Hypoxia is a state where oxygen availability/delivery is below the level necessary to maintain physiological oxygen tension for a particular tissue. It is well-established that when tissue demand exceeds its oxygen supply, a cascade of intracellular events is activated. Meanwhile, the expression of hypoxia-inducible factors (HIFs) is increased. HIFs are transcription factors that respond to changes in available oxygen in the cellular environment. The elevation of the expression of HIFs induces the extensive transcriptional response regulating angiogenesis, glucose metabolism, cell growth, metastasis and other processes.
HIFs are a family of three members and they are heterodimers of an O2 sensitive α subunit (HIF-1α, or HIF-2α or HIF-3α) and an O2 insensitive HIF-1β subunit12. HIF-1 and HIF-2 can mediate the hypoxic response, which has both overlapping and unique target genes. Importantly, HIF-1 and HIF-2 can exert opposite effects on the regulation of angiogenic response. Although both isoforms may upregulate the expression of pro-angiogenic vascular endothelial growth factor (VEGF), HIF-1 diminished the expression of interleukin-8 (IL-8) by inhibition of the Nrf2 transcription factor whereas HIF-2 augmented the expression of IL-8 in an Nrf2-independent way but via upregulation of SP-1 activity. Moreover, the opposite regulation of c-Myc transcription factor by both HIF isoforms may influence IL-8 regulation.
M1002 is a potent HIF-2 agonist.
M1002 can enhance the expression of HIF-2 target genes (i.e. VEGA, EPO, and NDRG1) with greater efficacy than M1001. M1002 enhances the physical association of HIF-2α and ARNT in a dose-dependent fashion. M1002 could increase the interactions between HIF-1α and ARNT, but only at higher compound concentrations. But M1002 had no discernible effect on the association of NPAS3 with ARNT. M1002 also shows synergy with prolyl-hydroxylase domain (PHD) inhibitors.
All in all, M1002, a HIF-2 agonist, can enhance the expression of HIF-2 target genes. M1002 shows synergy with prolyl-hydroxylase domain (PHD) inhibitors.