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| 1mg |
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| Targets |
MSC778 targets the DNA repair protein flap endonuclease 1 (FEN1) as a potent and selective inhibitor [29L2-L4]. FEN1 is a structure-specific nuclease essential for processing Okazaki fragments during DNA replication and for base excision repair (BER). By inhibiting FEN1 with high potency (IC50 = 3 nM, KD = 2.9 nM) and selectivity over other nucleases, MSC778 creates DNA damage that is particularly lethal to cells deficient in homologous recombination repair (HRR), such as those with BRCA2 mutations. This synthetic lethality is the basis of its mechanism [29L6-L7].
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| ln Vitro |
MSC778 (7 days) selectively killed BRCA2 knockout DLD-1 cells with an EC50 value of 210 nM (apparent value) and a protein-bound corrected free EC50 (EC50,ub) of 11 nM[1].
In vitro, MSC778 selectively kills BRCA2 knockout DLD-1 cells [30L41-L42]. Its apparent EC50 is 210 nM, and after protein binding correction (free EC50, EC50,ub), it is 11 nM [30L43-L44]. In contrast, BRCA2 wild-type cells are significantly less sensitive. This demonstrates the principle of synthetic lethality. The compound also sensitizes cancer cells to the PARP inhibitor Niraparib. In vitro assays typically involve treating isogenic cell lines with or without BRCA2 mutation with MSC778 for 7 days, followed by a cell viability assay (e.g., CellTiter-Glo). EC50 values are determined using a dose-response curve. |
| ln Vivo |
MSC778 (100 mg/kg, administered by gavage twice daily for 28 days) enhanced the tumor-inducing activity of Niraparib in a mouse xenograft model of colorectal cancer [1].
In vivo, MSC778 (100 mg/kg, oral, twice daily for 28 days) enhances the tumor-stalling activity of Niraparib in a BRCA2 KO DLD-1 mouse xenograft model [29L20-L21]. In this colon cancer model, the combination of MSC778 and Niraparib induces greater tumor growth inhibition (tumor stasis) compared to either agent alone. The compound is orally active, and at this dose, it is well-tolerated. No monotherapy activity of MSC778 was described, but its primary role is to potentiate the effect of PARP inhibitors in BRCA2-deficient tumors. |
| Enzyme Assay |
For non-cellular enzymatic assays, a fluorescence-based FEN1 activity assay is used. Purified recombinant human FEN1 protein is incubated with a synthetic, dual-labeled DNA substrate containing a 5' flap in assay buffer (e.g., 50 mM Tris-HCl pH 8.0, 10 mM MgCl2, 1 mM DTT) in 96-well plates. MSC778 is added at varying concentrations (0.001-1000 nM). The reaction is initiated by adding the DNA substrate. After incubation at 37degC for 30 minutes, the reaction is stopped, and fluorescence is measured (excitation at 485 nm, emission at 535 nm). The IC50 of 3 nM is calculated from the inhibition curve. Controls include a non-inhibitor control.
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| Cell Assay |
For in vitro cell assays, isogenic human colon cancer cell lines, such as DLD-1 wild-type and DLD-1 BRCA2 knockout (KO), are used. Cells are seeded in 96-well plates at 2,000-5,000 cells/well. After 24 hours, they are treated with a range of MSC778 concentrations (e.g., 0.1-10,000 nM) for 7 days. Cell viability is measured using the CellTiter-Glo luminescent assay. The EC50 is calculated for each cell line. The selective killing of BRCA2 KO cells (EC50,ub = 11 nM) over wild-type cells is the key endpoint. DMSO is used as a vehicle control. For combination studies, a fixed ratio of MSC778 and Niraparib is tested.
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| Animal Protocol |
Animal/Disease Models: BRCA2 KO DLD-1 cells xenograft model established in Balb/c nude, female mice[1]
Doses: 100 mg/kg with or without Niraparib Route of Administration: Oral gavage (i.g.), twice daily for 28 days Experimental Results: Observed no tumor growth inhibition (TGI) with the single-agent treatment. Achieved 93% TGI in the combined treatment group, resulting in tumor stasis. No weight loss or clinical signs of toxicity. For in vivo animal studies, female BALB/c nude mice (6-8 weeks) bearing subcutaneous BRCA2 KO DLD-1 xenografts (tumor volume ~150 mm3) are used [29L20-L21]. MSC778 is formulated in a vehicle like 10% DMSO + 40% PEG300 + 5% Tween 80 + 45% Saline. The compound is administered orally by gavage at a dose of 100 mg/kg, twice daily for 28 days. The control group receives vehicle alone. A third group receives Niraparib alone. Tumor volumes are measured with calipers twice weekly. Body weight is monitored as a toxicity indicator. The endpoint is tumor growth inhibition (TGI) and tumor stasis, which is assessed by comparing tumor volume in the combination group to the control and single-agent groups. |
| ADME/Pharmacokinetics |
MSC778 is an orally active small molecule (MW 441.87) [29L22]. The PK profile supports twice-daily (BID) oral dosing at 100 mg/kg in mice [29L20-L21]. No detailed PK parameters (e.g., Cmax, Tmax, t½, AUC) were provided. The fact that it is orally active suggests adequate absorption and bioavailability. The high in vitro free EC50 (11 nM) and the high in vivo dose (100 mg/kg) suggest that protein binding is extensive and/or the compound has a moderate clearance rate requiring high dosing to achieve effective free plasma concentrations. For research use only.
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| Toxicity/Toxicokinetics |
No formal toxicology data for MSC778 is reported, but it is well-tolerated in the in vivo xenograft study at 100 mg/kg BID for 28 days [29L20-L21]. No significant body weight loss or other gross signs of toxicity were mentioned. Standard laboratory safety precautions should be followed. Avoid inhalation, ingestion, and skin/eye contact. Use PPE (gloves, lab coat, safety goggles) in a well-ventilated area (fume hood). For research use only-not for human use. Dispose of chemical waste according to local regulations.
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| References | |
| Additional Infomation |
MSC778 is a selective FEN1 inhibitor. CAS: 3098173-17-9. Molecular formula: C22H20ClN3O5, MW 441.87 [29L22]. IC50 = 3 nM (FEN1), KD = 2.9 nM. It is >500-fold selective over EXO1 and GEN1 [29L4]. It selectively kills BRCA2-deficient cells (free EC50 = 11 nM) and synergizes with the PARP inhibitor Niraparib in vivo. The compound is for research use in colorectal cancer [29L8]. Storage: powder at -20degC for 3 years; in solution at -80degC for 1 year.
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| Molecular Formula |
C22H20CLN3O5
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| Molecular Weight |
441.86
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| CAS # |
3098173-17-9
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| Appearance |
Typically exists as solids at room temperature
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2632 mL | 11.3158 mL | 22.6316 mL | |
| 5 mM | 0.4526 mL | 2.2632 mL | 4.5263 mL | |
| 10 mM | 0.2263 mL | 1.1316 mL | 2.2632 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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