Abstract
<jats:p>COMPASS (Complex of proteins associated with Set1) are highly conserved chromatin regulatory complexes responsible for all methylation marks on histone H3 lysine 4 (H3K4). The COMPASS protein SET1A is upregulated in metastatic breast cancer, and its H3K4 methyltransferase activity promotes metastasis in a palmitic acid diet setting. We identify and characterize FCD-11, a first-in-class small molecule inhibitor of COMPASS activity designed to disrupt the termolecular interface between COMPASS SET domains, ASH2L, and RBBP5. FCD-11 significantly inhibited the H3K4me3 methyltransferase activity of SET1A/COMPASS and MLL1/COMPASS in vitro. ChIP-seq and CETSA indicated that FCD-11 selectively inhibits SET1A/COMPASS activity in mouse embryonic stem cells and breast cancer cell lines. FCD-11 significantly reduced tumor size and extended survival in mouse models of breast cancer. Our findings establish FCD-11 as a potent, COMPASS-specific inhibitor lead compound with preclinical efficacy in breast cancer models and therapeutic potential for cancers with abnormal dependence on SET1A/COMPASS activity.</jats:p>