Polθ-IN-10
Polθ-IN-10 is an orally active Polθ-pol inhibitor (with a human IC50 of 1.3 nM) that exhibits oral bioavailability in mice and rats. Polθ-IN-10 binds to the allosteric site of Polθ-pol, disrupts the microhomology-mediated end-joining DNA repair pathway, and inhibits CYP2C9 (IC50=1.63 μM). Polθ-IN-10 selectively inhibits the proliferation of HR-deficient cancer cells and induces apoptosis. Polθ-IN-10 is applicable to the research of HR-deficient cancers.
For research use only. We do not sell to patients.
- CAS No.: 3068829-46-6
- Formula: C27H24F4N6O3
- Molecular Weight:556.51
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
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Biological Activity
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CYP2C9 1.63 μM (IC50) |
Polθ-IN-10 (Compound 20) (10-60 min) potently and selectively inhibits the polymerase activity of human Polθ, with an IC50 of 1.3 nM, and does not inhibit other human DNA polymerases at a concentration of 10 μM[1].
Polθ-IN-10 (3-10 d) selectively inhibits the proliferation of HR-deficient cancer cell lines with an IC50 value ranging from 2.49 to 5.60 μM, while exerting minimal effects on HR-proficient cancer cell lines and normal cell lines[1].
Polθ-IN-10 (0-50.0 μM) preferentially inhibits CYP2C9 with an IC50 of 1.63 μM; it shows weak inhibitory activity against other CYP subtypes and exhibits no inhibitory effect on CYP1A2 even at concentrations as high as 50 μM[1].
Polθ-IN-10 (1.25-20 μM; 3-14 d) selectively and dose-dependently inhibits colony formation in HR-deficient MDA-MB-436 cells, while exerting no significant effect on normal MCF10A cells[1].
Polθ-IN-10 (5-20 μM; 7 d) dose-dependently induces apoptosis in HR-deficient MDA-MB-436 cells[1].
Polθ-IN-10 (1.25-10 μM; 2-48 h) induces time- and dose-dependent DNA damage in homologous recombination-deficient MDA-MB-436 cells[1].
Polθ-IN-10 (100 μM; 30 min) directly binds to Polθ protein in MDA-MB-436 cells and enhances its thermal stability[1].
Polθ-IN-10 (1 μM; 60 min) exhibits excellent metabolic stability in human, mouse and rat liver microsomes, with a half-life ranging from 121.6 to 247.5 min[1].
Polθ-IN-10 (30 μM; acute exposure) exhibits weak inhibitory activity against hERG channels, inducing only 24.0% inhibition at the concentration of 30 μM, which suggests that it possesses favorable cardiac safety profiles[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:HR-deficient cancer cell lines (MDA-MB-436, Capan-1, DLD-1 BRCA2-/-); HR-proficient/normal cell lines (DLD-1 BRCA2WT, MCF10A)
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Concentration:Serial dilutions
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Incubation Time:7 days (MDA-MB-436, Capan-1); 10 days (DLD-1 BRCA2-/-); 3 days (MCF10A)
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Result:Exhibited antiproliferative activity with IC50 values of 2.49 μM in MDA-MB-436 cells, 5.60 μM in Capan-1 cells, and 4.63 μM in DLD-1 BRCA2-/- cells.
Showed minimal activity with an IC50 >20 μM in DLD-1 BRCA2WT and MCF10A cells.
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Cell Line:HR-deficient breast cancer cell line MDA-MB-436
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Concentration:5-20 μM
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Incubation Time:7 days
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Result:Induced apoptosis in 24.7%, 33.1%, and 57.8% of MDA-MB-436 cells at concentrations of 5, 10, and 20 μM respectively, compared to the control group.
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Cell Line:HR-deficient breast cancer cell line MDA-MB-436
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Concentration:5 μM (time-dependent assay); 1.25-10 μM (dose-dependent assay)
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Incubation Time:2-12 h (time-dependent assay); 48 h (dose-dependent assay)
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Result:Induced a time-dependent increase in γH2AX levels, with significant upregulation observed at 4 h and sustained through 12 h at 5 μM.
Also induced a dose-dependent increase in γH2AX levels, with significant upregulation at concentrations ≥2.5 μM after 48 h.
| Species | Dose | Route | Cmax | Tmax | T1/2 | MRT0-t | MRT0-∞ | AUC0-t | AUC0-∞ | F | CL | Vd |
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| Mice[1] | 2 mg/kg | i.v. | 2580 ng/mL | / | 2.22 h | 2.03 h | 2.37 h | 4330 ng·h/mL | 4470 ng·h/mL | / | 0.45 L/h/kg | 1.06 L/kg |
| Mice[1] | 10 mg/kg | p.o. | 7560 ng/mL | 0.50 h | 1.65 h | 2.45 h | 2.59 h | 22800 ng·h/mL | 23100 ng·h/mL | 103.36 % | / | / |
| Rat[1] | 3 mg/kg | i.v. | 949 ng/mL | / | 1.48 h | 1.73 h | 1.73 h | 911 ng·h/mL | 911 ng·h/mL | / | 3.51 L/h/kg | 7.46 L/kg |
| Rat[1] | 30 mg/kg | p.o. | 1361 ng/mL | 1.00 h | 4.34 h | 4.02 h | 4.86 h | 5640 ng·h/mL | 5803 ng·h/mL | 63.71 % | / | / |
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:NSG mice (female, 18-20 g, subcutaneous xenograft of MDA-MB-436 BRCA1 mutant human breast cancer cells)[1]
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Dosage:25 mg/kg; 50 mg/kg; 100 mg/kg
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Administration:p.o.; once daily; 28 days
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Result:Achieved tumor growth inhibition (TGI) rates of 45.49%, 51.99%, and 61.14% at doses of 25 mg/kg, 50 mg/kg, and 100 mg/kg, respectively.
Showed no significant mouse body weight loss across all treatment doses.
Detected a significant, dose-dependent increase in γH2AX (a DNA damage marker) expression in tumor tissue from treated mice.
Revealed no significant toxicity in histological analysis of heart, liver, spleen, lungs, and kidneys.
Chemical Information
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CAS No. 3068829-46-6
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Molecular Weight 556.51
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Formula C27H24F4N6O3
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SMILES
O=C(N(CC#CC1=NN=C(C=C1)C(O)(C)C)C2=CC=C(C=C2)F)[C@@H](N3C4=NC(C)=CC(C(F)(F)F)=C4)CNC3=O
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Polθ-IN-10 Related Classifications
HY-181611 Related Classifications
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- Polθ-IN-10
- 3068829-46-6
- DNA/RNA Synthesis
- Apoptosis
- Cytochrome P450
- HR-deficient cancer cells
- HR-deficient cancers
- Polθ-pol
- human Polθ
- HR-deficient cancer cell lines
- normal cell lines
- MCF10A cells
- MDA-MB-436 cells
- HR-proficient cell lines
- microhomology-mediated end joining DNA repair pathway
- Inhibitor
- inhibitor
- inhibit