Figure 6.

Analysis of KDM1A target engagement and PK/PD of ORY-1001. A, IC₅₀ determination of rKDM1A inhibition of different compounds. B, KDM1A target engagement in human AML (MV(4;11); filled symbols) and prostate cancer cell lines (LNCaP; open symbols) after treatment with KDM1A inhibitors. KDM1A TE was measured after a 24-h incubation with ORY-1001 (circles), OG-675 (rhombi), TCP (squares), SP-2509 (inverted triangles), or PGL (triangle). In LNCaP, SP-2509 was tested at 250 nm due to overt cytotoxicity, and the treatment at 3 mm PGL was limited to 4 h for the same reason. C, KDM1A plasma pharmacokinetics (N = 1, n = 3, mean ± S.D. (error bars)) and PBMC pharmacodynamics (pooled samples from three animals; N = 2, n = 3, mean ± S.E. (error bars)) in rats treated with 2.5 μg/kg ORY-1001. D, KDM1A plasma pharmacokinetics (N = 1, n = 3, mean ± S.D. (error bars)) and PBMC pharmacodynamics (pooled samples from three animals; N = 2, n = 3, mean ± S.E. (error bars)) in rats treated with 15 μg/kg ORY-1001. N, biological replicates of independent experiments; n, technical replicates.