| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 2mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| Other Sizes |
|
Purity: ≥98%
ARS-853 is a novel, potent, selective, and covalent inhibitor of KRAS(G12C) with IC50 of 2.5 μM. It binds to the GDP-bound oncoprotein and blocks activation, thereby inhibiting mutant KRAS-driven signaling. About 30% of human malignancies have mutations that cause KRAS to become defunct. For cancers containing KRAS mutations, no targeted treatment has been found as of yet. As determined by ARS-853 engagement and inhibition rates as well as a mutant-specific mass spectrometry-based assay for determining KRAS activation status, KRAS(G12C) nucleotide state is in a state of dynamic flux that is influenced by upstream signaling factors. These studies offer strong evidence that the KRAS(G12C) mutation results in a "hyperexcitable" state as opposed to a "statically active" state, and that developing novel anti-RAS therapeutics by focusing on the GDP-bound, inactive form of the protein is a promising strategy.
| Targets |
KRAS(G12C) (IC50 = 2.5 μM)
|
||
|---|---|---|---|
| ln Vitro |
ARS853 is intended to bind KRASG12C highly selectively. When ARS853 is administered to lung cancer cells with KRASG12C mutations, the amount of GTP-bound KRAS is decreased by over 95% (10 μM). With an inhibitory concentration 50% (IC50) of 2.5 μM, ARS853 inhibits proliferation in a manner comparable to its IC50 for target inhibition. Six KRASG12C mutant lung cancer cell lines show varying degrees of inhibition from ARS853 (10 μM) on effector signaling and cell proliferation, but not in non-KRASG12C models. Likewise, it entirely nullifies the impacts of external KRASG12C expression on KRAS-GTP concentrations, KRAS-BRAF communication, and ERK signaling. Four KRASG12C mutant cell lines also undergo apoptosis in response to ARS-853 treatment. In KRASG12C-mutant cells, ARS853 specifically lowers KRAS-GTP levels and RAS-effector signaling while preventing cell division and causing cell death[1]. Through binding to GDP-bound oncoprotein and blocking activation, ARS-853 inhibits mutant KRAS-driven signaling[2].
|
||
| ln Vivo |
|
||
| Enzyme Assay |
Purified KRAS (1 μM) is incubated for 1 hour at room temperature with EDTA (10 mM), GDP (1 mM), or GTPηS (1 mM).The reaction is then stopped with the addition of MgCl2 (1 mM). After adding ARS853 (1 μM), the mixture is left to sit at room temperature for an additional hour. ARS853 is applied to HEK293 cells that express different KRAS mutants. A buffer containing 9 M urea, 10 mM DTT, and 50 mM ammonium bicarbonate, pH 8, is used to extract proteins. It is heated to 65°C for 15 minutes and alkylated for 30 minutes at 37°C using 50 mM iodoacetamide. The samples undergo gel filtration in Zeba spin desalting plates to remove salt, after which 10 μg/ml of sequencing-grade trypsin is added and the mixture is incubated for an hour at 37°C. The KRASG12C target peptide and KRAS normalization peptide heavy isotopic standards (25 fmol) are added to the samples, and then the samples are desalted in Strata-X polymeric reverse phase plates. Under standard conditions, LC-MS/MS analysis is carried out in a Q Exactive quadrupole orbitrap mass spectrometer. The ratio of the modified G12C peptide to the heavy isotopic standards[1] indicates how much KRASG12C is bound by the medication.
|
||
| Cell Assay |
ARS853 was applied to KRASG12C mutant cells (H358) for a duration of five hours. Using a KRAS-specific antibody and an RAS-binding domain pull-down (RBD:PD) assay, the impact on the amount of active, or GTP-bound, KRAS was assessed.
|
||
| Animal Protocol |
|
||
| References |
| Molecular Formula |
C22H29CLN4O3
|
|
|---|---|---|
| Molecular Weight |
432.94
|
|
| Exact Mass |
432.949
|
|
| Elemental Analysis |
C, 61.03; H, 6.75; Cl, 8.19; N, 12.94; O, 11.09
|
|
| CAS # |
1629268-00-3
|
|
| Related CAS # |
|
|
| Appearance |
Solid powder
|
|
| SMILES |
CC1(CC1)C2=CC(=C(C=C2Cl)O)NCC(=O)N3CCN(CC3)C4CN(C4)C(=O)C=C
|
|
| InChi Key |
IPFOCHMOYUMURK-UHFFFAOYSA-N
|
|
| InChi Code |
InChI=1S/C22H29ClN4O3/c1-3-20(29)27-13-15(14-27)25-6-8-26(9-7-25)21(30)12-24-18-10-16(22(2)4-5-22)17(23)11-19(18)28/h3,10-11,15,24,28H,1,4-9,12-14H2,2H3
|
|
| Chemical Name |
1-[3-[4-[2-[4-chloro-2-hydroxy-5-(1-methylcyclopropyl)anilino]acetyl]piperazin-1-yl]azetidin-1-yl]prop-2-en-1-one
|
|
| Synonyms |
|
|
| HS Tariff Code |
2934.99.9001
|
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
|
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
|
|---|
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3098 mL | 11.5489 mL | 23.0979 mL | |
| 5 mM | 0.4620 mL | 2.3098 mL | 4.6196 mL | |
| 10 mM | 0.2310 mL | 1.1549 mL | 2.3098 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.
 Identification of a covalent KRASG12Cinhibitor active in cells.Cancer Discov.2016 Mar;6(3):316-29 |
|---|
 Proteomic cysteine profiling of ARS-853 selectivity.Cancer Discov.2016 Mar;6(3):316-29 |
 Cellular activity and selectivity of ARS-853.Cancer Discov.2016 Mar;6(3):316-29
|
 Cellular activity and selectivity of ARS-853.Cancer Discov.2016 Mar;6(3):316-29 |
|---|
 The kinetics of cellular G12C engagement and signaling inhibition with a GDP-state selective inhibitor demonstrates rapid nucleotide cycling of KRASG12Cbetween GTP- and GDP-bound states.Cancer Discov.2016 Mar;6(3):316-29 |
 Modulation of KRASG12Cactivity alters ARS-853 target engagement and supports novel therapeutic strategies for targeting KRAS.Cancer Discov.2016 Mar;6(3):316-29 |
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
