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Mefuparib (CVL-218) HCl is a novel and potent PARP1/2 inhibitor (IC50 = 3.2/1.9 nM) with anticancer activity. It displays >406-fold over other PARP isoforms such as PARP3, TNKS1, TNKS2 and PARP6; It reduces poly(ADP-ribose) formation, enhances γH2AX levels, induces G2/M arrest and subsequent apoptosis in homologous recombination repair (HR)-deficient cells. Mefuparib shows potent in vitro and in vivo proliferation and growth inhibition against HR-deficient cancer cells and synergistic sensitization of HR-proficient xenografts to the anticancer drug temozolomide.
| ln Vitro |
In 48 hours, mefuparib hydrochloride (1–10 μM) causes cellular trafficking [1]. V-C8 enters cells through the normal G2/M phase when exposed to mefuparib hydrochloride (MPH; 1–10 μM; 24 hours) [1]. In MDA-MB-436 (BRCA1/) cells, mefuparib hydrochloride (1–10 μM; 24 hours) induces DSB accumulation and concentration-dependently increases γH2AX levels [1]. The efficient inhibition of magnetic field drift effect by hexane has an average IC50 of 2.16 μM (0.12 μM~3.64 μM)[1]. Mefuparib hydrochloride inhibits TNKS1 (IC50 = Apoptosis Assay), PARP3 (IC50 > 10 μM), and PARP6 (IC50 > 10 μM) [1].
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| ln Vivo |
Mefuparib hydrochloride (160 mg/kg; lateral; every other day; for 21 days) inhibited the growth of BR-05-0028 breast patient xenografts (PDX) without causing significant weight loss. This was in addition to the dose- and time-sensitive killing of V-C8 xenografts by mefoparib hydrochloride (MPH; 40-160 mg/kg; Atlantic; every other day; for 21 days). Mefuparib hydrochloride (10, 20, 40 mg/kg; oral) had a Cmax of 116-SD of 725 ng/mL and a T1/2 of 1.07-1.3 hours [1]. Cynomolgus monkeys treated with mefuparib hydrochloride (5, 10 1], 20 mg/kg; oral) have a T1/2 of 2.16-2.7 hours and a C max of 608 ng/mL [1].
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| Cell Assay |
Apoptosis Assay [1]
Cell Types: V-C8 Cell Tested Concentrations: 1, 3, 10 μM Incubation Duration: 48 hrs (hours) Experimental Results: Causes apoptosis. 1.6 μM), TNKS2 (IC50=1.3 μM)[1]. Cell cycle analysis[1] Cell Types: V-C8 Cell Tested Concentrations: 1, 3, 10 μM Incubation Duration: 24 hrs (hours) Experimental Results: Cells enter the typical G2/M arrest phase. Western Blot Analysis[1] Cell Types: MDA-MB-436 (BRCA1−/−) Cell Tested Concentrations: 1, 10 μM Incubation Duration: 24 hrs (hours) Experimental Results: Increased γH2AX levels in MDA lead to DSB accumulation MB-436 (BRCA1−/− ) cells are concentration dependent. |
| Animal Protocol |
Animal/Disease Models: V-C8 xenograft nude mice [1]
Doses: 40, 80, 160 mg/kg Route of Administration: oral; once every other day; lasted for 21 days Experimental Results: V-C8 xenograft demonstrated dose and Time-dependent killing was accompanied by complete disappearance of some xenografts, especially in the high-dose group. Animal/Disease Models: SD rat[1] Doses: 10, 20, 40 mg/kg (pharmacokinetic/PK/PK analysis) Route of Administration: Oral Experimental Results:T1/2 is 1.07-1.3 hrs (hrs (hours)), C max is 116-725 ng/ mL. |
| References |
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| Additional Infomation |
Mefuparib hydrochloride is the hydrochloride salt of mefuparib. It is a potent poly(ADP-ribose) polymerase inhibitor which exhibits strong anticancer activity and also inhibits SARS-CoV-2 in cell culture. It has a role as an anticoronaviral agent, an antineoplastic agent, an EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor and an apoptosis inducer. It contains a mefuparib(1+).
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| Molecular Formula |
C17H16CLFN2O2
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|---|---|
| Molecular Weight |
334.772546768188
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| Exact Mass |
334.088
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| CAS # |
1449746-00-2
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| Related CAS # |
1392502-82-7; 1449746-00-2 (HCl);
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| PubChem CID |
117734810
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
23
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| Complexity |
398
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl.FC1C=C(C(N)=O)C2=C(C=1)C=C(C1C=CC(CNC)=CC=1)O2
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| InChi Key |
GPFWTAVHQKERKY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H15FN2O2.ClH/c1-20-9-10-2-4-11(5-3-10)15-7-12-6-13(18)8-14(17(19)21)16(12)22-15;/h2-8,20H,9H2,1H3,(H2,19,21);1H
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| Chemical Name |
5-fluoro-2-[4-(methylaminomethyl)phenyl]-1-benzofuran-7-carboxamide;hydrochloride
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| Synonyms |
Mefuparib HClCVL-218 CVL 218 CVL218
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~25 mg/mL (~74.68 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.47 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 (7.47 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 (7.47 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 | 2.9871 mL | 14.9356 mL | 29.8713 mL | |
| 5 mM | 0.5974 mL | 2.9871 mL | 5.9743 mL | |
| 10 mM | 0.2987 mL | 1.4936 mL | 2.9871 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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