8K72

Factor-inhibiting hypoxia-inducible factor in complex with Zn(II) and 2-(3-hydroxy-2-((3-(phenylsulfonamido)propanoyl)imino)-2,3-dihydrothiazol-4-yl)acetic acid

Summary for 8K72

• Entry DOI: 10.2210/pdb8k72/pdb
• Descriptor: Hypoxia-inducible factor 1-alpha inhibitor, SULFATE ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: factor-inhibiting hypoxia-inducible factor, fih, 2og dependent dioxygenase, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 42016.02

Authors

Nakashima, Y.,Corner, T.P.,Teo, R.Z.R.,Brewitz, L.,Schofield, C.J. (deposition date: 2023-07-26, release date: 2023-12-13)

Primary citation

Corner, T.P.,Teo, R.Z.R.,Wu, Y.,Salah, E.,Nakashima, Y.,Fiorini, G.,Tumber, A.,Brasnett, A.,Holt-Martyn, J.P.,Figg Jr., W.D.,Zhang, X.,Brewitz, L.,Schofield, C.J.
Structure-guided optimisation of N -hydroxythiazole-derived inhibitors of factor inhibiting hypoxia-inducible factor-alpha.
Chem Sci, 14:12098-12120, 2023

PubMed Abstract: The human 2-oxoglutarate (2OG)- and Fe(ii)-dependent oxygenases factor inhibiting hypoxia-inducible factor-α (FIH) and HIF-α prolyl residue hydroxylases 1-3 (PHD1-3) regulate the response to hypoxia in humans catalysing hydroxylation of the α-subunits of the hypoxia-inducible factors (HIFs). Small-molecule PHD inhibitors are used for anaemia treatment; by contrast, few selective inhibitors of FIH have been reported, despite their potential to regulate the hypoxic response, either alone or in combination with PHD inhibition. We report molecular, biophysical, and cellular evidence that the -hydroxythiazole scaffold, reported to inhibit PHD2, is a useful broad spectrum 2OG oxygenase inhibitor scaffold, the inhibition potential of which can be tuned to achieve selective FIH inhibition. Structure-guided optimisation resulted in the discovery of -hydroxythiazole derivatives that manifest substantially improved selectivity for FIH inhibition over PHD2 and other 2OG oxygenases, including Jumonji-C domain-containing protein 5 (∼25-fold), aspartate/asparagine-β-hydroxylase (>100-fold) and histone -lysine demethylase 4A (>300-fold). The optimised -hydroxythiazole-based FIH inhibitors modulate the expression of FIH-dependent HIF target genes and, consistent with reports that FIH regulates cellular metabolism, suppressed lipid accumulation in adipocytes. Crystallographic studies reveal that the -hydroxythiazole derivatives compete with both 2OG and the substrate for binding to the FIH active site. Derivatisation of the -hydroxythiazole scaffold has the potential to afford selective inhibitors for 2OG oxygenases other than FIH.

PubMed: 37969593
DOI: 10.1039/d3sc04253g

Experimental method

X-RAY DIFFRACTION (2.45 Å)