ARS-853

製品コードS8156 バッチS815603

印刷

化学情報

Synonyms

N/A

Storage
(From the date of receipt)

3 years -20°C powder
1 years -80°C in solvent

化学式

C₂₂H₂₉ClN₄O₃

分子量

432.94

CAS No.

1629268-00-3

Solubility (25°C)*

体外

DMSO (warmed with 50ºC water bath)

86 mg/mL (198.64 mM)

Ethanol (warmed with 50ºC water bath)

7 mg/mL (16.16 mM)

Water

Insoluble

体内（毎回新しく調製した物を用意してください）

Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O この製剤はselleckのラボで検証済みです。上記の溶解方法がご要望を満たさない場合、selleckの営業担当までお問い合わせ頂ければ、個別の試験を行います。	4.300mg/ml (9.93mM)	Taking the 1 mL working solution as an example, add 50 μL of 86 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to clarify; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.
Clear solution	5% DMSO 1 95% Corn oil この製剤はselleckのラボで検証済みです。上記の溶解方法がご要望を満たさない場合、selleckの営業担当までお問い合わせ頂ければ、個別の試験を行います。	0.710mg/ml (1.64mM)	Taking the 1 mL working solution as an example, add 50 μL of 14.2 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. The mixed solution should be used immediately for optimal results.

* <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-853は、GDP結合オンコプロテインに結合し、活性化を阻害することで、変異型KRAS駆動シグナル伝達を阻害する選択的共有結合性KRAS(G12C)阻害剤です。ARS-853はアポトーシスも誘導します。
in vitro	ARS-853 treatment of KRAS^G12C cells led to a dose-dependent and nearly complete inhibition of CRAF-RBD (RBD)-mediated pulldown of KRAS from lysates, with an IC50 of approximately 1 μmol/L. Treatment of H358 cells by this compound resulted in a significant loss of KRAS–CRAF interactions. Consistent with an inactive state of KRAS^G12C once bound to this chemical, downstream signaling through both MAPK (including pMEK, pERK, and pRSK) and PI3K signaling (pAKT) pathways was inhibited by it in H358 and other KRAS^G12C cell lines. The inhibition of RAF-RBD pulldown and KRAS downstream signaling was sustained over a period of 72 hours, accompanied by G1 cell-cycle arrest, loss of Cyclin D1 and Rb expression, and an increase in the cell-cycle inhibitor p27 KIP1. In addition, hallmarks of apoptosis, including cleaved PARP and increases in sub-diploid DNA, were observed in H358 cells following treatment with this compound. No effects on RAF-RBD binding or downstream signaling were observed in A549 cells (KRASG12S), and the inhibitory effects of it in H358 cells could be rescued by ectopic expression of KRAS^G12V. KRAS^G12C is the most potent covalent target of this chemical across more than 2,700 cellular proteins and consistently find that it exerts no effects on cellular signaling or growth in non-KRAS^G12C cells at concentrations up to 10-fold higher than its KRAS^G12C potency. It reacts only with the inactive (GDP-bound), but the not the active (GTP-bound), state of KRAS. This compound reduced KRAS-GTP levels and ERK phosphorylation in human embryonic kidney 293 (HEK293) or H358 cells engineered to express KRAS^G12C but not in those expressing KRAS^G12C/A59G. It traps KRAS^G12C in a GDP-bound conformation by lowering its affinity for nucleotide exchange factors.

製品説明

ARS-853は、GDP結合オンコプロテインに結合し、活性化を阻害することで、変異型KRAS駆動シグナル伝達を阻害する選択的共有結合性KRAS(G12C)阻害剤です。ARS-853はアポトーシスも誘導します。

in vitro

ARS-853 treatment of KRAS^G12C cells led to a dose-dependent and nearly complete inhibition of CRAF-RBD (RBD)-mediated pulldown of KRAS from lysates, with an IC50 of approximately 1 μmol/L. Treatment of H358 cells by this compound resulted in a significant loss of KRAS–CRAF interactions. Consistent with an inactive state of KRAS^G12C once bound to this chemical, downstream signaling through both MAPK (including pMEK, pERK, and pRSK) and PI3K signaling (pAKT) pathways was inhibited by it in H358 and other KRAS^G12C cell lines. The inhibition of RAF-RBD pulldown and KRAS downstream signaling was sustained over a period of 72 hours, accompanied by G1 cell-cycle arrest, loss of Cyclin D1 and Rb expression, and an increase in the cell-cycle inhibitor p27 KIP1. In addition, hallmarks of apoptosis, including cleaved PARP and increases in sub-diploid DNA, were observed in H358 cells following treatment with this compound. No effects on RAF-RBD binding or downstream signaling were observed in A549 cells (KRASG12S), and the inhibitory effects of it in H358 cells could be rescued by ectopic expression of KRAS^G12V. KRAS^G12C is the most potent covalent target of this chemical across more than 2,700 cellular proteins and consistently find that it exerts no effects on cellular signaling or growth in non-KRAS^G12C cells at concentrations up to 10-fold higher than its KRAS^G12C potency. It reacts only with the inactive (GDP-bound), but the not the active (GTP-bound), state of KRAS. This compound reduced KRAS-GTP levels and ERK phosphorylation in human embryonic kidney 293 (HEK293) or H358 cells engineered to express KRAS^G12C but not in those expressing KRAS^G12C/A59G. It traps KRAS^G12C in a GDP-bound conformation by lowering its affinity for nucleotide exchange factors.

プロトコル(参考用のみ)

細胞アッセイ	細胞株	H358 (G12C) cells
	濃度	0.05, 0.1, 0.5, 1, 5, 10, 50 μM
	反応時間	5 h
	実験の流れ	KRAS^G12C mutant cells (H358) were treated with ARS853 for 5 hours. The effect on the level of active, or GTP-bound, KRAS was determined by a RAS-binding domain pull-down (RBD:PD) assay and immunoblotting with a KRAS-specific antibody.

参考

https://pubmed.ncbi.nlm.nih.gov/26739882/
https://pubmed.ncbi.nlm.nih.gov/26841430/

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：

Real-time monitoring of the reaction of KRAS G12C mutant specific covalent inhibitor by in vitro and in-cell NMR spectroscopy [ Sci Rep, 2023, 10.1038/s41598-023-46623-w]	PubMed: 37935773
HDLBP promotes hepatocellular carcinoma proliferation and sorafenib resistance by suppressing Trim71-dependent RAF1 degradation [ Cell Mol Gastroenterol Hepatol, 2022, S2352-345X(22)00216-8]	PubMed: 36244648
Profiling oncogenic KRAS mutant drugs with a cell-based Lumit p-ERK immunoassay [ SLAS Discov, 2022, S2472-5552(22)12517-7]	PubMed: 35288294
Investigation of KRAS Dependency Bypass and Functional Characterization of All Possible KRAS Missense Variants [ ProQuest, 2020, N/A]	PubMed: None
Coxsackievirus Type B3 Is a Potent Oncolytic Virus against KRAS-Mutant Lung Adenocarcinoma. [ Mol Ther Oncolytics, 2019, 14:266-278]	PubMed: 31463367

長期の保管のために-20°Cの下で製品を保ってください。

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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