Table 1 Ilorasertib enzyme and cellular pharmacodynamics potency

From: Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial

Kinase Biochemical IC50, nMa (95% confidence limits) Cellular PD marker IC50, nM (95% confidence limits)
Aurora A 120 (117–123) 189 (153–233)b
Aurora B 7 (2–14) 13 (5–27)b
   21 (11–42)c
Aurora B (Y156H)d 12 (11–17) ND
Aurora C 1 (1–2) 13 (5–27)b
VEGFR1 1 (0.6–2) 0.3 (0.1–0.4)e
VEGFR2 2 (1–3) 5 (4–7)e
VEGFR3 43 (18–93) 2 (0.1–23)e
FLT-3 1 (0.9–2) 2 (2–3)e
CSF-1R 3 (2–4) 3 (0.8–8)e
c-KIT 20 (6–25) 45 (33–64)e
PDGFR-α 11 (6–21) 16 (6–19)e
PDGFR-β 13 (1–46) 11 (4–28)e
  1. ATPadenosine triphosphate, CSF-1R colony-stimulating factor 1 receptor, FLT-3fms-like tyrosine kinase 3, IC50 half maximal inhibitory concentration, NDnot determined, PD pharmacodynamic, PDGFRplatelet-derived growth factor receptor, VEGFR vascular endothelial growth factor receptor.
  2. aEnzyme assays were conducted in homogeneous time-resolved fluorescence format using 1 mM ATP.14
  3. bAurora A, B, and C autophosphorylation was performed in nocodazole-arrested HeLa cells by western analysis using phospho-A, phospho-B, and phospho-C-specific antibodies.
  4. cPhosphorylation of histone H3.
  5. dAurora B kinase Y156H mutant.
  6. eCellular phosphorylation assays for VEGFR2, CSF-1R, KIT, PDGFR-α,14 and PDGFR-β were ligand stimulated for 5 to 20 min for optimal phosphorylation depending on receptor type. FLT-3 was constitutively phosphorylated in SEM cells; inhibition was determined after 60 min of exposure to the compound. VEGFR1 activity was determined in BaF3 cells expressing the TEL:VEGFR1 catalytic domain fusion using proliferation as a surrogate readout.
  7. Reproduced by kind permission of the American Society for Pharmacology and Experimental Therapeutics, from Glaser et al.10