IOX5 is a potent, selective HIF-prolyl hydroxylase (PHD) inhibitor with IC50 of 0.15 uM ((PHD2), does not inhibit other 2OG-dependent oxygenases (JMJD6, FIH, KDM6B etc.).
IOX5 shown to compete with 2OG for binding to PHD2, stabilizes HIF-1α at 0.5 μM in HEK293T cells.
IOX5 does not inhibit any of the other tested human 2OG-dependent oxygenases, including FIH and the histone-modifying 2OG oxygenases lysine-specific demethylase 4A (KDM4A), lysine-specific demethylase 5B (KDM5B), lysine-specific demethylase 6B (KDM6B), JMJD6 at 100 μM and the prolyl hydroxylase OGFOD1 at 50 uM.
stabilizes HIF-1α and substantially impacts AML growth and survival in vitro.
IOX5 compromises both MLL-rearranged and non-MLL AML in vivo, decreases AML engraftment and increases survival in vivo but does not affect normal hematopoiesis.
IOX5 compromises AML in a HIF-α dependent manner, requires the intact HIF system to exhibit its anti-leukemic activity.