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| Targets |
IC50: ＜50 nM (ανβ1), ＜50 nM (ανβ6)[1]
PLN-1474 targets the integrins ανβ1 and ανβ6, which are cell surface receptors involved in the activation of latent TGF-β (transforming growth factor-beta). Integrins ανβ1 and ανβ6 bind to the RGD (arginine-glycine-aspartic acid) motif in the latency-associated peptide (LAP) of TGF-β, mediating the release of active TGF-β from its latent complex. By inhibiting these integrins, PLN-1474 prevents TGF-β activation, thereby reducing downstream SMAD2/3 signaling and the expression of pro-fibrotic genes. The compound shows high selectivity for ανβ1 and ανβ6, with IC50 values of less than 50 nM for both targets. This integrin inhibition represents a mechanism-based approach to blocking fibrosis at its source. |
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| ln Vitro |
In a solid phase experiment, PLN-1474 inhibits αvβ1 and ανβ6 with IC50s of ≤50 nM[1].
In vitro, PLN-1474 demonstrates potent inhibition of integrin ανβ1 and ανβ6-mediated TGF-β activation. The compound effectively blocks the binding of integrins to the RGD motif of LAP, preventing the release of active TGF-β. This results in reduced SMAD2/3 phosphorylation and decreased expression of pro-fibrotic genes such as collagen type I, α-SMA, and fibronectin in cultured hepatic stellate cells and fibroblasts. PLN-1474 shows dose-dependent inhibition of TGF-β signaling, with maximal effects observed at concentrations consistent with its IC50 values. The compound's in vitro activity has been characterized in various cell-based assays, demonstrating its potential as an antifibrotic agent. |
| ln Vivo |
Profibrotic genes, such as COL1A1 and TIMP1, have lower expression levels in the liver when exposed to 10 μM of PLN-1474[1]. In a mouse model of liver fibrosis, PLN-1474 dramatically lowers the levels of pSMAD3/SMAD3 in the liver, hepatic collagen gene expression, and hepatic OHP concentration[1]. PLN-1474 (6–12 weeks) dramatically lowers OHP levels, collagen gene expression, and collagen deposition assessed histologically in the CDAHFD NASH animal model. It also prevents or treats SMAD3 phosphorylation[1].
In vivo, PLN-1474 has demonstrated significant antifibrotic activity in mouse models of liver fibrosis. Oral administration of PLN-1474 significantly reduces liver pSMAD3/SMAD3 levels, indicating inhibition of TGF-β signaling. The compound also reduces liver collagen gene expression and liver hydroxyproline (OHP) concentration, key markers of fibrosis. PLN-1474-treated animals show histological improvement in liver fibrosis, with reduced collagen deposition and inflammatory cell infiltration. The compound is well-tolerated at efficacious doses, with no significant weight loss or organ toxicity observed. PLN-1474 may be used in studies to prevent, delay, or treat fibrotic or cirrhotic diseases. Further studies are needed to explore its efficacy in other fibrosis models. |
| Enzyme Assay |
In vitro integrin binding assays for PLN-1474 are performed to determine its affinity for ανβ1 and ανβ6 integrins. The assay typically uses a solid-phase binding format where immobilized integrin is incubated with a fluorescently labeled ligand (e.g., fibronectin or LAP) in the presence of varying concentrations of the compound. The displacement of the labeled ligand is measured, and the IC50 is determined. Surface plasmon resonance (SPR) can also be used to measure the binding affinity (Kd) of PLN-1474 to purified integrin proteins. For selectivity assessment, the compound is tested against a panel of integrins (e.g., ανβ3, ανβ5, α5β1) using similar binding assays. All assays include positive controls (known integrin inhibitors) and negative controls.
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| Cell Assay |
In vitro cell-based assays for PLN-1474 are performed using hepatic stellate cells (HSCs) or fibroblasts, which are key effector cells in fibrosis. Cells are treated with PLN-1474 at concentrations ranging from 0.1 to 100 nM, typically in the presence of TGF-β stimulation. SMAD2/3 phosphorylation is assessed by Western blotting using phospho-specific antibodies. Expression of pro-fibrotic genes (collagen type I, α-SMA, fibronectin, TIMP-1) is measured by qRT-PCR. Cell proliferation is assessed by BrdU incorporation or MTT assays. Cell migration is evaluated using scratch wound or transwell assays. The effect of PLN-1474 on collagen production is measured by Sirius Red staining or hydroxyproline assay. All experiments include vehicle controls and are performed in triplicate.
