Name: Cobimetinib
Price: 392.00 USD

- Overview
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    Background
    
    Cobimetinib is a selective inhibitor of mitogen-activated protein kinase kinase (MEK) with IC50 value of 0.9 nM [1].MEK is a kinase enzyme which selectively phosphorylates Ser/Thr and Tyr residues and involved in the mitogen-activated protein kinase (MAPK) signaling pathways that play an important role in regulation of cell proliferation, survival, differentiation, motility and angiogenesis [2]. In a KRAS G13D and B-RAF G464V mutant MDA-MB-231T breast adenocarcinoma cells, Cobimetinib inhibited MEK with IC50 value of 0.2 nM [1]. In pharmacokinetic-pharmacodynamic (PK-PD) model, Cobimetinib showed a sustained tumor pharmacodynamic response due to longer residence in tumor than in plasma [3]. In WM-266-4 xenograft mice, Cobimetinib decreased %pERK in tumor with IC50 values of 0.78 (WM-266-4) and 0.52 mM. Also, Cobimetinib (3.89 mM) increased IC50 value in WM-266-4 mice. In A375 xenograft mice, Cobimetinib (0.3-30 mg/kg) showed antitumor efficacy in a dose-dependent way. Cobimetinib is currently in phase I clinical trials as a potential antitumor agent [3].
    
    [1]. Rice KD, Aay N, Anand NK, et al. Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med Chem Lett, 2012, 3(5): 416-421.
    [2]. Akinleye A, Furqan M, Mukhi N, et al. MEK and the inhibitors: from bench to bedside. J Hematol Oncol, 2013, 6: 27.
    [3]. Wong H, Vernillet L, Peterson A, et al. Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. Clin Cancer Res, 2012, 18(11): 3090-3099.
- Properties
  - Alternative Name
    
    GDC-0973;XL-518;GDC 0973;XL 518;GDC0973;XL518; [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone
    
    CAS Number
    
    934660-93-2
    
    Molecular Formula
    
    C21H21F3IN3O2
    
    Molecular Weight
    
    531.31
    
    Purity
    
    98.98%
    
    Solubility
    
    ≥26.55 mg/mL in DMSO; insoluble in H2O; ≥33.53 mg/mL in EtOH with gentle warming
    
    Storage
    
    Store at -20°C
    
    * For Research Use Only
- Reference
  - 1. Julia C Gutjahr, Elisabeth Bayer, et al. "CD44 Engagement Enhances Acute Myeloid Leukemia Cell Adhesion To The Bone Marrow Microenvironment By Increasing VLA-4 Avidity." Haematologica. 2020 Jul 2;haematol.2019.231944.. PMID:32616529
    2. White SM, Avantaggiati ML, et al. "YAP/TAZ Inhibition Induces Metabolic and Signaling Rewiring Resulting in Targetable Vulnerabilities in NF2-Deficient Tumor Cells." Dev Cell. 2019 May 6;49(3):425-443.e9. PMID:31063758
    3. Kulshrestha A, Katara GK, et al. "Targeting V-ATPase Isoform Restores Cisplatin Activity in Resistant Ovarian Cancer: Inhibition of Autophagy, Endosome Function, and ERK/MEK Pathway." J Oncol. 2019 Apr 1;2019:2343876. PMID:31057611
    4. Brunen D, de Vries RC, et al. "PIM Kinases Are a Potential Prognostic Biomarker and Therapeutic Target in Neuroblastoma." Mol Cancer Ther. 2018 Apr;17(4):849-857. PMID:29440296
    5. Gutjahr JC, Szenes E, et al. "Microenvironment-induced CD44v6 promotes early disease progression in chronic lymphocytic leukemia." Blood. 2018 Mar 22;131(12):1337-1349. PMID:29352038