ART558 |
Catalog No.GC62553
One-Click Copy Product Info
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ART558 is a potent and selective low-molecular-weight allosteric inhibitor of DNA polymerase Polθ, with a molecular weight (MW) in the nanomolar range and an IC50 of 7.9 nM.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 2603528-97-6
Sample solution is provided at 25 µL, 10mM.
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ART558 is a potent and selective low-molecular-weight allosteric inhibitor of DNA polymerase Polθ, with a molecular weight (MW) in the nanomolar range and an IC50 of 7.9 nM. Art558 functions by stabilizing the closed conformation of Polθ while bound to DNA, effectively blocking its polymerase activity. ART558 specifically targets Theta-Mediated End Joining, a major DNA repair process mediated by Polθ, while sparing Non-Homologous End Joining mechanisms [1-3].
ART558 (0-50 μM; 2 days) demonstrated maximal reduction of Cas9-induced mutation frequency at 10 μM in wild-type cells. Additionally, ART558(10 μM) attenuates mutagenic repair at Cas9-induced breaks in mouse embryonic stem cells [3]. ART558 (1-3 μM) induces Polθ-dependent radiosensitization in cancer cell lines. The cell-cycle-related effects of Polθ inhibition by ART558 in combination with radiation are also observed [4]. In the absence of Polθ, RAD52 accumulations suppress single-stranded DNA (ssDNA) gap-filling during the G2/M phase and promote MRE11 nuclease accumulation. Conversely, the survival of BRCA1-deficient cells treated with the Polθ inhibitor ART558 (10 μM) is not rescued by RAD52 suppression. Instead, ssDNA gap-filling is hindered by the direct inhibition of the polymerase activity itself [5]. Furthermore, ART558 (0–25 μM; 2 days) sensitized both pancreatic cell lines (Capan-1 and HTERT HPNE cells) to sub-lethal doses of cisplatin [6].
References:
[1]. Zatreanu, D., Robinson, et al. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat Commun 12, 3636 (2021). https://doi.org/10.1038/s41467-021-23463-8
[2]. Stockley ML, Ferdinand A, et al. Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta. J Med Chem. 2022 Oct 27;65(20):13879-13891. doi: 10.1021/acs.jmedchem.2c01142. Epub 2022 Oct 6. Erratum in: J Med Chem. 2023 Feb 23. doi: 10.1021/acs.jmedchem.3c00204. PMID: 36200480.
[3]. Schimmel J, Muñoz-Subirana N, et al. Modulating mutational outcomes and improving precise gene editing at CRISPR-Cas9-induced breaks by chemical inhibition of end-joining pathways. Cell Rep. 2023 Feb 28;42(2):112019. doi: 10.1016/j.celrep.2023.112019. Epub 2023 Jan 25. PMID: 36701230
[4]. Rodriguez-Berriguete G, et al. Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models. Clin Cancer Res. 2023 Apr 14;29(8):1631-1642. doi: 10.1158/1078-0432.CCR-22-2977. PMID: 36689546; PMCID: PMC10102842.
[5]. Ronson GE, Starowicz K, et al. Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting. Nat Commun. 2023 Nov 29;14(1):7834. doi: 10.1038/s41467-023-43677-2. PMID: 38030626; PMCID: PMC10687250.
[6]. Bugbee T, Gathoni M, et al. Inhibition of p300 increases cytotoxicity of cisplatin in pancreatic cancer cells. Gene. 2023 Dec 20;888:147762. doi: 10.1016/j.gene.2023.147762. Epub 2023 Sep 2. PMID: 37666373; PMCID: PMC10563798.
| Cell experiment [1]: | |
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Cell lines |
Mouse embryonic stem cells (mESC) |
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Preparation Method |
Wild-type and Pol-θ-deficient mESC were pretreated with ART558 at different concentrations and transfected with Cas9-wild type (WT) and sgHPRT_ex3.1. |
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Reaction Conditions |
0-50μM;2days |
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Applications |
ART558 exhibited maximal reduction in Cas9-induced mutation frequency at a concentration of 10 μM in wild-type cells, without exerting additional effects on the already reduced mutation frequency observed in Polϴ-deficient cells. |
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References: |
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| Cas No. | 2603528-97-6 | SDF | |
| Formula | C21H21F3N4O2 | M.Wt | 418.41 |
| Solubility | 85 mg/mL in DMSO(Need ultrasonic) | Storage | 4°C, away from moisture and light |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.39 mL | 11.95 mL | 23.9 mL |
| 5 mM | 478 μL | 2.39 mL | 4.78 mL |
| 10 mM | 239 μL | 1.195 mL | 2.39 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
μL
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Calculation results:
Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL saline, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >98.00% Appearance: A solid
- COA (Certificate of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 19 reference(s) in Google Scholar.)