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

Zhao, Z.; Karunanidhi, M.; Gold, S.; St John, L.; Liaqat, R.; Iwanaszko, M.; Bigas, C.; Uchida, E.; Mineji, K.; Watanabe, J.; Aznar-Benitah, S.; Hashizume, R.; Mishra, R.; Shilatifard, A.

doi:10.64898/2026.07.30.741768

bioRxiv · 10.64898/2026.07.30.741768

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

Zhao, Z.·Karunanidhi, M.·Gold, S.·St John, L.·Liaqat, R.·Iwanaszko, M.·Bigas, C.·Uchida, E.·Mineji, K.·Watanabe, J.·Aznar-Benitah, S.·Hashizume, R.·Mishra, R.·Shilatifard, A.

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Abstract

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.

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Zhao, Z., Karunanidhi, M., Gold, S., St John, L., Liaqat, R., Iwanaszko, M., Bigas, C., Uchida, E., Mineji, K., Watanabe, J., Aznar-Benitah, S., Hashizume, R., Mishra, R., Shilatifard, A.. 2026-07-31. FCD-11: A First-in-Class COMPASS Inhibitor in Cancer Therapeutics. https://doi.org/10.64898/2026.07.30.741768

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