ARS-1620

Catalog No.S8707

ARS-1620 Chemical Structure

Molecular Weight(MW): 430.84

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.

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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
KRAS (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].

Assay
Methods Test Index PMID
Western blot
RAS-GTP / RAS / pERK / p-S6 / p-AKT / Cleaved-PARP; 

PubMed: 29373830     


RAS-GTP pull-down and immunoblot analysis of KRAS mutant lung cancer cells following a 24 hr treatment with DMSO or ARS-1620, R-atropisomer, or an analog of ARS-1620 containing a saturated acrylamide

29373830
Growth inhibition assay
Cell viability; 

PubMed: 29373830     


(D) Rescue of ARS-1620 anti-proliferative effects in H358 cells by inducible overexpression of FLAG-KRAS (G12V) (n = 2 technical replicates). (E) The anti-proliferative effect of ARS-1620 on Ras-less MEFs ectopically expressing human WT, G12C, G12D, or G12V KRAS (n = 2 technical replicates).

29373830
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

Cell Research:

[1]

+ Expand
  • 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.


    (Only for Reference)
Animal Research:

[1]

+ Expand
  • Animal Models: 6- to 8-week-old male BALB/c mice
  • Formulation: formulated in water solution with 1% N-methyl-2-pyrrolidone, 19% polyethylene glycol 400, and 10% cyclodextrin and then sterilized by filtration for IV dosing; Oral formulation was prepared in solution (100% Labrasol)
  • Dosages: 2 and 10 mg/kg
  • Administration: intravenous (IV) bolus or oral gavage administration
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 86 mg/mL (199.61 mM)
Ethanol 60 mg/mL (139.26 mM)
Water 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.

Chemical Information

Molecular Weight 430.84
Formula

C21H17ClF2N4O2

CAS No. 1698055-85-4
Storage powder
in solvent
Synonyms N/A

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID