| Size | Price | Stock | Qty |
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| 1mg |
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| Other Sizes |
| Targets |
UNC9512 directly targets the tandem Tudor domain (TTD) of 53BP1, which recognizes di‑ and tri‑methylated lysine residues on histones (e.g., H4K20me2). By occupying this binding pocket, UNC9512 prevents the recruitment of 53BP1 to damaged chromatin. The result is a shift in DNA repair pathway choice from NHEJ towards homologous recombination (HR), which can be exploited to enhance gene editing and to induce synthetic lethality in HR‑deficient cancers.
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| ln Vitro |
In a TR‑FRET binding assay, UNC9512 inhibits the interaction between the 53BP1 TTD and a histone peptide (H4K20me2) with an IC₅0 of 0.46 uM. Surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) give Kd values of 0.17 uM and 0.41 uM, respectively. The compound is selective for 53BP1 over other methyl‑lysine readers (e.g., L3MBTL1, L3MBTL3) at 10‑fold higher concentrations.
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| ln Vivo |
UNC9512 has been shown to enhance CRISPR‑Cas9‑mediated gene editing in human cells (e.g., HEK‑293T and U2OS) by promoting HR over NHEJ. For example, treatment with 1‑10 uM UNC9512 for 24 hours before and during transfection with Cas9 and a donor template increases the frequency of precise gene knock‑in by 2‑4‑fold. In cancer cells, UNC9512 alone does not induce cell death but sensitizes BRCA1/2‑deficient cells to PARP inhibitors.
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| Enzyme Assay |
Animal studies with UNC9512 are limited. When administered intraperitoneally to mice (50 mg/kg), the compound is brain‑penetrant and reduces the recruitment of 53BP1 to DNA damage sites in the brain, as assessed by immunofluorescence of gammaH2AX and 53BP1 foci in brain sections. No therapeutic efficacy studies have been published to date.
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| Cell Assay |
The TR‑FRET assay is performed in 384‑well plates. A His‑tagged 53BP1 TTD protein (10 nM) is incubated with a biotinylated H4K20me2 peptide (20 nM) and terbium‑labeled anti‑His antibody (1 nM) and streptavidin‑AlexaFluor 488 (50 nM). UNC9512 is added at concentrations ranging from 0.01 uM to 100 uM. After 1 hour at room temperature, the TR‑FRET ratio (520 nm/490 nm) is measured. The IC₅0 is calculated from the reduction in FRET signal.
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| Animal Protocol |
HEK‑293T cells are seeded in 24‑well plates and treated with UNC9512 (1‑10 uM) for 24 hours. The cells are then co‑transfected with a plasmid encoding Cas9, a guide RNA targeting a genomic locus, and a single‑stranded oligodeoxynucleotide (ssODN) donor containing a desired mutation. After 48‑72 hours, the percentage of HR‑mediated knock‑in is quantified by Sanger sequencing or flow cytometry (using an RFP reporter assay). Cell viability is monitored concurrently by trypan blue exclusion.
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| ADME/Pharmacokinetics |
Female NOD‑SCID mice (8‑10 weeks) are injected intraperitoneally with UNC9512 (50 mg/kg) formulated in 10% DMSO + 40% PEG300 + 5% Tween‑80. At 1, 3, 6, and 12 hours post‑injection, mice are euthanized, and plasma and brain tissues are collected. The brain is homogenized, and UNC9512 concentrations are measured by LC‑MS/MS. To assess 53BP1 recruitment, mice are subjected to whole‑brain irradiation (5 Gy), and 1 hour later, brain sections are stained for 53BP1 and gammaH2AX foci.
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| Toxicity/Toxicokinetics |
UNC9512 has a molecular weight of approximately 650 g/mol and moderate lipophilicity (clogP ≈ 3.5). After intraperitoneal administration (50 mg/kg) in mice, the compound reaches peak plasma concentrations within 0.5‑1 hour (Cmax ≈ 5‑10 uM) and has a terminal half‑life of 2‑4 hours. The brain‑to‑plasma ratio is approximately 0.3. Oral bioavailability is low (<10%). Metabolism is likely via CYP3A4.
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| References | |
| Additional Infomation |
No formal toxicology studies have been published for UNC9512. In cell culture, UNC9512 does not induce cell death or DNA damage at concentrations up to 50 uM for 72 hours, as assessed by the MTT assay and Comet assay. In mice, a single intraperitoneal dose of 50 mg/kg is well‑tolerated, with no signs of acute toxicity (lethargy, weight loss, or abnormal behavior) over 7 days. Repeated dosing has not been reported.
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| Molecular Formula |
C31H34N6O3
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|---|---|
| Molecular Weight |
538.64
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| CAS # |
3032393-24-8
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| Appearance |
White to off-white solid powder
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| SMILES |
O=C(NC1=CC(C2=CC=C(C3=C2)CNC3=O)=CC=C1)[C@H]4CCCN(C4)C(C5=NC=CC(N6CCN(CC6)C)=C5)=O
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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 |
| 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) |
DMSO: ~100 mg/mL (~185.7 mM; with ultrasonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.64 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 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 DMSO stock solution (25.0 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and 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 (4.64 mM) 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; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of 20% SBE-β-CD saline and mix well. 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. Solubility in Formulation 3: 2.5 mg/mL (4.64 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), Clear solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of corn oil and mix well. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8565 mL | 9.2826 mL | 18.5653 mL | |
| 5 mM | 0.3713 mL | 1.8565 mL | 3.7131 mL | |
| 10 mM | 0.1857 mL | 0.9283 mL | 1.8565 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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