vh-298

Description: VH-298 is a novel and highly potent inhibitor of the VHL:HIF-alpha protein-protein interaction with a Kd value of 80 to 90 nM, and has been used in PROTAC technology. Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. VH298 is a potent VHL inhibitor that stabilizes HIF-alpha and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-alpha protein-protein interaction downstream of HIF-alpha hydroxylation by PHD enzymes. VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-alpha in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling.

References: Nat Commun. 2016 Nov 4; 7:13312.