Selective Inhibitors of a Human Prolyl Hydroxylase (OGFOD1) Involved in Ribosomal Decoding.

Cyrille C Thinnes,Radosław P Nowak,Udo Oppermann,Anthony Tumber,Christopher T Lohans,Martine I Abboud,Christoph Loenarz,Tzu‐Lan Yeh,Christopher J Schofield,Martin Attwood,Matthew E Cockman

doi:10.1002/chem.201804790

Cyrille C Thinnes, Radosław P Nowak + Show 9 more

Open Access

https://doi.org/10.1002/chem.201804790

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Abstract

Human prolyl hydroxylases are involved in the modification of transcription factors, procollagen, and ribosomal proteins, and are current medicinal chemistry targets. To date, there are few reports on inhibitors selective for the different types of prolyl hydroxylases. We report a structurally informed template‐based strategy for the development of inhibitors selective for the human ribosomal prolyl hydroxylase OGFOD1. These inhibitors did not target the other human oxygenases tested, including the structurally similar hypoxia‐inducible transcription factor prolyl hydroxylase, PHD2.

Highlights

In humans and other animals, prolyl hydroxylases (PHs) play critical roles in collagen biosynthesis and hypoxia sensing.[1,2,3] The PHs are FeII and 2-oxoglutarate (2OG) dependent oxygenases, which normally produce succinate and CO2 as coproducts.[4]
These comparisons, along with those shown for other human oxygenases,[4] suggest that inadvertent inhibition of the PHDs may represent a challenge in developing selective OGFOD1 inhibitors, and vice versa
Our results demonstrate the viability of a template-based approach for the development of selective 2OG oxygenase/prolyl hydroxylase inhibitors capable of differentiating between closely related active sites, such as those of the human prolyl hydroxylases OGFOD1 and PHD2

Summary

Introduction

In humans and other animals, prolyl hydroxylases (PHs) play critical roles in collagen biosynthesis and hypoxia sensing.[1,2,3] The PHs are FeII and 2-oxoglutarate (2OG) dependent oxygenases, which normally produce succinate and CO2 as coproducts.[4]. Of the ~ 60–70 human 2OG oxygenases, some are current medicinal chemistry targets, including enzymes involved in chromatin modification and lipid metabolism.[5,16] Inhibition of the procollagen hydroxylases is under consideration as a target to limit the overproduction of collagen associated with certain cancers and fibrotic diseases.[17] The PHDs are presently being targeted for the treatment of hypoxia-related diseases, with inhibitors in late-stage clinical trials for anaemia.[18] If OGFOD1 is involved in mRNA codon recognition, as suggested based on studies of yeast homologues,[8,13] smallmolecule-mediated inhibition of ribosomal hydroxylation could prove useful for the treatment of diseases such as muscular dystrophy that are caused by premature stop-codons through nonsense suppression.[19] due to the uncertainty regarding the specific roles of OGFOD1 and OGFOD1-catalysed hydroxylation in animals, it is unclear how exactly its inhibition might manifest. Triketone-based HPPD and plant growth inhibitors 1–5 (Figure 2 A), related to GSK1278863 6, displayed moderate inhibition of OGFOD1, while not inhibiting

Results

Discussion

Conflict of interest