) at 1 μM [1]
- Gene expression profiling: Total RNA is extracted from UNC1999-treated SU-DHL-4 cells (1 μM, 48 h), and qPCR is performed to quantify p21CIP1, p16INK4a, and BCL2 mRNA levels. Data are normalized to GAPDH [1] |
| Animal Protocol |
Dissolved in DMSO; ~150 mg/kg (i.p.), ~50 mg/kg (oral); i.p.injection or oral administration Male Swiss albino mice
Lymphoma xenograft model: Female nude mice (6–8 weeks old) are inoculated subcutaneously with 5×10⁶ Eμ-Myc lymphoma cells. When tumors reach ~100 mm³, mice are randomized into 2 groups (n=6/group): 1. Vehicle: Oral gavage of 10% DMSO in PBS daily; 2. UNC1999: Oral gavage of 25 mg/kg UNC1999 (dissolved in 10% DMSO/PBS) daily for 14 days. Tumor volume is measured every 3 days (V = L×W²/2), and survival is monitored. At euthanasia, tumor tissues are collected for H3K27me3 IHC [1] - Pharmacokinetic study: CD-1 mice receive a single oral dose of UNC1999 (25 mg/kg). Blood samples are collected at 0.5, 1, 2, 4, 8, and 24 h, and plasma concentrations are quantified by LC-MS/MS. Oral bioavailability is calculated by comparing AUC to intravenous administration (5 mg/kg) [1] |
| ADME/Pharmacokinetics |
Oral absorption: After oral administration (25 mg/kg) to mice, the Cmax of UNC1999 was 2.1 μM and the Tmax was 2 hours. The oral bioavailability was 35% and the terminal half-life (t1/2) was 4.5 hours [1]
- Plasma protein binding: Balanced dialysis showed that UNC1999 was bound to 92% of plasma proteins in mice, mainly albumin [1] - Metabolism: In mouse liver microsomes, UNC1999 is metabolized by CYP3A4-dependent hydroxylation. The major metabolite (M1) retained weak EZH2 inhibitory activity (IC50 = 1.2 μM) [1] - Tissue distribution: Two hours after administration, the highest drug concentrations were found in the liver (3.5 times the plasma concentration) and tumors (2.0 times the plasma concentration) [1] |
| Toxicity/Toxicokinetics |
In vitro cytotoxicity: UNC1999 showed low toxicity to normal human fibroblasts (CC50 > 20 μM) and hepatocytes (CC50 > 15 μM) after 72 hours [1]
- In vivo safety: Compared with the vector control group, mice treated with UNC1999 (25 mg/kg/day for 14 consecutive days) showed no significant changes in body weight, hematological parameters, or serum ALT/AST levels [1] - Acute toxicity: No deaths were observed in mice at single oral doses up to 200 mg/kg [1] |
| References | |
| Additional Infomation |
UNC1999 is a SAM-competitive, highly potent, and selective EZH2/1 inhibitor. Mechanism of action: UNC1999 competitively binds to the SAM binding pockets of EZH2 and EZH1, blocking histone methylation and relieving inhibition of tumor suppressor genes (e.g., CDKN2A, PTEN). It can also induce synthetic lethality in EZH2-mutant tumors [1]. Preclinical potential: UNC1999 is a validated chemical probe for studying EZH1/2 function and is a candidate drug for treating hematologic malignancies and solid tumors. Its oral bioavailability and good safety profile support its further development [1]. Limitations: Metabolite M1 may cause off-target effects. Clinical trials are needed to evaluate its efficacy and safety in humans [1].
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| Molecular Formula |
C33H43N7O2
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|---|---|---|
| Molecular Weight |
569.74
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| Exact Mass |
569.347
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| CAS # |
1431612-23-5
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| Related CAS # |
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| PubChem CID |
72551585
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
804.7±65.0 °C at 760 mmHg
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| Flash Point |
440.4±34.3 °C
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| Vapour Pressure |
0.0±2.9 mmHg at 25°C
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| Index of Refraction |
1.643
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| LogP |
4.17
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
42
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| Complexity |
1030
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
DPJNKUOXBZSZAI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C33H43N7O2/c1-7-8-24-15-23(6)37-33(42)28(24)19-35-32(41)27-16-26(17-30-29(27)20-36-40(30)22(4)5)25-9-10-31(34-18-25)39-13-11-38(12-14-39)21(2)3/h9-10,15-18,20-22H,7-8,11-14,19H2,1-6H3,(H,35,41)(H,37,42)
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| Chemical Name |
1-isopropyl-6-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.25 mg/mL (3.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 22.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.25 mg/mL (3.95 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 22.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 2.25 mg/mL (3.95 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7552 mL | 8.7759 mL | 17.5519 mL | |
| 5 mM | 0.3510 mL | 1.7552 mL | 3.5104 mL | |
| 10 mM | 0.1755 mL | 0.8776 mL | 1.7552 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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