ARS-1620

製品コードS8707 バッチS870703

印刷

化学情報

Chemical Structure Synonyms N/A Storage
(From the date of receipt)		 3 years -20°C powder
化学式

C21H17ClF2N4O2
分子量 430.84 CAS No. 1698055-85-4
Solubility (25°C)* 体外 DMSO 86 mg/mL (199.61 mM)
Ethanol 86 mg/mL (199.61 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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 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.
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].

プロトコル(参考用のみ)

細胞アッセイ 細胞株 H358 cells
濃度 4 μM
反応時間 4 h
実験の流れ

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.
動物実験 動物モデル 6- to 8-week-old male BALB/c mice
投薬量 2 and 10 mg/kg
投与方法 intravenous (IV) bolus or oral gavage administration

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Hedgehog signalling is involved in acquired resistance to KRASG12C inhibitors in lung cancer cells [ Cell Death Dis, 2024, 15(1):56] PubMed: 38225225
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
SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling [ J Exp Med, 2021, 218(1)e20201414] PubMed: 33045063
B2M gene expression shapes the immune landscape of lung adenocarcinoma and determines the response to immunotherapy [ Immunology, 2021, 164(3):507-523] PubMed: 34115389
RAS-Driven Macropinocytosis of Albumin or Dextran Reveals Mutation-Specific Target Engagement of RAS p.G12C Inhibitor ARS-1620 by NIR-Fluorescence Imaging [ Mol Imaging Biol, 2021, 10.1007/s11307-021-01689-8] PubMed: 34905147

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人間や獣医の診断であるか治療的な使用のためにでない。

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