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FCD-11: A First-in-Class COMPASS Inhibitor in Cancer Therapeutics

Zibo Zhao, Meenal Karunanidhi, Sarah Gold

    Biorxiv : the Preprint Server for Biology
    |August 20, 2026
    PubMed

    Insights

    A new drug, FCD-11, effectively inhibits COMPASS (Complex of proteins associated with Set1) activity, a key driver in metastatic breast cancer. This discovery offers promising therapeutic potential for treating cancers reliant on SET1A/COMPASS.

    Area of Science:

    • Biochemistry
    • Molecular Biology
    • Cancer Research

    Background:

    • COMPASS (Complex of proteins associated with Set1) regulates histone methylation (H3K4), crucial for gene expression.
    • SET1A, a COMPASS protein, is upregulated in metastatic breast cancer, promoting tumor spread.
    • Abnormal COMPASS activity is linked to various cancers, highlighting it as a therapeutic target.

    Purpose of the Study:

    • To identify and characterize a novel small molecule inhibitor of COMPASS activity.
    • To evaluate the preclinical efficacy of the inhibitor in breast cancer models.

    Main Methods:

    • Designed FCD-11 to disrupt the COMPASS complex interface (SET domains, ASH2L, RBBP5).
    • Assessed FCD-11's inhibitory effects on SET1A/COMPASS and MLL1/COMPASS methyltransferase activity in vitro.
    • Utilized ChIP-seq and CETSA to confirm FCD-11's selective inhibition of SET1A/COMPASS in cellular models.
    • Tested FCD-11's efficacy in reducing tumor size and improving survival in mouse models of breast cancer.

    Main Results:

    • FCD-11 demonstrated potent inhibition of H3K4 methyltransferase activity for SET1A/COMPASS and MLL1/COMPASS.
    • FCD-11 selectively targeted SET1A/COMPASS activity in both mouse embryonic stem cells and breast cancer cell lines.
    • In vivo studies showed FCD-11 significantly reduced tumor burden and prolonged survival in preclinical breast cancer models.

    Conclusions:

    • FCD-11 is a first-in-class, COMPASS-specific inhibitor with significant preclinical efficacy.
    • FCD-11 exhibits therapeutic potential for breast cancer and other malignancies dependent on SET1A/COMPASS activity.

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