Polθ-IN-11
Polθ-IN-11 is an orally active DNA polymerase θ (Polθ) ATPase inhibitor with an IC50 of 4.3 nM against human targets. Polθ-IN-11 activates the cGAS-STING pathway. Polθ-IN-11 upregulates the expression of PD-L1 in HR-deficient cancer cells. Polθ-IN-11 acts synergistically with PARP inhibition in HR-deficient cancer cells and in vivo xenograft models. Polθ-IN-11 can be used in studies related to HR-deficient cancers.
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- No. CAS: 3082173-75-6
- Fòrmula: C24H18FN5O3Se
- Peso molecular:522.39
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Almacenamiento:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Actividad biológica
Descripciòn
IC50 & Target
[1]|
Human pol θ 4.3 nM (IC50) |
TBK1 |
STAT1 |
In Vitro
Polθ-IN-11 (XL-20) (60 min) potently inhibits purified Polθ ATPase activity with an IC50 of 4.3 nM[1].
Polθ-IN-11 (up to 80 μM; 7 days) potently inhibits the growth of HR-deficient MDA-MB-436, HCT116, and SW48 cells with IC50 values of 8.1 μM, 16.5 μM, and 17.2 μM respectively, and shows minimal activity in HR-proficient MDA-MB-231 cells (IC50 >80 μM)[1].
Polθ-IN-11 (5-20 μM; 9 days) inhibits colony formation of MDA-MB-436 cells in a concentration-dependent manner[1].
Polθ-IN-11 (5-20 μM; 7 days) induces apoptosis in MDA-MB-436 cells in vitro in a concentration-dependent manner[1].
Polθ-IN-11 (5-20 μM; 7 days) induces concentration-dependent DNA double-strand break accumulation in MDA-MB-436 cells, as measured by γH2AX expression[1].
Polθ-IN-11 (5-20 μM; 24 h) inhibits S-phase DNA synthesis in MDA-MB-436 cells in vitro in a concentration-dependent manner[1].
Polθ-IN-11 (up to 10 μM) shows weak inhibition of the hERG potassium channel[1].
Polθ-IN-11 (5-40 μM; 7 days) exhibits synergistic antiproliferative activity with Olaparib (HY-10162) in MDA-MB-436 cells, supporting a combination therapeutic strategy[1].
Polθ-IN-11 (10 μM; 9-16 h) activates the cGAS-STING pathway in MDA-MB-436 cells, increasing phosphorylation of TBK1 and STAT1 and upregulating type I interferon-related genes and PD-L1, with stronger activity than AB25583 (HY-162859)[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:BRCA1-deficient MDA-MB-436 breast cancer cells
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Concentration:5, 10, 20 μM
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Incubation Time:9 days
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Result:Inhibited colony formation in a concentration-dependent manner; at 20 μM, reduced relative colony formation to ~0.1.
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Cell Line:BRCA1-deficient MDA-MB-436 breast cancer cells
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Concentration:5, 10, 20 μM
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Incubation Time:24 h
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Result:Inhibited S-phase DNA synthesis in a concentration-dependent manner; at 20 μM, reduced the percentage of EdU-positive cells.
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Cell Line:BRCA1-deficient MDA-MB-436 breast cancer cells
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Concentration:5, 10, 20 μM
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Incubation Time:7 days
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Result:Induced cell apoptosis in a concentration-dependent manner; at 20 μM, resulted in 17.7% apoptosis.
Parmacokinetics
| Species | Dose | Route | C0 | AUC0-t | AUC0-∞ | T1/2 | Vd | CL | MRT0-∞ | Cmax | Tmax | Vd/F | CL/F | F |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Rat[1] | 1 mg/kg | i.v. | 5047.5 ng/mL | 18622.7 ng·h/mL | 19488.0 ng·h/mL | 4.5 h | 0.4 L/kg | 0.06 L/h/kg | 5.2 h | / | / | / | / | / |
| Rat[1] | 10 mg/kg | i.g. | / | 256805.6 ng·h/mL | 267456.2 ng·h/mL | 5.1 h | / | / | 7.3 h | 29816.6 ng/mL | 2.3 h | 0.3 L/kg | 0.04 L/h/kg | 137.9 % |
In Vivo
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:BALB/C nude (female, 6-week-old, 18-20 g, subcutaneous xenograft of BRCA1-deficient human MDA-MB-436 breast cancer cells)[1]
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Dosage:20 mg/kg (monotherapy); 20 mg/kg + 30 mg/kg olaparib (combination)
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Administration:p.o.; daily; 12 days
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Result:Achieved a tumor growth inhibition (TGI) of 43.7%.
Increased γH2AX expression in tumor tissues compared to controls.
Showed no appreciable body weight loss.
Showed no significant drug-related toxicity via H&E staining of heart, liver, spleen, lung, and kidney.
Achieved a tumor growth inhibition (TGI) of 64% when combined with olaparib.
Increased γH2AX expression in tumor tissues to a greater extent than monotherapy compared to controls.
Chemical Information
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No. CAS 3082173-75-6
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Peso molecular 522.39
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Fòrmula C24H18FN5O3Se
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SMILES
COC1=CC=CC(F)=C1C2=C(C=NC(C)=C2)C(NC3=NN=C([Se]3)COC4=CC=C(C=C4)C#N)=O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Polθ-IN-11 Related Classifications
HY-183748 Related Classifications
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