ART6043
ART6043 (Polθ-IN-7) is an orally active, selective allosteric DNA polymerase θ (Polθ) inhibitor with an IC50 of 1.3 nM. ART6043 blocks microhomology-mediated end joining (MMEJ) by inhibiting the polymerase function of Polθ. ART6043 suppresses the survival of homologous recombination-deficient (HRD) cells and enhances the antitumor effects of PARP inhibitors. ART6043 can be used in studies of HRD tumors, including BRCA1-mutant triple-negative breast cancer, BRCA2-deficient colorectal cancer, RAD51C-deficient gastric cancer, and others.
For research use only. We do not sell to patients.
- CAS No.: 2923356-52-7
- Formula: C28H35F3N6O2
- Molecular Weight:544.61
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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
- Protocols
- Purity & Documentation
- References
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All DNA/RNA Synthesis Isoforms
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Biological Activity
Description
IC50 & Target
[1]|
DNA Polymerase 1.3 nM (IC50) |
In Vitro
ART6043 (0.00001-0.1 μM; 2 h) binds to Polθ in intact HEK-293 Polθ-NanoLuc cells with an EC50 of 0.6 nM, confirming its DNA non-competitive binding mode in a cellular environment[1].
ART6043 (0.001-10 μM; 24 h) selectively inhibits Polθ-mediated microhomology-mediated end joining (MMEJ) in cultured cells, with an EC50 of approximately 60 nM, and does not affect the non-homologous end joining (NHEJ) or homologous recombination (HR) repair pathways[1].
ART6043 (0.075-0.665 μM; 7 days) dose-dependently enhances the expression of Talazoparib-induced DNA damage biomarkers, including single-strand DNA markers (total RPA, pS8-RPA, pS33-RPA), double-strand break markers (pS824-KAP1, γH2AX), as well as micronucleus formation following 7 days of combined treatment in DLD-1 BRCA2-/- cells[1].
ART6043 (0.01-10 μM; 10-14 days) inhibits the survival of HR-deficient cancer cell lines (including MDA-MB-436 SHLD2-/-, DLD-1 BRCA2-/- and SNU-601) with EC50 values ranging from 0.059 to 0.88 μM, but exerts no significant effect on HR-proficient cell lines[1].
ART6043 (0.07-6 μM; 14 days) synergistically enhances the antiproliferative effects of PARP inhibitors (Talazoparib (HY-16106), Olaparib (HY-10162), Niraparib (HY-10619)) in HR-deficient cancer cell lines, including DLD-1 BRCA2-/-, but exerts no such effect on HR-proficient DLD-1 wild-type cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
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Cell Line:HR-deficient (MDA-MB-436 SHLD2-/-, DLD-1 BRCA2-/-, HCT 116 BRCA2-/-, PEO1 clone 10, DoTc2 4510, SNU-601) and HR-proficient (DLD-1, HCT 116, PEO4) cancer cell lines
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Concentration:0.01, 0.1, 1 and 10 μM
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Incubation Time:10-14 days
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Result:Inhibited survival of HR-deficient cell lines with EC50 values ranging from 0.059 μM (DoTc2 4510) to 0.88 μM (MDA-MB-436).
Inhibited survival of MDA-MB-436 SHLD2-/- cells with an EC50 of approximately 60 nM.
Showed minimal sensitivity in HR-proficient cell lines, with EC50 values > 6.0 μM.
In Vivo
When combined with Talazoparib, ART6043 (5-50 mg/kg; p.o.; twice daily for 35 days) induces a dose-dependent increase in DNA damage biomarkers, superadditive micronucleated reticulocyte formation, and enhanced tumor growth inhibition, including achieving tumor regression in DLD-1 BRCA2-/- colorectal cancer xenografts in female F344-RAG2Null IL2RGnull rats[1].
Combination treatment with ART6043 (50 mg/kg; p.o.; twice daily for 25 days) and Talazoparib achieves 95% tumor growth inhibition, which significantly enhances the efficacy of Talazoparib in DLD-1 BRCA2-/- colorectal cancer xenografts in female BALB/c nude mice[1].
Combination treatment with ART6043 (50 mg/kg; p.o.; twice daily for 50 days) and Niraparib induces 90% tumor regression, and significantly enhances the efficacy of niraparib in the HBCx-10 BRCA2-deficient breast cancer PDX xenograft model in female athymic Nude-Foxn1nu mice[1].
ART6043 (50 mg/kg; p.o.; twice daily for 125 days) combined with Niraparib induces 82% tumor regression, doubles the median survival time to 232.5 days, and significantly enhances the efficacy of Niraparib in MDA-MB-436 BRCA1-deficient triple-negative breast cancer xenografts in female BALB/c nude mice[1].
Combination treatment with ART6043 (50 mg/kg; p.o.; twice daily for 50 days) and Niraparib achieves 92% tumor growth inhibition, which significantly enhances the efficacy of Niraparib in a SNU-601 RAD51C-deficient gastric cancer xenograft model in female BALB/c nude mice[1].
Combination of ART6043 (50 mg/kg; p.o.; twice daily for 300 days) with Niraparib extends the median survival to > 200 days, significantly enhancing the efficacy of Niraparib in orthotopic KB1P4.N1 BRCA1-deficient syngeneic breast cancer grafts in female wild-type FVB/N mice[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:BALB/c (female)[1]
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Dosage:50 mg/kg
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Administration:p.o.; twice daily for 15 days
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Result:Induced 63% tumour growth inhibition (TGI) relative to vehicle control.
