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    Brigatinib (AP26113)
    Brigatinib (AP26113)

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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 #: V0607
    CAS #: 1197953-54-0 Purity ≥98%

    Description: Brigatinib (formerly known as AP-26113(ALK-IN-1); trade name: Alunbrig) is an orally bioavailable, highly potent and selective ALK inhibitor with IC50 of 0.62 nM in a cell-free assay, it demonstrated the ability to overcome crizotinib resistance mediated by a L1196M mutation. Brigatinib has been approved be FDA in 2017 to treat patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor which has been implicated in numerous solid and hematologic cancers. ALK mutations are reported in about 5-7% of neuroblastoma cases but the ALK-positive percentage increases significantly in the relapsed patient population. AP26113 analog binds to and inhibits ALK kinase and ALK fusion proteins as well as EGFR and mutant forms. This leads to the inhibition of ALK kinase and EGFR kinase, disrupts their signaling pathways and eventually inhibits tumor cell growth in susceptible tumor cells. Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.

    References: Proc Natl Acad Sci U S A. 2011 May 3;108(18):7535-40;  2016 May 26;59(10):4948-64;  2016 May 17;7(20):29011-22.

    Related CAS: 1197953-54-0; 1197958-12-5 (Brigatinib analog)

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    Molecular Weight (MW)584.09
    FormulaC₂₉H₃₉ClN₇O₂P 
    CAS No.1197953-54-0 (Brigatinib); 
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 45 mg/mL (85.1 mM)        
    Water: <1 mg/mL
    Ethanol: 106 mg/mL (200.4 mM)
    Solubility (In vivo)NMP+polyethylene glycol 300 (10+90, v+v): 1 mg/mL
    Synonyms

    AP-26113; AP 26113; Brigatinib-analog; AP26113; Brigatinib; Alunbrig

    Chemical Name: (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

    InChi Key: AILRADAXUVEEIR-UHFFFAOYSA-N

    InChi Code: InChI=1S/C29H39ClN7O2P/c1-35-15-17-37(18-16-35)21-11-13-36(14-12-21)22-9-10-24(26(19-22)39-2)33-29-31-20-23(30)28(34-29)32-25-7-5-6-8-27(25)40(3,4)38/h5-10,19-21H,11-18H2,1-4H3,(H2,31,32,33,34)

    SMILES Code: CN1CCN(C2CCN(C3=CC=C(NC4=NC=C(Cl)C(NC5=CC=CC=C5P(C)(C)=O)=N4)C(OC)=C3)CC2)CC1



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    In Vitro

    In vitro activity: AP26113 is highly active against both sensitive and resistant H3122 cells, decreasing cell growth, suppressing ALK phosphorylation and inducing apoptosis in a dose dependent manner. AP26113 decreases p-ALK in the H3122 and H3122 CR cells, with IC50 values of 7.4 versus 16.8 nM, respectively. AP26113 decreases cell number in Ba/F3 cells expressing either native or mutant EML4-ALK with IC50 of 10 nM and 24 nM, respectively. AP26113 inhibits cell growth of SU-DHL-1, H3122 and Ba/F3-EML4-ALK v1 cell lines with GI50 of 9 nM, 4 nM and 13 nM, respectively. AP26113 inhibits phosphorylation of ALK with IC50 of 3.2 nM, 1.5 nM and 2.1 nM in Karpas-299, SU-DHL-1 and L-82 cell lines. AP26113 dose-dependently inhibits phosphorylation of ALK and ERK in Karpas-299 and H3122 cells. AP26113 inhibits cell growth with IC50 of 11 nM and 16 nM in Ba/F3 line (native EML4-ALK) and Ba/F3 line (EML4-ALK G1269S mutants). AP26113 inhibits ALK phosphorylationh with IC50 of 74 nM and 335 nM in Ba/F3 line (native EML4-ALK) and Ba/F3 line (EML4-ALK E1210K mutants). AP26113 (10 mg/kg-75 mg/kg) is efficacious in PF-02341066-resistant EML4-ALK mutant mouse xenograft models. AP26113 induces regression of tumors expressing native EML4-ALK and the G1269S and L1196M mutants at 25 mg/kg, 50 mg/kg and 50 mg/kg, respectively. AP26113 inhibits EGFR phosphorylation and viability with IC50 of 75 nM and 114 nM, respectively, in Ba/F3 cells expressing EGFR-DEL. AP26113 inhibits EGFR phosphorylation and viability with IC50s of 15 and 281 nM, respectively, in Ba/F3 cells expressing EGFR-DEL/T790M. AP26113 inhibits EGFR phosphorylation with an IC50 of 62 nM and cell growth with a GI50 of 165 nM in a NSCLC line expressing EGFR-DEL (HCC827). AP26113 inhibits EGFR phosphorylation with an IC50 of 59 nM and cell growth with a GI50 of 245 nM in HCC827 cells expressing EGFR-DEL/T790M. AP26113 potently inhibits SLC34A2-ROS-driven signaling and proliferation in a dose dependent manner in HCC78 NSCLC cells.


    Kinase Assay: In vitro HotSpotSM kinase profiling of 289 kinases is performed. The assay is conducted in the presence of 10 μM [33P]-ATP, using brigatinib concentrations ranging from 0.05 nM to 1 μM.


    Cell Assay: Cell growth is assessed using either Cell Titer 96 Aqueous One Solution Cell Proliferation Assay or CyQuant Cell proliferation Assay. 24 hours after plating, cells are treated with AP26113 and grown for 72 hours. The concentration that causes 50% growth inhibition (GI50) is determined by correcting for the cell count at time zero (time of treatment) and plotting data as percent growth relative to vehicle (DMSO) treated cells using XLfit version 4.2.2 for Microsoft Excel. SU-DHL-1, H3122 and Ba/F3-EML4-ALK v1 cell lines are used.

    In VivoAP26113 (< 50 mg/kg) dose-dependently inhibits p-ALK in tumor of Karpas-299 xenograft mice model. AP26113 (< 50 mg/kg) dose-dependently inhibits tumor growth in Karpas-299 xenograft mice model and H3122 xenograft mice model. AP26113 demonstrates favorable properties including moderate in vitro plasma protein binding (47%, 70% and 76% in human, rat, mouse), negligible inhibition of major CYP isoforms. AP26113 (10 mg/kg) is well-tolerated with Cmax of 2587 ng/mL and AUC of 41120 hr.ng/mL in rats. AP26113 (25 mg/kg) leads to tumor regression in HCC827(EGFR-DEL) or HCC827(EGFR-DEL/T790M) xenograft mice model.
    Animal modelKarpas-299 or H3122 xenograft mice model
    Formulation & DosageFormulated in NMP/PEG-400 (10%:90%);  100 mg/kg;  Oral gavage
    ReferencesProc Natl Acad Sci U S A. 2011 May 3;108(18):7535-40


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

    AP26113

    Two different ALK kinase inhibitors, NVP-TAE684 and AP26113, overcome crizotinib resistance in H3122 CR cells. Proc Natl Acad Sci U S A. 2011 May 3; 108(18): 7535–7540.


    AP26113

    AP26113

    Effect of brigatinib in a xenograft neuroblastoma model.  2016 May 17;7(20):29011-22.

    AP26113

    Effect of brigatinib on ALK gain-of-function rough eye phenotypes in a Drosophila ALK model.  2016 May 17;7(20):29011-22.


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