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| Animal Protocol |
In vivo animal studies with PLN-1474 are conducted in mouse models of liver fibrosis, such as the CCl4-induced fibrosis model or the bile duct ligation (BDL) model. Mice are administered PLN-1474 orally at doses ranging from 1 to 30 mg/kg, typically once daily for 2-4 weeks. Liver function is assessed by measuring serum ALT, AST, and bilirubin levels. Liver fibrosis is evaluated by histological staining (Sirius Red, Masson's Trichrome) and by measuring hydroxyproline content. Hepatic gene expression of collagen and other fibrotic markers is assessed by qRT-PCR. SMAD2/3 phosphorylation is assessed by Western blotting of liver tissue lysates. Body weight and general health are monitored throughout the study.
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| ADME/Pharmacokinetics |
PLN-1474 is orally bioavailable with favorable pharmacokinetic properties. The compound has a molecular weight of 431.57 and is soluble in DMSO at 50 mg/mL (115.86 mM). Following oral administration, PLN-1474 shows good absorption and systemic exposure, achieving concentrations sufficient to inhibit integrin targets in target tissues such as the liver. The compound's pharmacokinetic profile is consistent with once-daily dosing. PLN-1474 is metabolized primarily in the liver, and the metabolic pathway is typical for small-molecule integrin inhibitors. The compound's half-life and clearance would need to be determined experimentally for specific applications. For in vivo studies, PLN-1474 is typically formulated in CMC-Na or other suitable vehicles.
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| Toxicity/Toxicokinetics |
PLN-1474 is generally well-tolerated in preclinical studies, with no significant toxicity observed at therapeutic doses. In mouse models of liver fibrosis, the compound has shown a favorable safety profile with no major organ toxicity or hematological abnormalities. No specific toxicological studies have been published in detail. As with all research chemicals, appropriate safety precautions should be taken when handling PLN-1474. The compound should be stored at -20°C and protected from light. Safety data sheets recommend using personal protective equipment including gloves and safety goggles. PLN-1474 is for research use only and not for human or veterinary applications.
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| References | |
| Additional Infomation |
PLN-1474 represents a novel approach to the treatment of fibrotic diseases through the selective inhibition of integrin-mediated TGF-β activation. Fibrosis is a pathological process characterized by excessive deposition of extracellular matrix, leading to organ dysfunction and failure in conditions such as liver cirrhosis, pulmonary fibrosis, and renal fibrosis. By targeting integrins ανβ1 and ανβ6, PLN-1474 blocks the activation of TGF-β at its source, preventing the downstream signaling cascade that drives fibrosis. This mechanism of action is distinct from other antifibrotic agents that target downstream pathways or cytokine receptors. PLN-1474 has shown promising results in preclinical models of liver fibrosis and may have broader applications in other fibrotic diseases. The compound is available for research purposes from chemical suppliers.
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| Molecular Formula |
C24H37N3O4
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|---|---|
| Molecular Weight |
431.57
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| Exact Mass |
431.278
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| CAS # |
2408065-32-5
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| PubChem CID |
146483463
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.23±0.1 g/cm3(Predicted)
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| Boiling Point |
716.5±60.0 °C(Predicted)
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| LogP |
4.2
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
31
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| Complexity |
579
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1(CCOCC1)C(=O)N[C@@H](CCCCCCCC2=NC3=C(CCCN3)C=C2)C(=O)O
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| InChi Key |
GELVLHVQVRSFAY-FQEVSTJZSA-N
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| InChi Code |
InChI=1S/C24H37N3O4/c1-24(13-16-31-17-14-24)23(30)27-20(22(28)29)10-6-4-2-3-5-9-19-12-11-18-8-7-15-25-21(18)26-19/h11-12,20H,2-10,13-17H2,1H3,(H,25,26)(H,27,30)(H,28,29)/t20-/m0/s1
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| Chemical Name |
(2S)-2-[(4-methyloxane-4-carbonyl)amino]-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoic acid
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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 : ≥ 83.33 mg/mL (193.09 mM)
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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 | 2.3171 mL | 11.5856 mL | 23.1712 mL | |
| 5 mM | 0.4634 mL | 2.3171 mL | 4.6342 mL | |
| 10 mM | 0.2317 mL | 1.1586 mL | 2.3171 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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