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Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-\u03b1 and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-\u03b1 protein\u2013protein interaction downstream of HIF-\u03b1 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-\u03b1 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.<\/jats:p>","DOI":"10.1038\/ncomms13312","type":"journal-article","created":{"date-parts":[[2016,11,4]],"date-time":"2016-11-04T09:12:34Z","timestamp":1478250754000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":220,"title":["Potent and selective chemical probe of hypoxic signalling downstream of HIF-\u03b1 hydroxylation via VHL inhibition"],"prefix":"10.1038","volume":"7","author":[{"given":"Julianty","family":"Frost","sequence":"first","affiliation":[]},{"given":"Carles","family":"Galdeano","sequence":"additional","affiliation":[]},{"given":"Pedro","family":"Soares","sequence":"additional","affiliation":[]},{"given":"Morgan S.","family":"Gadd","sequence":"additional","affiliation":[]},{"given":"Katarzyna M.","family":"Grzes","sequence":"additional","affiliation":[]},{"given":"Lucy","family":"Ellis","sequence":"additional","affiliation":[]},{"given":"Ola","family":"Epemolu","sequence":"additional","affiliation":[]},{"given":"Satoko","family":"Shimamura","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8343-8977","authenticated-orcid":false,"given":"Marcus","family":"Bantscheff","sequence":"additional","affiliation":[]},{"given":"Paola","family":"Grandi","sequence":"additional","affiliation":[]},{"given":"Kevin D.","family":"Read","sequence":"additional","affiliation":[]},{"given":"Doreen A.","family":"Cantrell","sequence":"additional","affiliation":[]},{"given":"Sonia","family":"Rocha","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8654-1670","authenticated-orcid":false,"given":"Alessio","family":"Ciulli","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2016,11,4]]},"reference":[{"key":"BFncomms13312_CR1","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/nchembio.1197","volume":"9","author":"ME Bunnage","year":"2013","unstructured":"Bunnage, M. 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