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    Alectinib (CH5424802)
    Alectinib (CH5424802)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0606
    CAS #: 1256580-46-7 (free base)Purity ≥98%

    Description: Alectinib (formerly also known as AF802, CH5424802 or RO5424802) is a potent, selective, and orally bioavailable ALK (anaplastic lymphoma kinase)  tyrosine kinase inhibitor with IC50 value of 1.9 nM in cell-free assays. Alectinib was approved by the Food and Drug Administration (FDA) for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC).

    References: Cancer Cell. 2011 May 17;19(5):679-90; Bioorg Med Chem. 2012 Feb 1;20(3):1271-80. 

    Related CAS: 1256589-74-8 (HCl); 1256580-46-7 (free base) 

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    Molecular Weight (MW)482.62
    FormulaC30H34N4O2
    CAS No.1256580-46-7 (free base)
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 0.5 mg/mL (1.0 mM)
    Water: <1 mg/mL
    Ethanol:<1 mg/mL
    Solubility (In vivo)30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL
    SynonymsAlectinib, CH5424802, CH 5424802, RO 5424802; AF802, CH-5424802, RO5424802, AF 802, AF-802, RO-5424802, brand name: Alecensa


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    In Vitro

    In vitro activity: The dissociation constant (KD) value of CH5424802 for ALK in an ATP-competitive manner is 2.4 nM. CH5424802 has substantial inhibitory potency against both native ALK and L1196M with Ki of 0.83 nM and 1.56 nM, respectively. CH5424802 prevents autophosphorylation of ALK in NCI-H2228 NSCLC cells expressing EML4-ALK. CH5424802 also suppresses the phosphorylation of STAT3 and AKT, but not of ERK1/2. CH5424802 completely inhibits the phosphorylation of STAT3 at Tyr705. CH5424802 is preferentially efficacious against NCI-H2228 cells expressing EML4-ALK, but not ALK fusion-negative NSCLC cell lines, including HCC827 cells (EGFR exon 19 deletion), A549 cells (KRAS mutant), or NCI-H522 cells (EGFR wild-type, KRAS wild-type, and ALK wild-type) in monolayer culture. CH5424802 elicits an apoptotic marker—caspase-3/7-like activation—in NCI-H2228 spheroid cells. CH5424802 blocks the growth of two lymphoma lines, KARPAS-299 and SR, with NPM-ALK fusion protein but does not influence the growth of an HDLM-2 lymphoma line without ALK fusion. CH5424802 displays high target selectivity and the stronger anti-proliferative activity against KARPAS-299. CH5424802 inhibits KAPRAS-299 with an IC50 of 3 nM, and KDR with IC50 of 1.4 μM. The metabolic stability of CH5424802 is very high.


    Kinase Assay: The inhibitory ability against each kinase except for MEK1 and Raf-1 is evaluated by examining their ability to phosphorylate various substrate peptides in the presence of CH5424802 using time-resolved fluorescence resonance energy transfer (TR-FRET) assay or fluorescence polarization (FP) assay. The inhibitory activity against MEK1 is evaluated by quantitative analysis of the phosphorylation of a substrate peptide by a recombinant ERK2 protein in the presence of CH5424802. The inhibitory activity against Raf-1 is evaluated by examining the ability of the kinases to phosphorylate MEK1 in the presence of CH5424802.


    Cell Assay: Cells (NSCLC, A549 and HCC827) are seeded in 96-well plates overnight and incubated with various concentrations of CH5424802 for the indicated time. For spheroid cell growth inhibition assay, cells are seeded on spheroid plates, incubated overnight, and then treated with compound for the indicated times. The viable cells are measured by the Luminescent Cell Viability Assay. Caspase-3/7 assay is evaluated using the Caspase-Glo 3/7 Assay Kit.

    In VivoOral administration of CH5424802 dose-dependently inhibits tumor growth with an ED50 of 0.46 mg/kg and tumor regression. Treatment of 20 mg/kg CH5424802 reveals rapid tumor regression by 168%, the tumor volume in any mouse is<30 mm3 after 11 days of treatment (at day 28), a potent antitumor effect is maintained, and tumor regrowth does not occur throughout the 4-week drug-free period. The half-life and the oral bioavailability of CH5424802 in mice are 8.6 hours and 70.8%, respectively. At a repeated dose of 6 mg/kg, the mean plasma levels reached 1.7, 1.5, and 0.3 nM at 2, 7, and 24 hours post-dose, respectively. Administration of CH5424802 leads to tumor growth prevention and tumor regression. Tumor growth inhibition at 20 mg/kg is 119% for KARPAS-299 and 104% for NB-1 on day 20. CH5424802 inhibits the phosphorylation of STAT3 in a dose-dependent manner (2–20 mg/kg). A partial decrease in AKT phosphorylation is also observed in CH5424802-treated xenograft tumors.
    Animal modelSCID or nude mice bearing NCI-H2228
    Formulation & DosageFormulated in 0.02 N HCl, 10% DMSO, 10% Cremophor EL, 15% PEG400, and 15% HPCD (2-hydroxypropyl-β-cyclodextrin);  20 mg/kg;  Oral gavage
    References

    Cancer Cell. 2011 May 17;19(5):679-90; Bioorg Med Chem. 2012 Feb 1;20(3):1271-80. 


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Alectinib (CH5424802)

    The structure and cytotoxicity of alectinib. . 2017 Mar; 49(3): e303.

    Alectinib (CH5424802)

    Potentiation of the anticancer effects of paclitaxel by alectinib in the KBv200 cell xenograft nude mice model. The tumor growth curve was drawn to monitor the tumor volume with time after implantation. The data shown are expressed as the mean±s.d. of the tumor volume for each group (n=9) (a).  . 2017 Mar; 49(3): e303.

    Alectinib (CH5424802)

    Effect of alectinib on the intracellular accumulations of DOX and Rho 123 in MDR cells and in their parental sensitive cells. . 2017 Mar; 49(3): e303.

    Alectinib (CH5424802)

    Effect of alectinib on the efflux of Rho 123, ATPase activity and the [125I]-IAAP photoaffinity labeling of ABCB1 and ABCG2. . 2017 Mar; 49(3): e303.

    Alectinib (CH5424802)

    Effect of alectinib on the expression levels of ABCB1 or ABCG2 in MDR cells. . 2017 Mar; 49(3): e303.

    Alectinib (CH5424802)

    Effect of alectinib on the inhibition of AKT, ERK and c-Met phosphorylation. . 2017 Mar; 49(3): e303.

    Alectinib (CH5424802)

    Alectinib increased the accumulation of Rho 123 and enhanced the cytotoxicity of DOX in ABCB1-overexpressing primary leukemia blasts. . 2017 Mar; 49(3): e303.

    Alectinib (CH5424802)

    A schematic model illustrating the reversal of MDR by alectinib. . 2017 Mar; 49(3): e303.



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