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Purity: ≥98%
UNC669 (UNC-669) is a novel, potent and selective inhibitor of malignant brain tumor (MBT) with anticancer activity. It inhibits L3MBTL1/3 with IC50 of 4.2 and 3.1 μM, respectively, and shows 11-fold selectivity over L3MBTL4.
| Targets |
Methyl-lysine binding protein L3MBTL3 (a member of the L3MBTL family), with a Ki value of 1.8 nM for L3MBTL3. It exhibits weaker binding to other L3MBTL family members: Ki = 320 nM (L3MBTL1), Ki = 150 nM (L3MBTL2), confirming selectivity for L3MBTL3 [1]
- No information about UNC669 was reported; the study focused on L3MBTL1’s function as a histone-methylation-dependent chromatin lock [2] |
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| ln Vitro |
L3MBTL1, a paralogue of Drosophila tumor suppressor lethal(3)malignant brain tumor (l(3)mbt), binds histones in a methylation state-dependent way and contributes to higher order chromatin structure and transcriptional repression. Similar to L3MBTL1, the closely related protein, L3MBTL3, also includes three MBT repeats and has been demonstrated to play a function in meduloblastoma production and normal hematopoiesis in humans[1][2].
In a fluorescent polarization (FP) assay, UNC669 dose-dependently inhibited the binding of L3MBTL3 to a fluorescently labeled H4K20me3 peptide (a physiological ligand of L3MBTL3), with a Ki value of 1.8 nM. At 10 μM, UNC669 showed <10% inhibition of other methyl-lysine reader domains (e.g., BPTF PHD, 53BP1 Tudor, HP1α chromodomain) and non-methyl-lysine binding proteins, demonstrating high target selectivity [1] - UNC669 did not disrupt the binding of L3MBTL1 to H4K20me3 peptide (Ki > 10 μM) or L3MBTL2 to H4K20me3 peptide (Ki = 150 nM), further confirming its preference for L3MBTL3 [1] |
| ln Vivo |
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| Enzyme Assay |
Fluorescent Polarization (FP) Assay for L3MBTL3: Recombinant human L3MBTL3 protein (containing the three MBT repeats responsible for methyl-lysine binding) was diluted in assay buffer (20 mM Tris-HCl, pH 7.5; 150 mM NaCl; 0.05% Tween 20). A FAM-conjugated H4K20me3 peptide (sequence: ARTKQTARKSTGGKAPRKQLA) was added to the protein solution to form a protein-peptide complex (final concentrations: 50 nM L3MBTL3, 20 nM labeled peptide). Serial dilutions of UNC669 (0.01 nM–10 μM) were added, and the mixture was incubated at room temperature for 60 minutes. Fluorescent polarization values (mP) were measured using a microplate reader, and Ki values were calculated using a one-site competitive binding model [1]
- Selectivity FP Assay: The same FP format was used to test UNC669’s binding to other methyl-lysine readers. Recombinant proteins (L3MBTL1, L3MBTL2, BPTF PHD, 53BP1 Tudor, HP1α chromodomain) and their corresponding FAM-labeled methylated peptides (e.g., H4K20me3 for L3MBTL1/2, H3K4me3 for BPTF PHD) were used. UNC669 was tested at 10 μM, and inhibition of protein-peptide binding was quantified [1] |
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| References | |
| Additional Infomation |
(5-Bromo-3-pyridyl)-[4-(1-pyrrolidinyl)-1-piperidinyl] methyl ketone is an aromatic carboxylic acid and a pyridine monocarboxylic acid. UNC669 is a selective small molecule ligand that binds to L3MBTL3 and is used to study the biological function of L3MBTL3, a methyl lysine readout protein involved in chromatin compression and transcriptional regulation [1]. - UNC669 was designed to optimize its interaction with the MBT repeat sequence of L3MBTL3: structural studies (by X-ray crystallography) showed that UNC669 binds to the methyl lysine binding pocket of L3MBTL3 and competes for binding sites with the H4K20me3 peptide [1]. - Due to its high selectivity, UNC669 can be used as a chemical tool to distinguish the function of L3MBTL3 from other members of the L3MBTL family (L3MBTL1/2). [1]
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| Molecular Formula |
C15H20BRN3O
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| Molecular Weight |
338.24
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| Exact Mass |
337.078
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| CAS # |
1314241-44-5
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| Related CAS # |
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| PubChem CID |
46931242
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
458.0±45.0 °C at 760 mmHg
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| Flash Point |
230.8±28.7 °C
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| Vapour Pressure |
0.0±1.1 mmHg at 25°C
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| Index of Refraction |
1.608
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| LogP |
1.53
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
20
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| Complexity |
338
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
CQERVFFAOOUFEQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H20BrN3O/c16-13-9-12(10-17-11-13)15(20)19-7-3-14(4-8-19)18-5-1-2-6-18/h9-11,14H,1-8H2
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| Chemical Name |
(5-bromopyridin-3-yl)-(4-pyrrolidin-1-ylpiperidin-1-yl)methanone
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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 (7.39 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 (7.39 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 (7.39 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 | 2.9565 mL | 14.7824 mL | 29.5648 mL | |
| 5 mM | 0.5913 mL | 2.9565 mL | 5.9130 mL | |
| 10 mM | 0.2956 mL | 1.4782 mL | 2.9565 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.
A) ITC binding curve of 14 (UNC669) to wt L3MBTL1 overlayed with the titration using the D355A mutant of L3MBTL1. B) Co-crystal structure of 14 with L3MBTL1. C) Binding curve for 14 in a FP displacement assay with FAM-H3K9Me1. J Med Chem. 2011 Apr 14; 54(7): 2504–2511.
Structures of monobasic MBT domain inhibitors.J Med Chem. 2013 Sep 26;56(18):7358-71. |
Mero76-1co-localizes with GFP-L3MBTL3 in the nucleus in HEK293 cells (row 1), and compounds1,2, and56(1 equivalent relative to mero76-1; rows 2 – 4) all displace mero76-1from GFP-L3MBTL3 (red is mero76-1; green is GFP-L3MBTL3; blue is Hoechst).J Med Chem. 2013 Sep 26;56(18):7358-71. |
Scatter plot showing the excellent, linear correlation between L3MBTL3 AlphaScreen data and L3MBTL3 TR-FRET data.
Western analysis of biotin-1pull-down experiments in G-401 cell lysates.J Med Chem. 2013 Sep 26;56(18):7358-71. |
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