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| Targets |
Inclisiran targets PCSK9 (proprotein convertase subtilisin/kexin type 9) mRNA in the liver. As a synthetic siRNA, it is loaded into the RNA-induced silencing complex (RISC), where the antisense strand guides RISC to bind to the complementary sequence on PCSK9 mRNA. This leads to the endonucleolytic cleavage and degradation of the mRNA, which in turn reduces PCSK9 protein synthesis. Lower PCSK9 levels result in increased LDL receptor (LDLR) expression on hepatocytes and enhanced clearance of LDL-cholesterol from the circulation.
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| ln Vitro |
In vitro, Inclisiran is a double-stranded siRNA that inhibits the transcription of PCSK9, leading to reduced PCSK9 mRNA and protein levels in human hepatoma cells (e.g., HepG2, Huh-7). By reducing PCSK9, inclisiran upregulates the LDL receptor and enhances LDL-cholesterol uptake. It also inhibits pyroptosis, activates PPARgamma, and reduces NLRP3, cleaved caspase-1, IL-1beta, and IL-18, exhibiting anti-inflammatory, lipid-regulating, and anti-atherosclerotic activities. No specific IC50 values are reported.
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| ln Vivo |
In vivo, Inclisiran is a highly effective lipid-lowering drug. It is administered subcutaneously (SC) once every 6 months, offering a convenient dosing regimen. In clinical trials (e.g., ORION-9, ORION-10, ORION-11), inclisiran demonstrated robust and sustained reductions in LDL-cholesterol (by approximately 50%) in patients with heterozygous familial hypercholesterolemia, ASCVD, and ASCVD risk equivalents. Inclisiran also reduces pro-inflammatory cytokines and exhibits anti-atherosclerotic effects in animal models.
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| Enzyme Assay |
Inclisiran is an siRNA; it does not bind directly to proteins or enzymes. Its mechanism of action involves Watson-Crick base pairing with PCSK9 mRNA. The binding is characterized by its melting temperature (Tm) and its ability to activate the RNA-induced silencing complex (RISC). For analytical purposes, the purity and identity of inclisiran are confirmed by HPLC and LC-MS/MS. In vitro potency is assessed by measuring PCSK9 mRNA knockdown in human hepatoma cells by qRT-PCR.
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| Cell Assay |
For cellular assays, human hepatoma cells (e.g., HepG2, Huh-7) are seeded in 6- or 96-well plates. Inclisiran is delivered using a transfection reagent (e.g., Lipofectamine 2000) or by free uptake (gymnosis) for primary human hepatocytes. Cells are treated with inclisiran at concentrations of 0.1-1000 nM for 24-72 hours. PCSK9 mRNA levels are quantified by qPCR. PCSK9 protein levels in the culture medium are measured by ELISA. LDLR protein levels in cell lysates are measured by Western blot. Functional LDL uptake is assessed by incubating cells with fluorescently labeled LDL (DiI-LDL) and analyzing by flow cytometry.
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| Animal Protocol |
For preclinical evaluation, 6-8-week-old female C57BL/6 mice or human PCSK9 transgenic mice are used. Inclisiran is administered subcutaneously (SC) at doses of 3-30 mg/kg once weekly or once every 4 weeks. Blood is collected periodically (up to 8 weeks). Plasma PCSK9 levels are measured by ELISA, and plasma lipid profiles (total cholesterol, LDL-C, HDL-C, triglycerides) are measured by enzymatic assays. Livers are harvested for quantification of PCSK9 mRNA by qPCR and PCSK9 and LDLR protein levels by Western blot. In atherosclerosis models (e.g., ApoE-/- mice fed a high-fat diet), inclisiran reduces aortic plaque burden and inflammation.
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| ADME/Pharmacokinetics |
Inclisiran sodium (C₇₈H140N11O34P, MW = 1806.97, purity ≥98%, CAS 1639324-58-5) is a white to off-white solid powder. For storage, the powder should be kept at -20degC or -80degC, sealed, and protected from moisture. For in vitro use, stock solutions in nuclease-free water or PBS (1-10 mg/mL) can be prepared and stored at -20degC or -80degC. Avoid repeated freeze-thaw cycles. For in vivo SC administration, it is formulated in PBS or saline. After SC injection, inclisiran is rapidly absorbed, with a Tmax of 2-4 hours. It is primarily taken up by the liver, where it has a prolonged duration of action. The terminal elimination half-life is approximately 9 hours, but the pharmacodynamic effect (LDL lowering) lasts for up to 6 months due to the long-lived RISC complex.
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| Toxicity/Toxicokinetics |
In clinical trials, inclisiran was generally well-tolerated. The most common adverse events were mild-to-moderate injection site reactions (e.g., pain, erythema, rash), which occurred in approximately 5% of patients. No significant elevations in liver enzymes or creatinine kinase were observed. In preclinical toxicology studies, inclisiran showed no significant off-target effects or organ toxicity at therapeutically relevant doses. High doses may cause hepatotoxicity, but the therapeutic index is wide. No specific LD50 values are reported.
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| References | |
| Additional Infomation |
Inclisiran (brand name Leqvio®) is the first and only FDA-approved siRNA therapy for the treatment of hypercholesterolemia. It was approved by the FDA in December 2021. Inclisiran offers a major advantage over other PCSK9 inhibitors (evolocumab, alirocumab) because it requires only twice-yearly subcutaneous administration, improving patient adherence. Inclisiran is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. The recommended dose is 284 mg (equivalent to 300 mg inclisiran sodium) administered as a single subcutaneous injection initially, at 3 months, and then every 6 months thereafter. The compound is for research use only in its research-grade form; the clinical-grade product is not available for research sale. Inclisiran is available from chemical suppliers for research purposes.
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| Molecular Formula |
C78H140N11O34P
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| Molecular Weight |
1806.97328567505
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| CAS # |
1639324-58-5
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| Appearance |
Solid powder
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| SMILES |
P(=O)(O)(O)OC[C@@H]1C[C@H](CN1C(CCCCCCCCCCC(NC(COCCC(NCCCNC(CCCCO[C@H]1[C@@H]([C@H]([C@H]([C@@H](CO)O1)O)O)NC(C)=O)=O)=O)(COCCC(NCCCNC(CCCCO[C@H]1[C@@H]([C@H]([C@H]([C@@H](CO)O1)O)O)NC(C)=O)=O)=O)COCCC(NCCCNC(CCCCO[C@H]1[C@@H]([C@H]([C@H]([C@@H](CO)O1)O)O)NC(C)=O)=O)=O)=O)=O)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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), 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) |
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 | 0.5534 mL | 2.7671 mL | 5.5341 mL | |
| 5 mM | 0.1107 mL | 0.5534 mL | 1.1068 mL | |
| 10 mM | 0.0553 mL | 0.2767 mL | 0.5534 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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