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Animal Model:F344-RAG2Null IL2RGnull (female)[1]
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Dosage:5 mg/kg; 50 mg/kg (in combination with talazoparib 0.04 mg/kg)
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Administration:p.o.; twice daily for 35 days
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Result:Increased tumour pS8-RPA and pS824-KAP1 H-scores significantly relative to vehicle and talazoparib alone at 14 days; induced a super-additive increase in micronucleated reticulocytes (MN-RETs) (~2-fold over vehicle at 7 days) and achieved tumour stasis with a mean free ART6043 concentration of ~40 nM.
Increased tumour pS8-RPA and pS824-KAP1 H-scores significantly relative to vehicle and talazoparib alone at 7 and 14 days; induced a super-additive increase in MN-RETs (~4-fold over vehicle at 7 days); caused tumour regressions with a mean free ART6043 concentration of ~150 nM.
Was well tolerated with no significant body weight loss for both combinations.
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Animal Model:BALB/c (female)[1]
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Dosage:50 mg/kg (in combination with talazoparib 0.05 mg/kg)
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Administration:p.o.; twice daily for 25 days
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Result:Achieved 95% tumour growth inhibition (TGI) relative to vehicle control, compared to 21% TGI with ART6043 alone and 40% TGI with talazoparib alone.
Was well tolerated with no significant body weight loss.
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Animal Model:athymic Nude-Foxn1nu (female)[1]
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Dosage:50 mg/kg (in combination with niraparib 25 mg/kg)
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Administration:p.o.; twice daily for 50 days
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Result:Caused 90% tumour regression relative to baseline, compared to tumour stasis with niraparib alone and 0% TGI with ART6043 alone.
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Animal Model:BALB/c (female)[1]
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Dosage:50 mg/kg (in combination with niraparib 25 mg/kg)
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Administration:p.o.; twice daily for 125 days
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Result:Induced 82% tumour regression, maintained tumour-free status in mice until treatment cessation at day 120, and doubled median survival to 232.5 days compared to 119 days with niraparib alone.
Was well tolerated with no significant body weight loss during long-term dosing.
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Animal Model:BALB/c (female)[1]
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Dosage:50 mg/kg (in combination with niraparib 25 mg/kg)
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Administration:p.o.; twice daily for 50 days
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Result:Achieved 92% tumour growth inhibition (TGI) relative to vehicle control, compared to 39% TGI with ART6043 alone and 72% TGI with niraparib alone.
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Animal Model:FVB/N (female, wild-type)[1]
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Dosage:50 mg/kg (in combination with niraparib 25 mg/kg)
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Administration:p.o.; twice daily for 300 days
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Result:Extended median survival to >200 days, compared to 13 days with vehicle, 13.5 days with ART6043 alone, and 60 days with niraparib alone.
Was well tolerated with no treatment-associated body weight loss.
Chemical Information
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CAS No. 2923356-52-7
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Molecular Weight 544.61
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Formula C28H35F3N6O2
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SMILES
O=C1[C@@]2([H])N(C3=CC(C(F)(F)F)=CC(C)=N3)C(C[C@]2([H])CN(C4=C(C)C=CC=C4N1C)CCN5CCN(CC5)C)=O
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Synonyms
Polθ-IN-7
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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.
Protocols
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CRISPR-Cas9 HDR knock-in/precise editing
CRISPR-Cas9 HDR knock-in uses a guide RNA to direct Cas9 to a genomic target adjacent to a PAM, where Cas9 creates a double-strand break; if a donor DNA template with homology to the cut region is present, cellular HDR can copy the donor sequence into the genome, producing a precise substitution, tag, reporter, or insertion rather than an indel. The readout is the fraction of alleles or cells carrying the intended donor-derived edit, measured by junction PCR, restriction-fragment analysis, Sanger sequencing, amplicon deep sequencing, flow cytometry for reporter knock-in, or clone genotyping; NHEJ indels and partial or non-HDR insertions are measured in parallel because they compete with or confound precise HDR outcomes.
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Cell Cytotoxicity Assay
Cytotoxicity assays are usually based on the assessment of cell membrane damage, which can also be indirectly detected by measuring cell viability. Detection methods include MTT assay, CKK-8 assay, LDH assay and ATP assay, etc.
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Breast Cancer Modeling
Breast cancer is a heterogeneous cancer, and it has been distinguished into four subtypes: luminal A, luminal B, HER2-positive and basal-like. Molecular mutations, epigenetic alterations, hormone exposure and immune microenvironment are related to the progression of breast cancer.
Purity & Documentation
References
[1]. Robinson HMR, et al. The pharmacological profile of ART6043, a first-in-class clinical DNA polymerase theta polymerase domain inhibitor potentiating PARP inhibitor efficacy. Clinical cancer research : an official journal of the American Association for Cancer Research. 2026 Jul 13. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
ART6043 Related Classifications
HY-153755 Related Classifications
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Keywords
- ART6043
- 2923356-52-7
- Polθ-IN-7
- ART 6043
- ART-6043
- DNA/RNA Synthesis
- DLD-1 BRCA2-/-
- microhomology-mediated end joining
- HEK-293 Polθ-NanoLuc cells
- triple-negative breast cancer
- DNA polymerase theta
- homologous recombination deficient cells
- BRCA1-mutant tumours
- PARP inhibitors
- MDA-MB-436 SHLD2-/-
- RAD51C-null tumours
- Inhibitor
- inhibitor
- inhibit