P3FI-90 is a specific small molecule inhibitor of KDM3B with SPR KD of 7.68 uM, inhibits PAX3-FOXO1 activity and blocks PAX3-FOXO1 downstream target gene expression.
P3FI-90 can phenocopies shRNA knockdown of PAX3-FOXO1 when considering the sum of normalized enrichment scores of downregulated PAX3-FOXO1 gene sets.
P3FI-90 does not decrease the amount of PAX3-FOXO1 protein.
P3FI-90 downregulatesthe target genes of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma (FP-RMS) and had broad activity in other pediatric solid tumor cell lines.
P3FI-90 inhibits multiple KDMs including KDM3B, KDM4B, KDM5A, and KDM6B, with highest potency against KDM3B with IC50 of 7 uM.
P3FI-90 shows no inhibitory activity against HDAC1, HDAC2, HDAC3, or PRMT5.
P3FI-90 increases H3K4 and H3K9 methylation.
P3FI-90 shows sub-micromolar EC50 activity in fusion-positive rhabdomyosarcoma (FP-RMS) (RH4, EC50=0.9 uM).
P3FI-90 decreases chromatin loop strength and decreases topologically associating domains (TADs) at PAX3-FOXO1 sites.
P3FI-90 inhibits multiple KDMs with highest selectivity for KDM3B.
P3FI-90 also exerts potent growth inhibitory activity on Ewing's sarcoma and osteosarcoma cell lines.
P3FI-90 effectively inhibits FP-RMS tumor growth in mouse models of RMS without significant weight loss at 25 mg/kg.