Avutometinib

Catalog No.S7170 Batch:S717003

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Technical Data

Formula

C21H18FN5O5S
Molecular Weight 471.46 CAS No. 946128-88-7
Solubility (25°C)* In vitro DMSO 94 mg/mL (199.38 mM)
Water Insoluble
Ethanol 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 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.
Targets
BRAF V600E [1]
(cell-free assay)		 BRAF [1]
(cell-free assay)		 CRAF [1]
(cell-free assay)		 MEK1 [1]
(cell-free assay)
8.2 nM 19 nM 56 nM 160 nM
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]

Protocol (from reference)

Kinase Assay:

[1]
  • MEK and RAF kinase enzyme assays

    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.
Cell Assay:

[3]
  • Cell lines

    SK-MEL-28, SK-MEL-2, MIAPaCa-2, SW480, A549, HCT15, HCT116, and PC3 cells

  • Concentrations

    ~10 μM

  • Incubation Time

    72 h

  • Method

    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.
Animal Study:

[1]
  • Animal Models

    Female BALB-nu/nu mice bearing HCT116, Calu-6 or COLO205 tumors

  • Dosages

    ~25 mg/kg

  • Administration

    p.o.

Selleck's Avutometinib has been cited by 16 publications

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

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