| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
ART558 targets DNA polymerase Polθ, an enzyme involved in DNA repair. It acts as an allosteric inhibitor of the polymerase function of Polθ. ART558 does not inhibit other human DNA polymerases, namely Polα, Polδ, Polη and Polγ, as well as a panel of 78 oncology-focused kinases, including PARP1 and PARP2.
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| ln Vitro |
In an isogenic model of BRCA1 deficiency that has been previously described, ART558 (0~10 μM; 7 days) demonstrated synthetic lethality when combined with PARPi olaparib [1]. γH2AX accumulates in cells treated with ART558 (5μM; 0~72 hours; BRCA2 wild-type or BRCA2-/- cells) [1]. Without affecting nonhomologous end joining, ART558 suppresses the primary Polβ-mediated DNA repair mechanism, Theta-mediated end joining. In tumor cells with BRCA1 or BRCA2 mutations, ART558 causes damage to DNA, promotes synthetic lethality, and amplifies the effects of PARP inhibitors. In 53BP1-deficient cells, ART558 raises biomarkers and synthetic lethality of single-stranded DNA; however, these effects are reversed when DNA nucleases that induce end resection are inhibited, indicating that these effects are connected to the process of synthetic lethality. YFP-labeled full-length Polθ has a longer residency duration at the site of laser-induced DNA damage when treated with ART558 [1].
In vitro, ART558 inhibits Polθ with an IC50 of 7.9 nM. In an isogenic model of BRCA1 deficiency, ART558 (0~10 μM; 7 days) demonstrated synthetic lethality when combined with the PARP inhibitor olaparib. γH2AX accumulates in cells treated with ART558 (5 μM; 0~72 hours). ART558 suppresses the Polθ-mediated DNA repair mechanism, Theta-Mediated End Joining, without affecting Non-Homologous End Joining. In tumor cells with BRCA1 or BRCA2 mutations, ART558 causes DNA damage, promotes synthetic lethality, and amplifies the effects of PARP inhibitors. |
| ln Vivo |
In vivo activity data for ART558 are not extensively detailed in the available sources. The compound is a research tool for studying Polθ function in DNA repair and cancer. It is anticipated to have utility in studies exploring synthetic lethality and PARP inhibitor resistance, but specific in vivo efficacy data in animal models are not provided.
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| Enzyme Assay |
The in vitro enzyme assay for ART558 involves measuring the inhibition of Polθ polymerase activity. Recombinant Polθ is incubated with a DNA substrate and nucleotides in the presence of varying compound concentrations. The IC50 value (7.9 nM) is determined by quantifying the reduction in DNA synthesis using radioactive or fluorescence-based assays.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: BRCA2 wild type or BRCA2−/− Cell Tested Concentrations: 0~10 μM Incubation Duration: 7 days Experimental Results: Demonstrated synthetic lethality in previously described BRCA1-isogenic model and with PARPi olaparib The combined effect is insufficient. Western Blot Analysis [1] Cell Types: BRCA2 wild type or BRCA2−/− Cell Tested Concentrations: 5μM Incubation Duration: 0~72 hrs (hours) Experimental Results: Shows intracellular γH2AX accumulation. Cellular assays are performed using BRCA2 wild-type or BRCA2-/- cells. Cells are treated with ART558 at concentrations ranging from 0 to 10 μM for up to 72 hours. γH2AX accumulation is assessed by Western blotting as a marker of DNA damage. Cell viability is assessed using standard assays to evaluate synthetic lethality. |
| Animal Protocol |
In vivo animal studies for ART558 are not detailed in the available sources. The compound is a research tool for studying Polθ function. Specific animal models, dosing regimens, and efficacy data have not been reported in the supplier documentation or the primary literature cited.
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| ADME/Pharmacokinetics |
Pharmacokinetic data for ART558 are not available in the provided sources. The compound has a molecular weight of 418.41 g/mol, a formula of C21H21F3N4O2, and a calculated LogP of 3.9. It is soluble in DMSO (10 mM in DMSO at 4.2 mg/mL) and should be stored as a powder at -20°C for up to 3 years.
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| Toxicity/Toxicokinetics |
Toxicity data for ART558 are not reported in the available sources. As a research compound, it is not intended for therapeutic use. The compound has been evaluated in cellular assays at concentrations up to 10 μM, but specific toxicological profiles have not been characterized.
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| References | |
| Additional Infomation |
ART558 is a research compound for studying Polθ-mediated DNA repair in cancer. It is a potent and selective allosteric inhibitor that elicits BRCA-gene synthetic lethality and DNA damage. The compound is available from commercial suppliers for research use only. A reference describing its discovery is available (Zatreanu D, et al. Nat Commun. 2021 Jun 17;12(1):3636).
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| Molecular Formula |
C21H21F3N4O2
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|---|---|
| Molecular Weight |
418.412255048752
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| Exact Mass |
418.161
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| CAS # |
2603528-97-6
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| PubChem CID |
156068882
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| Appearance |
White to off-white solid powder
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| LogP |
3.9
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
30
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| Complexity |
679
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| Defined Atom Stereocenter Count |
2
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| SMILES |
FC(C1C=C(C)N=C(C=1C#N)N1CC[C@H]([C@H]1C(N(C)C1C=CC=C(C)C=1)=O)O)(F)F
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| InChi Key |
YHMDHAMZFMNMTF-MSOLQXFVSA-N
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| InChi Code |
InChI=1S/C21H21F3N4O2/c1-12-5-4-6-14(9-12)27(3)20(30)18-17(29)7-8-28(18)19-15(11-25)16(21(22,23)24)10-13(2)26-19/h4-6,9-10,17-18,29H,7-8H2,1-3H3/t17-,18+/m1/s1
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| Chemical Name |
(2S,3R)-1-[3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl]-3-hydroxy-N-methyl-N-(3-methylphenyl)pyrrolidine-2-carboxamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~170 mg/mL (~406.30 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (11.95 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: 4.25 mg/mL (10.16 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 42.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3900 mL | 11.9500 mL | 23.9000 mL | |
| 5 mM | 0.4780 mL | 2.3900 mL | 4.7800 mL | |
| 10 mM | 0.2390 mL | 1.1950 mL | 2.3900 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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