An activator of PHD2, KRH102140, decreases angiogenesis via inhibition of HIF-1α.

Hypoxia-inducible transcription factors (HIFs) play a pivotal role in the response of cells to hypoxia. HIFs are dimers of an oxygen-sensitive α-subunit (HIF-1α or HIF-2α), and a constitutively expressed β-subunit. In normoxia, HIF-1α is destabilized by post-translational hydroxylation of Pro-564 and Pro-402 by a family of oxygen-sensitive dioxygenases. Prolyl hydroxylation leads to von Hippel–Lindau protein-dependent ubiquitination and rapid degradation of HIF-1α. We previously reported that KRH102053, an activator of PHD2, rapidly decreased HIF-1α and eventually inhibited angiogenesis. Here, we report a potent activator of PHD2, KRH102140, which has a structure similar to KRH102053. KRH102140 more efficiently suppressed HIF-1α than KRH102053 in human osteosarcoma cells under hypoxia. Furthermore, KRH102140 decreased the mRNA levels of HIF-regulated downstream target genes associated with angiogenesis and energy metabolism such as vascular endothelial growth factor, adrenomedullin, Glut1, aldolase A, enolase 1 and monocarboxylate transporter 4. KRH102140 also inhibited tube formation in human umbilical vein endothelium cells. The results suggest that KRH102140 has potential therapeutic effects in alleviating various diseases associated with HIFs.