Avutometinib

製品コードS7170 バッチS717004

印刷

化学情報

Synonyms

RO5126766,CH5126766,VS 6766, CKI-27, R-7304, RG-7304

Storage
(From the date of receipt)

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

化学式

C₂₁H₁₈FN₅O₅S

分子量

471.46

CAS No.

946128-88-7

Solubility (25°C)*

体外

DMSO

94 mg/mL (199.38 mM)

Water

Insoluble

Ethanol

Insoluble

体内（毎回新しく調製した物を用意してください）

Clear solution

5% DMSO 1 45% PEG 300 2 ddH2O

1.0mg/ml

Taking the 1 mL working solution as an example, add 50 μL of 20 mg/ml clarified DMSO stock solution to 450 μL PEG 300, mix evenly to clarify it; then continue to add 500 μL ddH2O to adjust the volume to 1 mL. 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	Avutometinib(RO5126766,CH5126766,VS 6766, CKI-27, R-7304, RG-7304) is a dual RAF/MEK inhibitor with IC50 of 8.2 nM,19 nM, 56 nM, and 160 nM for BRAF V600E, BRAF, CRAF, and MEK1, respectively. Phase 1.
in vitro	In HCT116 KRAS-mutant colorectal cancer cells, CH5126766 significantly reduces the levels of phospho-MEK and phospho-ERK. CH5126766 inhibits RAF kinase by binding to MEK1, and causes MEK to become a dominant negative inhibitor of RAF. ^[1] In Raf or RAS-mutant cell lines SK-MEL-28, SK-MEL-2, MIAPaCa-2, SW480, HCT116, and PC3 cells, CH5126766 inhibits cell growth with IC50 of 65, 28, 40, 46, and 277 nM, respectively. In two melanoma cell lines with the BRAF V600E or NRAS mutation, RO5126766 induces G1 cell cycle arrest accompanied by up-regulation of the CDK inhibitor p27 and down-regulation of cyclinD1. ^[3]
in vivo	In an HCT116 (G13D KRAS) mouse xenograft model, CH5126766 (25 mg/kg, p.o.) inhibits ERK signaling output more effectively than a standard MEK inhibitor that induces MEK phosphorylation and has potent antitumor activity. ^[1] In the HCT116 (K-ras) and COLO205 (B-raf) mutant xenografts, CH5126766 (0.3 mg/kg) causes significant decreases in [18 F]FDG uptake. ^[2] In the SK-MEL-2 xenograft model, RO5126766 also suppresses the tumor growth. ^[3]

プロトコル(参考用のみ)

キナーゼアッセイ	MEK and RAF kinase enzyme assays
キナーゼアッセイ	The inhibitory activities against CRAF, BRAF, or BRAF V600E enzymes are measured by quantification of phosphorylation of inactive K97R MEK1 [MEK1] by recombinant RAF proteins [BRAF: B-RAF wt, BRAF V600E: B-RAF V600E or CRAF: Raf-1] with Europium-anti-MEK1/2 (pSer218/222) antibody and SureLight allophycocyanine-anti-6his antibody by measuring time-resolved fluorescence (TRF). Alternatively, the inhibitory activities against the RAF enzymes are measured by quantification of phosphorylation of a fluorescein-labeled peptide corresponding to human MEK1 212-224 and human MEK2 217-229 (5-Fl-SGQLIDSMANSFV-NH2, MEKtide) by using the IMAP fluorescence polarization (FP) Screening Express Kit. Inhibition of MEK1 is evaluated by a coupled assay with active MEK1 (MEK1 S218E/S222E) and unactive dephosphorylated ERK2 (MAP kinase 2/Erk 2). The phosphorylation of a fluorescent-labeled peptide substrate (FAM-Erktide, IPTTPITTTYFFFK-5FAM-COOH) by ERK2 is quantified by using the IMAP FP Screening Express Kit.
細胞アッセイ	細胞株	SK-MEL-28, SK-MEL-2, MIAPaCa-2, SW480, A549, HCT15, HCT116, and PC3 cells
	濃度	~10 μM
	反応時間	72 h
	実験の流れ	The number of viable cells is determined using the Cell Counting Kit-8 assay according to the manufacturer's instructions. After the incubation of cells for 72 h with the indicated concentrations of various agents, kit reagent WST-8 is added to the medium and incubated for a further 4 h. The absorbance of samples (450 nm) is determined using a scanning multiwell spectrophotometer that serves as an ELISA reader. Cell numbers and viability are also measured using the ViaCount Assay according to the manufacturer's instructions.
動物実験	動物モデル	Female BALB-nu/nu mice bearing HCT116, Calu-6 or COLO205 tumors
	投薬量	~25 mg/kg
	投与方法	p.o.

参考

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：

Neuronal differentiation drives the antitumor activity of mitogen-activated protein kinase kinase (MEK) inhibition in glioblastoma [ Neurooncol Adv, 2023, 5(1):vdad132]	PubMed: 38130900
Anatomic position determines oncogenic specificity in melanoma [ Nature, 2022, 604(7905):354-361]	PubMed: 35355015
Strategies to inhibit FGFR4 V550L-driven rhabdomyosarcoma [ Br J Cancer, 2022, 10.1038/s41416-022-01973-6]	PubMed: 36097178
AP1/Fra1 confers resistance to MAPK cascade inhibition in pancreatic cancer [ Cell Mol Life Sci, 2022, 80(1):12]	PubMed: 36534167
Targeting Discoidin Domain Receptors DDR1 and DDR2 overcomes matrix-mediated tumor cell adaptation and tolerance to BRAF-targeted therapy in melanoma [ EMBO Mol Med, 2021, e11814]	PubMed: 34957688
Inhibition of MEK pathway enhances the antitumor efficacy of chimeric antigen receptor T cells against neuroblastoma [ Cancer Sci, 2021, 112(10):4026-4036]	PubMed: 34382720
Structural basis for the action of the drug trametinib at KSR-bound MEK [ Nature, 2020, 588(7838):509-514]	PubMed: 32927473
Growth Factor Receptor Signaling Inhibition Prevents SARS-CoV-2 Replication [ Mol Cell, 2020, 80(1):164-174.e4]	PubMed: 32877642
Activation of Skeletal Stem and Progenitor Cells for Bone Regeneration Is Driven by PDGFRβ Signaling. [ Dev Cell, 2019, 51(2):236-254]	PubMed: 31543445
Dual-targeting of EGFR and Neuropilin-1 attenuates resistance to EGFR-targeted antibody therapy in KRAS-mutant non-small cell lung cancer. [ Cancer Lett, 2019, 466:23-34]	PubMed: 31521695

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。

各々の製品のための特定の保管と取扱い情報は、製品データシートの上で示されます。大部分のSelleck製品は、推薦された状況の下で安定です。製品は、推薦された保管温度と異なる温度で、時々出荷されます。長期の保管のために必要とされてそれと異なる温度で、多くの製品は、短期もので安定です。品質を維持するが、夜通しの積荷のために最も経済的な貯蔵状況を用いてあなたの送料を保存する状況の下に、製品が出荷されることを、我々は確実とします。製品の受領と同時に、製品データシートの上で貯蔵推薦に従ってください。