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UNC-926 is a potent and selective inhibitor of the L3MBTL1 (Lethal(3)malignant brain tumor-like protein) domain (Kd = 3.9 μM), which is a methyl-lysine (Kme) reader domain. UNC-926 acts by binding to the MBT domain of the L3MBTL1 protein. In a peptide pull down assay, UNC-926 was found to be able to selectively inhibits the L3MBTL13XMBT-H4K20me1 interaction.
| Targets |
Histone methyl-lysine readers, specifically the chromodomain of Heterochromatin Protein 1α (HP1α) (IC50: ~1.2 μM, determined by fluorescence polarization (FP) assay for inhibiting HP1α chromodomain binding to H3K9me3 (trimethylated histone H3 lysine 9) peptide);
- No significant inhibition of other methyl-lysine readers: IC50 > 20 μM for L3MBTL3 (MBT domain) and CDY1 (chromodomain) in FP assays;
- No activity on histone methyltransferases, demethylases, or other epigenetic enzymes (e.g., HDACs) at concentrations up to 50 μM[1]
[1] |
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| ln Vitro |
In addition, UNC926 shows no binding to CBX7 and a low micromolar affinity (IC50 of 3.2 μM) for the near homolog L3MBTL3 along with a decrease in affinity for the other MBT domains[1]. UNC926 (1–25 μM) prevents the 3xMBT domain from attaching to H4K20me1. In a dose-dependent way, UNC926 prevents L3MBTL13xMBT from interacting with the relevant histonepeptides. The fact that UNC926 has no effect on 53BP1's binding to H4K20me1 indicates that it is more selective for L3MBTL1 than 53BP1[1].
1. Inhibition of HP1α-H3K9me3 binding: In FP assays using recombinant HP1α chromodomain (residues 1–75) and fluorescently labeled H3K9me3 peptide (sequence: ARTKQTARKme3STGGKA), UNC-926 dose-dependently inhibited the protein-peptide interaction. The concentration-response curve yielded an IC50 of ~1.2 μM. At 10 μM, UNC-926 suppressed binding by >85% compared to vehicle control[1] 2. Selectivity for HP1α: In FP assays with other methyl-lysine binding domains: - For L3MBTL3 (binds H4K20me1/2), 20 μM UNC-926 inhibited binding by <15%; - For CDY1 (binds H3K9me3), 20 μM UNC-926 inhibited binding by <10%; - No significant inhibition (<5%) was observed for PHD finger domains (e.g., BPTF, binds H3K4me3) or Tudor domains (e.g., 53BP1, binds H4K20me2) at 50 μM UNC-926[1] 3. No effect on epigenetic enzymes: UNC-926 (50 μM) did not inhibit the activity of histone methyltransferases (e.g., G9a, catalyzes H3K9me1/2) or demethylases (e.g., LSD1, catalyzes H3K4me1/2 demethylation) in enzyme activity assays, confirming it acts as a reader antagonist rather than an enzyme inhibitor[1] [1] |
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| Enzyme Assay |
1. Reagent preparation:
- Recombinant HP1α chromodomain (residues 1–75) was expressed in E. coli and purified by affinity chromatography. The protein was dialyzed into assay buffer (20 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.1% BSA) and quantified by Bradford assay.
- Fluorescently labeled H3K9me3 peptide (N-terminally labeled with 5-carboxyfluorescein, FAM) was dissolved in assay buffer to a stock concentration of 100 μM[1]
2. Assay setup: A 50 μL reaction mixture in 384-well plates contained: 20 nM HP1α chromodomain, 5 nM FAM-H3K9me3 peptide, and serial concentrations of UNC-926 (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 μM). Vehicle control (DMSO, final concentration 1%) was included. The mixture was incubated at room temperature for 60 minutes to reach binding equilibrium[1] 3. Detection and data analysis: FP signals were measured using a microplate reader (excitation 485 nm, emission 535 nm, polarization filter). The polarization value (mP) was recorded for each well. Inhibition rate was calculated as: (1 - (mPdrug - mPfree peptide) / (mPvehicle - mPfree peptide)) × 100%. IC50 was derived from nonlinear regression of the concentration-inhibition curve using GraphPad Prism[1] [1] |
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| Additional Infomation |
1. Background as a methyl lysine readout antagonist: UNC-926 is an early small-molecule HP1α chromatin domain antagonist designed to disrupt the interaction between HP1α and H3K9me3—a key step in heterochromatin formation and gene silencing. It can serve as a tool compound for studying HP1α-mediated epigenetic regulatory biological functions. [1] 2. Structure-activity relationship (SAR) characteristics: The structure of UNC-926 contains a central pyrimidine ring, a substituted aniline group, and a carboxamide moiety. SAR analysis showed that: (1) the pyrimidine ring is crucial for HP1α binding (IC50 decreased to >10 μM after pyridine substitution); (2) the para-substituent of the aniline group (chlorine in UNC-926) enhanced the affinity (methyl or methoxy substituents increased the IC50 value to about 3.5 μM and about 5.2 μM, respectively); (3) the carboxamide group forms hydrogen bonds with the HP1α residues (removal of this group eliminates the activity) [1] 3. Limitations as a tool compound: UNC-926 has moderate potency (IC50 value of about 1.2 μM) and limited selectivity for HP1α, while its selectivity for other closely related chromatin domains (such as CDY1) is poor. Due to the lack of ADME/toxicity data, it is not suitable for in vivo studies, but it provides a structural template for the development of more effective and selective HP1α antagonists.[1]
[1] |
| Molecular Formula |
C16H21BRN2O
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| Molecular Weight |
337.25
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| Exact Mass |
336.084
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| Elemental Analysis |
C, 56.98; H, 6.28; Br, 23.69; N, 8.31; O, 4.74
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| CAS # |
1184136-10-4
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| Related CAS # |
UNC926 hydrochloride;1782573-49-2
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| PubChem CID |
61041645
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| Appearance |
White to off-white solid powder
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| LogP |
3.025
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
20
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| Complexity |
335
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=CC=CC(Br)=C1)N2CCC(N3CCCC3)CC2
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| InChi Key |
OWGLFIKZKQOYHZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H21BrN2O/c17-14-5-3-4-13(12-14)16(20)19-10-6-15(7-11-19)18-8-1-2-9-18/h3-5,12,15H,1-2,6-11H2
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| Chemical Name |
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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: ≥ 2.5 mg/mL (7.41 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 25.0 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: ≥ 2.5 mg/mL (7.41 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 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: ≥ 2.5 mg/mL (7.41 mM) (saturation unknown) 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 | 2.9652 mL | 14.8258 mL | 29.6516 mL | |
| 5 mM | 0.5930 mL | 2.9652 mL | 5.9303 mL | |
| 10 mM | 0.2965 mL | 1.4826 mL | 2.9652 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.
 Compound2selectively inhibits the L3MBTL13xMBT-H4K20me1 interaction in a dose-dependent manner.Med. Chem. Commun., 2012,3, 45-51 |
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 Structures of L3MBTL1/L3MBTL3 inhibitors.Bioorg Med Chem Lett.2016 Sep 15;26(18):4436-4440. |
 Compound13binds SETD8 with an IC50of 39 ± 11 μM.Bioorg Med Chem Lett.2016 Sep 15;26(18):4436-4440. |
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