Polθ-IN-9
Polθ-IN-9 is an orally active Polθ polymerase inhibitor (IC50 = 9.6 nM, Kd = 47.5 nM). Polθ-IN-9 shows remarkable selectivity with no inhibitory activity against other human DNA polymerases, including Pol α, Pol ε, Pol γ, Pol λ, and Pol μ. Polθ-IN-9 exhibits strong antiproliferative activity in DLD1 BRCA2 KO cells (IC50 = 2.9 μM), and high sensitivity to MDA-MB-436 cells (IC50 = 4.9 μM). Polθ-IN-9 increases DNA damage accumulation, induces γH2AX levels, and inhibits tumor growth in combination with Olaparib (HY-10162), in the MDA-MB-436 xenograft model. Polθ-IN-9 can be used for the research of homologous recombination (HR)-deficient cancers such as breast cancer.
For research use only. We do not sell to patients.
- CAS No.: 3050552-13-8
- Formula: C30H31ClF5N5O2
- Molecular Weight:624.04
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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
- Purity & Documentation
- References
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Help & FAQs
All DNA/RNA Synthesis Isoforms
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Biological Activity
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DNA Polymerase |
Human pol θ |
Polθ-IN-9 (Compound 33) (7 days) enhances antiproliferative activity in DLD1 BRCA2 KO cells (IC50 = 2.9 μM), MDA-MB-436 wild-type cells (IC50 = 4.9 μM), MDA-MB-436 SHLD2 KO cells (IC50 = 2.4 μM) and pancreatic cancer cells (Capan-1) (IC50 = 13.8 μM)[1].
Polθ-IN-9 (0.097-25 μM, 14 days) enhances cellular potency in MDA-MB-436 cells[1].
Polθ-IN-9 shows enhanced enzymatic potency and significantly improved metabolic stability, with T1/2 increasing to 48.3 min in mouse liver microsomes and 30.5 min in human liver microsomes, respectively[1].
Polθ-IN-9 (93.75-1500 nM, 14 days) has a synergistic effect with Olaparib (HY-10162), enhancing the antitumor effect of Olaparib in MDA-MB-436 cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:MDA-MB-436 cells
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Concentration:0.097, 0.39, 1.56, 6.25, 25 μM
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Incubation Time:14 days
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Result:Exhibited better activity compared to ART-558.
Induced almost no colonies in cells at a concentration of 6.25 μM.
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Cell Line:MDA-MB-436 cells treated with Olaparib (HY-10162)
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Concentration:93.75, 375, 1500 nM
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Incubation Time:14 days
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Result:Exhibited a synergistic effect with Olaparib and enhanced its antitumor activity.
Reduced the effective dose of Olaparib to 12.5 nM, when coadministered at 375 nM or 1500 nM, achieving complete inhibition of cell growth.
| Species | Dose | Route | T1/2 | Tmax | Cmax | MRT0-inf | AUC0-t | AUC0-inf | F | C0 | CL | Vdss |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mice[1] | 10 mg/kg | p.o. | 4.08 h | 0.5 h | 601 ng/mL | 3.67 h | 1587 ng·h/mL | 1601 ng·h/mL | 27.7 % | / | / | / |
| Mice[1] | 2 mg/kg | i.v. | 4.90 h | / | / | 3.51 h | 1141 ng·h/mL | 1157 ng·h/mL | / | 895 ng/mL | 30.6 mL/min/kg | 6.52 L/kg |
| Mice[1] | 200 mg/kg | i.p. | 11.02 h | 2 h | 4889 ng/mL | 14.31 h | 55355 ng·h/mL | 90381 ng·h/mL | / | / | / | / |
| Mice[1] | 200 mg/kg | p.o. | 8.92 h | 1.67 h | 3401 ng/mL | 11.98 h | 36838 ng·h/mL | 43720 ng·h/mL | 37.7 % | / | / | / |
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:MDA-MB-436 xenograft model in NOD SCID mice (6-8 weeks)[1]
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Dosage:50 mg/kg
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Administration:oral administration (p.o.), daily for 25 days
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Result:Exerted only a weak and transient inhibitory effect on tumor growth when administered alone, with the minor initial effect diminishing over time.
Achieved a remarkable tumor growth inhibition (TGI) of 85% in combination with Olaparib, greater than that achieved by Olaparib monotherapy (10 mg/kg, 13%).
Did not cause significant tissue damage in major organs, including the heart, liver, spleen, lung, and kidney.
Chemical Information
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CAS No. 3050552-13-8
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Molecular Weight 624.04
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Formula C30H31ClF5N5O2
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SMILES
COCCN1CCN(CC1)C2=CC=C3N([C@@H](CC3=C2)C(N(C)C4=CC(Cl)=C(C=C4F)F)=O)C5=CC(C(F)(F)F)=CC(C)=N5
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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)
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