Potent and Selective Chemical Probe of Hypoxic Signalling Downstream of HIF-α Hydroxylation via VHL Inhibition

Julianty Frost, Carles Galdeano, Pedro Soares, Morgan S Gadd, Katarzyna M Grzes, Lucy Ellis, Ola Epemolu, Satoko Shimamura, Marcus Bantscheff, Paola Grandi, Kevin D Read, Doreen A Cantrell, Sonia Rocha, etc.

Nat Commun. 2016 Nov 4;7:13312.

PMID: 27811928

Abstract:

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. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4245531	VH298			Price