AP-1
Based on 1 Customer Validation
AP-1 is a targeted ALK PROTAC degrader. AP-1 effectively degrades various ALK fusion/mutation forms, including degradation of NPM-ALK (DC50 = 4.6 nM) and EML4-ALK (DC50 = 357.6 nM), and exhibits a typical hook effect at high concentrations. AP-1 inhibits phosphorylation of downstream STAT3, downregulates gene expression in the JAK-STAT pathway, and kills ALK-positive tumor cells via activating the caspase-3-dependent apoptosis pathway. AP-1 shows cytotoxicity against a variety of cancer cells and possesses anti-tumor activity. AP-1 can be used in research related to non-small cell lung cancer, neuroblastoma, and anaplastic large cell lymphoma.
(Pink: Anaplastic lymphoma kinase (ALK) ligand (HY-169482); Blue: Cereblon ligand (HY-10984); Black: linker).
Para uso exclusivo en investigación. No vendemos a pacientes.
- Pureza: 97.8%
- No. CAS: 3027918-96-0
- Fòrmula: C39H40ClN9O8S
- Peso molecular:830.31
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Almacenamiento:Powder -20°C, 3 years ; In solvent -80°C, 6 months , -20°C, 1 month
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Actividad biológica
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p-STAT3 |
Caspase-3 |
NPM-ALK 4.6 nM (DC50) |
EML4-ALK 357.6 nM (DC50) |
AP-1 (0.2-1200 nM; 0-24 h) potently degrades NPM-ALK in Karpas299 cells via the ubiquitin-proteasome system, with a DC50 of 4.6 nM and a maximum degradation rate of 92.28%, and inhibits the phosphorylation of downstream STAT3[1].
AP-1 (30 nM-10 μM; 72 h) exhibits potent cytotoxic activity against Karpas299 cells with an IC50 of 0.1265 nM, and also shows cytotoxic activity against 3122 cells[1].
AP-1 (16 h) degrades EML4-ALK in H3122 cells in a concentration-dependent manner, with a DC50 of 357.6 nM and a maximum degradation rate of 81.34%, and this degradation effect is reversible after drug withdrawal[1].
Treatment with AP-1 for 16 h downregulates the gene expression of oncogenic ALK and JAK-STAT pathways in H3122 cells[1].
AP-1 induces the colocalization of ALK and CRBN in H3122 cells, promoting the formation of the ternary complex required for PROTAC-mediated protein degradation[1].
AP-1 (1 nM-100 μM; 16 h) exhibits high selectivity for ALK, as it does not degrade the off-target proteins Aurora A or FAK in Karpas299 cells[1].
AP-1 (0.0001 nM-100 μM; 24-60 h) exhibits high selectivity for ALK-dependent cells, and shows extremely low cytotoxicity in non-ALK-dependent THP-1, HeLa and 293T cells compared with LDK378[1].
AP-1 kills H3122 cells via an apoptotic pathway involving caspase-3 activation[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Karpas299 cells expressing NPM-ALK
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Concentration:0.2, 0.4, 0.8, 1.5, 3, 6, 12, 25, 50, 100, 200, 400, 800 and 1200 nM (16 h); 100 nM (time-course); 1, 3, 10, 30, 100, 300 and 1000 nM (co-treated with 2 and 5 μM MG-132 (HY-13259), 16 h)
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Incubation Time:16 h (concentration-dependent; proteasome inhibition); 0, 2, 4, 8, 16 and 24 h (time-course)
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Result:Induced concentration-dependent degradation of NPM-ALK, with observable degradation at 10 nM, maximum degradation at ~300 nM, and slight reduction at 1 μM due to the hook effect.
Blocked NPM-ALK degradation when co-treated with MG-132, confirming proteasome-dependent activity.
Showed significant NPM-ALK degradation by 8 h, with maximum degradation at 16 h; p-ALK levels decreased with slower kinetics than total NPM-ALK.
Reduced p-STAT3 levels without affecting total STAT3.
Determined a DC50 of 4.6 nM and a maximum degradation level (Dₘₐₓ) of 92.28% for NPM-ALK from three repeated experiments.
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Cell Line:Karpas299 cells expressing NPM-ALK
H3122 cells expressing EML4-ALK -
Concentration:30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM
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Incubation Time:72 h
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Result:Exhibited potent cytotoxicity against Karpas299 cells, with an IC50 of 0.1265 nM.
Showed cytotoxicity 71.53% higher than ALK ligand A1 (IC50 0.4444 nM) and 80.63% higher than LDK378 (HY-15656) (IC50 0.6532 nM).
Exhibited cytotoxicity against H3122 cells.
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Cell Line:Karpas299 cells expressing NPM-ALK
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Concentration:1 nM, 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM, 30 μM, 100 μM
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Incubation Time:16 h
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Result:Did not cause significant degradation of Aurora A or FAK proteins, even at concentrations up to 100 μM.
| Species | Dose | Route | T1/2 | Cmax |
|---|---|---|---|---|
| Rat[1] | 1 mg/kg | i.v. | 0.73 h | 1114.80 μg/L |
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Female NOD/SCID mice (6-8 weeks old) were subcutaneously inoculated with 1 × 106 NCI-H3122 cells in the right flank. When the tumors reached a mean volume of approximately 100 mm3, the treatment was initiated.
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Dosage:25 mg/kg; 50 mg/kg; 100 mg/kg
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Administration:i.p.; once every 2 days
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Result:Produced tumor growth inhibition (TGI) values of 56.51% at 25 mg/kg, 72.50% at 50 mg/kg, and 69.18% at 100 mg/kg.
Demonstrated equivalent antitumor efficacy to positive control LDK378 (25 mg/kg, TGI 57.66%) at 25 mg/kg dose.
Caused no significant body weight loss in treated mice.
Induced no notable liver or kidney function abnormalities at low-to-medium doses, with only slight increases in ALT, AST, and UREA-J indices at 100 mg/kg dose.
Chemical Information
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No. CAS 3027918-96-0
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Appearance Solid
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Peso molecular 830.31
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Fòrmula C39H40ClN9O8S
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Color Yellow to orange
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SMILES
O=C1NC(C(CC1)N2C(C3=C(C2=O)C(NCC(N4CCN(CC4)C5=CC=C(C(OC)=C5)NC6=NC=C(C(NC7=C(S(=O)(C(C)C)=O)C=CC=C7)=N6)Cl)=O)=CC=C3)=O)=O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Powder -20°C 3 years In solvent -80°C 6 months -20°C 1 month
Pureza y Documentación
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Ficha de datos (276 KB)
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SDS (252 KB)
- English - EN (252 KB)
- Français - FR (252 KB)
- Deutsch - DE (252 KB)
- Norwegian - NO (252 KB)
- Español - ES (252 KB)
- Swedish - SV (252 KB)
- Italian - IT (252 KB)
- Korean - KR (252 KB)
- Portuguese - PT (252 KB)
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Instrucciones de manejo (2659 KB)
Referencias
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
AP-1 Related Classifications
HY-169481 Related Classifications
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