FCD-11 is a first-in-class, selective small molecule inhibitor of histone methyltransferases COMPASS (Complex of proteins associated with Set1), specifically inhibits the H3K4me3 activity of SET1A/COMPASS and MLL1/COMPASS with IC50 of 1.32 uM and 3.26 uM.
FCD-11 shows no activity against DOT1L, G9a, PRDM9, and SETDB1.
FCD-11 potently inhibits SET1A/COMPASS-mediated H3K4me3 activity with IC50 of 0.46 uM in in vitro methylation assays, weakly affects SET1B and MLL3 activities.
FCD-11 inhibits MLL4-mediated H3K4me1 activity and MLL1-mediated H3K4me3 activity, with an IC50 of approximately 0.85 uM for MLL1.
FCD-11 disrupts the ASH2L-RBBP5 interaction, which is correlated with SET1A/COMPASS HMTase inhibition.
FCD-11 resembles genetic loss of catalytic SET1A/COMPASS activity in mESCs.
FCD-11 inhibits breast cancer cell viability, diminishes SET1A/COMPASS deposited H3K4me3 peaks, and impairs in vivo tumor growth.