ARS-1620

Catalog No.S8707 Batch:S870705

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Technical Data

Formula

C21H17ClF2N4O2
Molecular Weight 430.84 CAS No. 1698055-85-4
Solubility (25°C)* In vitro DMSO 86 mg/mL (199.61 mM)
Ethanol 5 mg/mL (11.6 mM)
Water Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description ARS-1620 is a potent, orally bioavailable covalent inhibitor of KRASG12C and could achieve rapid and sustained in vivo target occupancy to induce tumor regression.
Targets
K-Ras(G12C) [1]
In vitro

ARS-1620 covalently inhibits KRAS (G12C) activity with high potency and atropisomeric selectivity in p.G12C mutant cancer cells. ARS-1620 rapidly engaged G12C in a concentration- and time- dependent manner consistent with its covalent mechanism of inhibition. Across a panel of cell lines harboring the mutant allele, ARS-1620 exhibited a half maximal G12C target engagement (TE50) at ~0.3 μM and near complete engagement at 3.0 μM after 2 hr of treatment. RS-1620 inhibits RAS-GTP and the phosphorylation of MEK, ERK, RSK, S6, and AKT in a dose-dependent and selective manner in H358 (p.G12C) but not in negative control lung cancer cell lines lacking p.G12C (A549, H460, and H441). ARS-1620 elicits sub-micromolar allele-specific potency (IC50 = 0.3 μM; IC90 = 1 μM). The activity of ARS-1620 is specific to the G12C allele and mediated by the covalent modification of Cys-12[1].
In vivo

ARS-1620 exhibits excellent oral bioavailability (F > 60%) in mice. In MIA-PaCa2 xenografts (p.G12C), ARS-1620 significantly inhibits tumor growth (p < 0.001) in a dose-dependent manner with marked regression at a dose of 200 mg/kg, given once daily. Xenografts of H441 (p.G12V) lack a response at all doses tested and the R-atropisomer of ARS-1620 lacks activity in both models. ARS-1620 selectively induces tumor regression in patient-derived tumor models (harboring KRAS p.G12C)[1].

Protocol (from reference)

Cell Assay:

[1]
  • Cell lines

    H358 cells

  • Concentrations

    4 μM

  • Incubation Time

    4 h

  • Method

    Cells are maintained in a humidified incubator at 37 C with 5% CO2, and grown in RPMI 1640 or DMEM supplemented with 10% FBS and 50 IU ml-1 penicillin/streptomycin.
Animal Study:

[1]
  • Animal Models

    6- to 8-week-old male BALB/c mice

  • Dosages

    2 and 10 mg/kg

  • Administration

    intravenous (IV) bolus or oral gavage administration

Selleck's ARS-1620 has been cited by 17 publications

Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer [ Nat Commun, 2024, 15(1):3741] PubMed: 38702301
Hedgehog signalling is involved in acquired resistance to KRASG12C inhibitors in lung cancer cells [ Cell Death Dis, 2024, 15(1):56] PubMed: 38225225
Tumor Cell Spatial Organization Directs EGFR/RAS/RAF Pathway Primary Therapy Resistance through YAP Signaling [ bioRxiv, 2024, 2024.09.26.615226] PubMed: 39386679
Therapy-induced APOBEC3A drives evolution of persistent cancer cells [ Nature, 2023, 620(7973):393-401] PubMed: 37407818
Multiscale Analysis and Validation of Effective Drug Combinations Targeting Driver KRAS Mutations in Non-Small Cell Lung Cancer [ Int J Mol Sci, 2023, 24(2)997] PubMed: 36674513
Creating MHC-restricted neoantigens with covalent inhibitors that can be targeted by immune therapy [ Cancer Discov, 2022, CD-22-1074] PubMed: 36250888
KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy [ Cell Rep, 2022, 39(12):110993] PubMed: 35732135
Development of a biotin-streptavidin-enhanced enzyme-linked immunosorbent assay (BA-ELISA) for high-throughput screening of KRASG12C inhibitors [ SLAS Discov, 2022, 27(2):107-113] PubMed: 35058184
Clinical Acquired Resistance to KRASG12C Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS-MAPK Reactivation [ Cancer Discov, 2021, 11(8):1913-1922] PubMed: 33824136
Selective and noncovalent targeting of RAS mutants for inhibition and degradation [ Nat Commun, 2021, 12(1):2656] PubMed: 33976200

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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