ORY-1001 is a highly potent and selective KDM1A inhibitor with IC50 value of 18nM. It engaged
enzymatically active KDM1A in THP1 cells with an EC50 of 0.63nM and 0.55 nM after 24 and 96 hr of treatment, respectively. Inhibition of KDM1A by ORY-1001 induced H3K4me2 accumulation on KDM1A target genes. The ten genes that were most potently induced after 96 hr were VCAN, S100A8, S100A9, S100A12, LYZ, ANXA2, ANXA8, OSBPL11, KCKN13, and FCRLA. Genes significantly downregulated by ORY-1001 include genes de-regulated in MLL-translocated AML (CCL5, RHOBTB3, HOXA9, HOXA10, HOXA11) as well as genes identified as direct targets of MLL-AF9 or MLL-AF4 (HOXA10, CDK6, SLC38A1, HIVEP2, ARHGAP25, TAPT1, REEP3, PPP3R2, and FLT3) and KIT. ORY-1001 potently reduced the colony-forming potential in a variety of AML cell lines, with MLL-translocated AML cell lines such as THP1 (MLL-AF9) and MV(4;11) (MLL-AF4) being the most sensitive, and induced blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibited potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduced growth of an AML xenograft model, and extends survival in a mouse PDX model of T cell acute leukemia at dose of 0.0125mg/kg[2].
作用机制
ORY-1001 could rapidly and covalently bind to the FAD cofactor in KDM1A in a manner analogous to tranylcypromine.[2]
搜索
