ART558 |
カタログ番号GC62553
One-Click Copy Product Info
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ART558は有効的な、選択的なDNAポリメラーゼPol θの低分子量アロステリックの阻害剤である。分子量（MW）はナノモル範囲以内であり、IC50は7.9nMである。
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.
ART558は有効的な、選択的なDNAポリメラーゼPol θの低分子量アロステリックの阻害剤である。分子量（MW）はナノモル範囲以内であり、IC50は7.9nMである。それはDNAに結合したときにPol θの閉じたコンフォメーションを安定させ、ポリメラーゼ活性を効果的に遮断することに役立つ。ART558は特にThetaが媒介した末端結合をターゲットにし（Pol θによって媒介される主要なDNA修復プロセス）、その同時に非相同末端連結機構の保持もできる[1-3]。ART558（0~50 μ M；2日）が野生型細胞で10 μ Mを示したときにCas9誘発した突然変異頻度が最小化させる。なお、ART558(10 μM)はCas9誘導した鼠の胚幹細胞断裂の変異形成修復を弱めることができる[3]。ART558 (1-3 μM)はがん細胞株におけるPol θ依存性放射線増感を誘発する。ART558 と放射線の組み合わせは、Polθ の細胞周期関連効果を阻害することも観察できる[4]。 Polθが不足の場合では、RAD52の蓄積はG2/M 期の一本鎖 DNA (ssDNA) ギャップの充填を阻害でき、MRE11ヌクレアーゼの蓄積を促進する。逆に、Polθ阻害剤ART558（10μM）で処理したBRCA1欠損細胞の生存はRAD52阻害によって回復されなかった。対照的に、ポリメラーゼ活性自体を直接阻害すると、ssDNA ギャップの充填がブロックされる [5]。なお、ART558（0-25 μ M、2days）は2つの膵臓細胞株（Capan-1とHTERT HPNE細胞）を致死量未満のシスプラチンに対して感作させる[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.
| 細胞実験[1]: | |
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細胞株 |
鼠の胚性幹細胞 (mESC) |
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準備方法 |
野生型およびPol-θ欠陥型mESCに異なる濃度のART558で前処理し、Cas9野生型（WT）およびsgHPRT_ex3.1でトランスフェクションする。 |
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反応条件 |
0-50μM;2days |
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アプリケーション |
ＡＲＴ５５８は、野生型細胞において１０μＭの濃度でＣａｓ９誘発変異頻度の最小化を示し、Ｐｏｌκ欠損細胞で観察されたすでに減少した変異頻度にさらなる効果を及ぼさなかった。 |
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References: |
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| Cas No. | 2603528-97-6 | SDF | |
| Formula | C21H21F3N4O2 | M.Wt | 418.41 |
| 溶解度 | 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.)