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    TAK-733
    TAK-733

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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 #: V0459
    CAS #: 1035555-63-5Purity ≥98%

    Description: TAK-733 is a novel, potent, selective and orally bioavailable allosteric (non-ATP competitive) inhibitor of MEK with potential anticancer activity. It inhibits MEK with an IC50 of 3.2 nM for MEK1, ans shows no effects against Abl1, AKT3, c-RAF, CamK1, CDK2, c-Met. TAK-733 has potential antineoplastic activity and has been advanced to Phase I clinical studies for cancer treatment. It selectively binds to and inhibits the activity of MEK1/2, preventing the activation of MEK1/2-dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling and tumor cell proliferation. TAK-733 has been reported to broadly inhibit tumor activity in mouse xenograft models of human cancer (melanoma, colorectal, NSCLC, pancreatic and breast cancer).

    References: Bioorg Med Chem Lett. 2011 Mar 1;21(5):1315-9.

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    Molecular Weight (MW)504.23
    FormulaC17H15F2IN4O4
    CAS No.1035555-63-5
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 101 mg/mL (200.3 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    SMILESO=C1C(C(NC2=CC=C(I)C=C2F)=C(F)C(N3C)=O)=C3N=CN1C[[email protected]@H](O)CO
    Synonyms

    TAK 733; TAK733; TAK-733

    Chemical Name: (R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

    InChi Key: RCLQNICOARASSR-SECBINFHSA-N

    InChi Code: InChI=1S/C17H15F2IN4O4/c1-23-15-12(16(27)24(7-21-15)5-9(26)6-25)14(13(19)17(23)28)22-11-3-2-8(20)4-10(11)18/h2-4,7,9,22,25-26H,5-6H2,1H3/t9-/m1/s1

    SMILES Code: O=C1C(C(NC2=CC=C(I)C=C2F)=C(F)C(N3C)=O)=C3N=CN1C[[email protected]@H](O)CO 


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    In Vitro

    In vitro activity: TAK-733 is a novel potent, selective and orally bioavailable allosteric inhibitor of MEK with IC50 of 3.2 nM for MEK1, it is inactive to Abl1, AKT3, c-RAF, CamK1, CDK2, c-Met, etc. TAK-733 has potential antineoplastic activity and has been advanced to Phase I clinical studies for cancer treatment. It selectively binds to and inhibits the activity of MEK1/2, preventing the activation of MEK1/2-dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling and tumor cell proliferation. TAK-733 has been reported to broadly inhibit tumor activity in mouse xenograft models of human cancer (melanoma, colorectal, NSCLC, pancreatic and breast cancer). TA


    Kinase Assay: K-733 is highly potent and selective MEK allosteric site inhibitor with IC50 of 3.2 nM. TAK-733 shows potent enzymatic and cell activity with an EC50 of 1.9 nM against ERK phosphorylation in cells. 


    Cell Assay: TAK-733 showed broad activity in most melanoma cell lines with relative resistance observed at IC50 > 0.1 μmol/L in vitro. Moreover, Cell lines with a BRAF or KRAS mutation were associated with sensitivity to TAK-733 with an IC50 value of < 0.5μM.

    In VivoTAK-733 demonstrates broad antitumor activity in mouse xenograft models of human cancer including models of melanoma, colorectal, NSCLC, pancreatic and breast cancer. TAK-733 is well tolerated with pharmacokinetics and pharmacodynamics that support once-daily oral dosing in humans. TAK-733 shows maximally efficacious doses at once daily orally doses of 10 mg/kg.
    Animal modelHuman solid tumor xenograft models including NSCLC (NCI H23 [KRAS and LKB1 mutations]), CRC (SW620 [KRAS, APC, p53 mutations]) Pancreatic cancer (Panc 1 and Capan 1 [KRAS mutations] and BxPC-3 [No MAPK mutations]) models in immunocompromised mice.
    Formulation & DosageDissolved in saline; 10 mg/kg; Oral gavage
    ReferencesBioorg Med Chem Lett. 2011 Mar 1;21(5):1315-9.


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

    TAK-733

    (A) Tumor growth inhibition index of 11 PDTX tumor models administered with TAK-733 (10 mg/kg) for 30 days. (B-E) Representative tumor growth inhibition curves of four melanoma PDTX models administered with vehicle or TAK-733 (10 mg/kg) for the indicated study days.  2015 Feb;14(2):317-25.

    TAK-733

    Pharmacokinetic and pharmacodynamic effects of TAK-733 in A375 tumor-bearing mice following oral administration of (A) 1 mg/kg or (B) 10 mg/kg dose. A375 tumor cells were implanted subcutaneously in the flank of nu/nu mice (3/time point). Administration was initiated when all mice had tumors ranging in size from 300 to 500 mm3 (Day 10). TAK-733 was given as a single oral dose.  2015 Feb;14(2):317-25.

    TAK-733

    Effects of TAK-733 on growth of A375 melanoma tumor xenografts in athymic nude mice. A375 melanoma cells were implanted subcutaneously in the flank of nu/nu mice (5/group). Administration was initiated 10 days after the tumor implant, when all mice had tumors ranging in size from 80 to 225 mm3 (Day 10). TAK-733 was given orally daily for 14 days (QD 1-14) or 3 days per week for 2 cycles (M, TH, SAT ×2).  2015 Feb;14(2):317-25.

    TAK-733

    Tumor regrowth kinetics for PDTX model MB1374 administered with vehicle or TAK-733 (10 mg/kg). Inset, original tumor growth inhibition study for 30 days. Red lines indicate TAK-733 administration times, black lines indicate cessation of TAK-733 for tumor regrowth periods.  2015 Feb;14(2):317-25.

    TAK-733

    Antiproliferative effects of TAK-733 against a panel of human cutaneous melanoma cell lines. Cell lines were treated with increasing doses of TAK-733 for 72 hours and proliferation was assessed using the SRB assay. IC50 values are depicted. BRAF and NRAS mutational status in depicted in the table below.  2015 Feb;14(2):317-25.

    TAK-733

    Immunoblot analysis of downstream effectors upon administration of TAK-733. A375 and RPMI 7951 cell lines were serum starved overnight and then administered TAK-733 for 1 hr. Cells were then challenged with 10% FBS for 30 mins, harvested and immunoblotted with the indicated antibodies.  2015 Feb;14(2):317-25.


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