ARS-853 |
| رقم الكتالوجGC19037 |
ARS-853 هو مثبط نشط للخلايا وانتقائي وتساهمي KRAS G12C مع IC 50 من 2.5 ميكرومتريثبط ARS-853 الإشارات التي تحركها KRAS المتحولة من خلال الارتباط بالبروتين الورمي المرتبط بالناتج المحلي الإجمالي ومنع التنشيط
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Cas No.: 1629268-00-3
Sample solution is provided at 25 µL, 10mM.
ARS-853 is a selective, covalent KRASG12C inhibitor with an IC50 of 2.5 uM.
ARS853 is designed to bind KRASG12C with high affinity. Treatment of KRASG12C-mutant lung cancer cells with ARS853 reduces the level of GTP-bound KRAS by more than 95% (10 uM). ARS853 inhibits proliferation with an inhibitory concentration 50% (IC50) of 2.5 uM, which is similar to its IC50 for target inhibition. ARS853 (10 uM) inhibits effector signaling and cell proliferation to varying degrees in six KRASG12C mutant lung cancer cell lines, but not in non-KRASG12C models. Similarly, it completely suppresses the effects of exogenous KRASG12C expression on KRAS-GTP levels, KRAS-BRAF interaction, and ERK signaling. ARS-853 treatment also induces apoptosis in four KRASG12C mutant cell lines. ARS853 selectively reduces KRAS-GTP levels and RAS-effector signaling in KRASG12C-mutant cells, while inhibiting their proliferation and inducing cell death[1]. ARS-853 inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation[2].
References:
[1]. Lito P, et al. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science. 2016 Feb 5;351(6273):604-8.
[2]. Patricelli MP, et al. Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. Cancer Discov. 2016 Mar;6(3):316-29.
Kinase experiment: | Purified KRAS (1 μM) is incubated EDTA (10 mM) and GDP (1 mM) or GTPγS (1 mM) at room temperature for 1 h followed by addition of MgCl2 (1 mM) to terminate the reaction. ARS853 (1 μM) is then added and the mixture is incubated for another hour at room temperature. HEK293 cells expressing various KRAS mutants are treated with ARS853. Proteins are extracted using a buffer containing 9M urea, 10 mM DTT and 50 mM ammonium bicarbonate, pH 8, heated to 65°C for 15 min and alkylated using 50 mM iodoacetamide at 37°C for 30 min. The samples are desalted by gel filtration in Zeba spin desalting plates followed by addition of sequencing-grade trypsin to a concentration of 10 μg/ml, and incubation for one hour at 37°C. Heavy isotopic standards (25 fmol) of the KRASG12C target peptide and KRAS normalization peptide are added to the samples followed by desalting in Strata-X polymeric reverse phase plates. LC-MS/MS analysis is performed in a Q Exactive quadrupole orbitrap mass spectrometer under standard condition. The amount of KRASG12C bound by the drug is determined by the ratio of the modified G12C peptide to that of the heavy isotopic standards[1]. |
References: [1]. Lito P, et al. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science. 2016 Feb 5;351(6273):604-8. | |
| Cas No. | 1629268-00-3 | SDF | |
| Canonical SMILES | ClC1=C(C2(C)CC2)C=C(NCC(N3CCN(C4CN(C(C=C)=O)C4)CC3)=O)C(O)=C1 | ||
| Formula | C22H29ClN4O3 | M.Wt | 432.94 |
| الذوبان | DMSO : ≥ 71 mg/mL (164.00 mM) | Storage | Store at -20°C |
| 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 | 2.3098 mL | 11.5489 mL | 23.0979 mL |
| 5 mM | 0.462 mL | 2.3098 mL | 4.6196 mL |
| 10 mM | 0.231 mL | 1.1549 mL | 2.3098 mL |
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