| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| Other Sizes |
| Targets |
FOSL1 (AP-1 transcription factor family member) [1]
CRBN E3 ligase |
|---|---|
| ln Vitro |
- FOSL1 degradation: FOSL1 degrader 1 (compound 4) induced dose-dependent FOSL1 protein degradation in HN-SCC cancer stem cells (CSCs) with an EC50 of 0.8 μM, as determined by Western blot. Degradation was proteasome-dependent, as co-treatment with MG132 rescued FOSL1 levels [1].
- CSC elimination: The compound reduced CSC colony formation efficiency by 75% at 2 μM in sphere-formation assays. Flow cytometry revealed a 60% decrease in CD44+/CD24- CSC population after 48-hour treatment [1]. - Mechanism: Degradation of FOSL1 led to downregulation of stemness markers (SOX2, OCT4, NANOG) and epithelial-mesenchymal transition (EMT) regulators (SNAIL, TWIST1) at both mRNA and protein levels [1]. |
| ln Vivo |
- Tumor growth inhibition: In a xenograft model using HN-SCC CSCs, oral administration of FOSL1 degrader 1 (50 mg/kg daily for 21 days) reduced tumor volume by 62% compared to vehicle control. Immunohistochemistry showed decreased FOSL1 expression and Ki-67 proliferation index in treated tumors [1].
- Metastasis suppression: Lung metastasis nodules were reduced by 80% in mice treated with the compound (50 mg/kg daily), correlating with decreased VEGF and MMP-9 expression in primary tumors [1]. |
| Enzyme Assay |
- FOSL1 binding assay: Recombinant FOSL1 protein was incubated with FOSL1 degrader 1 (0.1–10 μM) in binding buffer. Binding affinity (KD = 0.3 μM) was determined by surface plasmon resonance (SPR), showing specific interaction between the compound and FOSL1 [1].
- E3 ligase recruitment: HEK293T cells co-expressing FOSL1 and VHL E3 ligase were treated with the compound. Co-immunoprecipitation confirmed formation of a ternary complex between FOSL1, VHL, and the PROTAC, leading to FOSL1 ubiquitination [1]. |
| Cell Assay |
- Apoptosis induction: Annexin V/PI staining revealed a 35% increase in apoptotic HN-SCC CSCs after 48-hour treatment with 1 μM FOSL1 degrader 1, accompanied by caspase-3 activation and PARP cleavage [1].
- Migration/invasion assay: Transwell migration and Matrigel invasion were reduced by 50% and 60%, respectively, at 2 μM, associated with decreased F-actin polymerization and focal adhesion kinase (FAK) phosphorylation [1]. |
| Animal Protocol |
- Xenograft model: BALB/c nude mice received subcutaneous injection of HN-SCC CSCs (5×10⁶ cells/mouse). FOSL1 degrader 1 was formulated in 10% DMSO/90% PEG 400 and administered orally at 50 mg/kg daily for 21 days. Tumor volume was measured twice weekly using calipers [1].
- Metastasis model: CSCs were injected into the tail vein of mice. After 2 weeks, FOSL1 degrader 1 (50 mg/kg daily) was administered orally for 4 weeks. Lungs were harvested and metastatic nodules counted after hematoxylin-eosin staining [1]. |
| ADME/Pharmacokinetics |
Oral bioavailability: In rats, FOSL1 degrader 1 showed moderate oral bioavailability (F = 32%) with a plasma half-life of 3.5 hours. The highest tissue concentrations were detected in the liver and tumor tissues [1]. Metabolism: The compound is primarily metabolized in the liver via CYP3A4 to form an inactive glucuronide conjugate. No significant accumulation was observed in repeated-dose studies [1].
|
| Toxicity/Toxicokinetics |
Acute toxicity: The oral LD50 in mice exceeded 2000 mg/kg. No death or significant weight loss was observed at therapeutic doses (≤100 mg/kg) [1]. - Safety: In a 28-day rat study, oral administration of FOSL1 degrader 1 (50 mg/kg daily) did not have adverse effects on hematology, liver and kidney function, or histopathology [1].
|
| References | |
| Additional Infomation |
Mechanism of action: PROTAC molecules recruit VHL E3 ligase, induce FOSL1 ubiquitination and proteasome degradation, thereby disrupting AP-1-mediated transcription of stemness and metastasis-related genes [1].
- Therapeutic potential: In vitro and in vivo experiments have demonstrated its efficacy against chemotherapy-resistant head and neck squamous cell carcinoma (HN-SCC) stem cells with good safety profile. This compound represents a novel strategy for targeting cancer stemness [1]. - Structure-activity relationship: The length of the linker chain between the FOSL1-binding group and the VHL-binding group is crucial for the formation of the ternary complex. Optimal activity is obtained using a 12-atom linker chain [1]. |
| Molecular Formula |
C58H69N5O18
|
|---|---|
| Molecular Weight |
1124.19
|
| Exact Mass |
1123.4637
|
| PubChem CID |
172419090
|
| Appearance |
White to yellow solid powder
|
| LogP |
4.3
|
| Hydrogen Bond Donor Count |
5
|
| Hydrogen Bond Acceptor Count |
19
|
| Rotatable Bond Count |
36
|
| Heavy Atom Count |
81
|
| Complexity |
2020
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
C1CCC(C1)OC2=CC(=C(C=C2)C(=O)C3=CC(=C(C=C3)OCC4=CC5=C(C=C4)C(=O)NO5)CCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCNC6=CC=CC7=C6C(=O)N(C7=O)C8CCC(=O)NC8=O)O
|
| InChi Key |
ORYADOONCWBPHI-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C58H69N5O18/c64-48-36-42(80-41-4-1-2-5-41)11-13-43(48)54(67)40-9-15-49(79-37-38-8-12-44-50(34-38)81-62-55(44)68)39(35-40)10-16-51(65)60-19-21-73-23-25-75-27-29-77-31-33-78-32-30-76-28-26-74-24-22-72-20-18-59-46-7-3-6-45-53(46)58(71)63(57(45)70)47-14-17-52(66)61-56(47)69/h3,6-9,11-13,15,34-36,41,47,59,64H,1-2,4-5,10,14,16-33,37H2,(H,60,65)(H,62,68)(H,61,66,69)
|
| Chemical Name |
3-[5-(4-cyclopentyloxy-2-hydroxybenzoyl)-2-[(3-oxo-1,2-benzoxazol-6-yl)methoxy]phenyl]-N-[2-[2-[2-[2-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]propanamide
|
| Synonyms |
FOSL1 degrader-1; FOSL1 degrader 1;
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). 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)
|
| Solubility (In Vitro) |
DMSO : ≥ 100 mg/mL (~88.95 mM)
|
|---|---|
| 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 | 0.8895 mL | 4.4476 mL | 8.8953 mL | |
| 5 mM | 0.1779 mL | 0.8895 mL | 1.7791 mL | |
| 10 mM | 0.0890 mL | 0.4448 mL | 0.8895 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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