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    ML323
    ML323

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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 #: V1330
    CAS #: 1572414-83-5Purity ≥98%

    Description: ML323 (ML-323; ML 323) is a novel, potent and highly selective USP1-UAF1 inhibitor with potential antitumor activity. It inhibits USP1-UAF1 with an IC50 of 76 nM. ML323 inhibits the USP1-UAF1 deubiquitinase complex with excellent selectivity against human DUBs, deSUMOylase, deneddylase and unrelated proteases. ML323 links deubiquitination to DNA damage responses. ML323 potentiates cisplatin cytotoxicity in non-small cell lung cancer and osteosarcoma cells. USP1-UAF1 is a key regulator of the DNA damage response and a target for overcoming resistance to the platinum-based anticancer drugs. 

    References: Nat Chem Biol. 2014 Apr;10(4):298-304

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    Molecular Weight (MW)384.48
    FormulaC23H24N6
    CAS No.1572414-83-5
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 76 mg/mL (197.7 mM)
    Water:<1 mg/mL
    Ethanol: 38 mg/mL (98.8 mM)
    SMILES Code CC1=CN=C(C2=CC=CC=C2C(C)C)N=C1NCC3=CC=C(N4N=NC=C4)C=C3
    Synonyms ML-323; ML 323; ML323.


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    In Vitro

    In vitro activity: ML323 inhibits the deubiquitination of PCNA and FANCD2 by inhibiting USP1–UAF1 activity in H596 cells. Moreover, ML323 potentiates cisplatin cytotoxicity in NSCLC H596 cells and U2OS osteosarcoma cells by targeting two major DNA damage response pathways (TLS and FA).


    Kinase Assay: For HTS, USP1-UAF1 activity is monitored using ubiquitin-rhodamine 110 as a substrate, where hydrolysis of the amide bond between the C-terminal glycine of ubiquitin and rhodamine results in an increase in fluorescence. The assay is miniaturized to a 4 μL volume in a 1,536-well format and is used to screen approximately 402,701 compounds in quantitative HTS mode, with each compound tested over a range of four to five concentrations. The assay shows robust performance with an average Z’factor of 0.8 throughout the screen.  


    Cell Assay: For the colony-forming assay, cells are seeded at a density of 300–500 cells per well in six-well plates and grown overnight. Cells are then treated with ML323 alone, cisplatin alone or a combination of cisplatin and ML323 (1:1 or 1:4) at the indicated concentrations. Cells treated with an equal volume of DMSO and saline are used as control. After 48 h of treatment, fresh growth medium is added, and cells are incubated for an additional 5-10 d to allow for colony formation. For UV combination treatment, the cells are treated with ML323 at the indicated concentrations or an equal volume of DMSO. After 48 h, the medium is removed, and cells are irradiated at 254 nm at the indicated dosage. Fresh growth medium is added, and the cells are incubated for an additional 5-10 d to allow for colony formation. The cells without UV irradiation but treated with ML323 or an equal volume of DMSO are used as controls and designated as 100%. After the formation of the colonies, cells are fixed with methanol and stained with 0.5% crystal violet. Colonies consisting of >50 cells are scored. The number of colonies is determined from triplicate plates. The dose-response curves are generated using GraphPad Prism and analyzed by using CalcuSyn to calculate the combination index, which is determined for the fraction of cells affected after the addition of fixed ratios of cisplatin and the USP1-UAF1 inhibitor.

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    References

    Nat Chem Biol. 2014 Apr;10(4):298-304


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

    ML323

    Selective inhibition of USP1 by ML323 revealed by DUB profiling.  2014 Apr;10(4):298-304.

    ML323

    The effect of inhibiting USP1-UAF1 by ML323 in the TLS and FA pathways.  2014 Apr;10(4):298-304.
     


    ML323

    Inhibition of USP1-UAF1 by ML323 decreases HR and SCE in U2OS cells.  2014 Apr;10(4):298-304.


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