HIF (Hypoxia-inducible factor) is a transcriptional factor that plays a role in the physiologic responses to hypoxia. Most oxygen-breathing species express the highly conserved transcriptional complex HIF-1. HIF-1 is a heterodimer consisting of an oxygen-regulated HIF-1α and HIF-2α subunits and a constitutively expressed HIF-1β subunit. The HIF signaling cascade mediates the effects of hypoxia, the state of low oxygen concentration, on the cell. Importantly, Hypoxia often keeps cells from differentiating. However, hypoxia promotes the formation of blood vessels, and is important for the formation of a vascular system in embryos, and cancer tumors. The hypoxia in wounds also promotes the migration of keratinocytes and the restoration of the epithelium.
HIF-α is the master transcriptional regulator of cellular and developmental response to hypoxia. Under normoxic conditions, HIF-α subunits have a very short half-life. Cells continuously synthesize and degrade HIF-α protein. However, under decreasing concentrations of oxygen, the degradation of HIF-α is retarded. The dysregulation and overexpression of HIF-α play an important role in cancer biology, as well as a number of other pathophysiologies, specifically in areas of vascularization and angiogenesis, energy metabolism, cell survival, and tumor invasion.
FM19G11 is a potent inhibitor of HIF-α protein in hypoxia. FM19G11 can inhibit HIF-α protein accumulation in tumor cell lines and embryonic stem cells. Meanwhile, directly regulates expression and inhibits transcriptional activity of pluripotency markers (Sox2 and Oct4) in rodent and human stem cells under hypoxic conditions, driving differentiation. Therefore, FM19G11 promotes oligodendrocyte differentiation under hypoxia. Besides, FM19G11 favors spinal cord injury regeneration and stem cell self-renewal by mitochondrial uncoupling and glucose metabolism induction. In vivo, FM19G11 treatment improves locomotion in severe spinal cord injury.
All in all, FM19G11, a HIF-α-subunit inhibitor, inhibits transcriptional activity of HIF-α isoforms.