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- | YM311 / Astellas, FibroGen
Journal: Discovery of DS44470011: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia. (Pubmed Central) - Jun 6, 2024
By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels.
- | EPZ004777 / Epizyme, BMS, YM311 / Astellas, FibroGen
Journal: Identification of EPZ004777 and FG2216 as inhibitors of TGF-β1 induced Treg cells by screening a library of epigenetic compounds. (Pubmed Central) - Jun 8, 2022
Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels. EPZ004777 and FG-2216 have been identified as potent epigenetic modulators that can reverse TGF-β1 induced T regulatory cells and may be used to treat diverse immune disorders.
- | YM311 / Astellas, FibroGen
Preclinical, Journal: A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats. (Pubmed Central) - Nov 29, 2021
In conclusion, the HIF-PHI FG-2216 improved renal and cardiovascular outcomes, and reduced obesity in a rat model of kidney disease with metabolic syndrome. Thus, in addition to correcting anemia, HIF-PHIs may provide renal and cardiac protection to patients suffering from kidney disease with metabolic syndrome.
- | Journal: Sensing an Oxygen Sensor: Development and Application of Activity-Based Assays Directly Monitoring HIF Heterodimerization. (Pubmed Central) - Nov 11, 2021
Applicability was demonstrated using a panel of PHD inhibitors, including roxadustat, molidustat, daprodustat, desidustat, vadadustat, and FG-2216, for which concentration-response curves were generated, allowing for the derivation of potency (EC) and efficacy (E) data. The broad applicability of the biosensors was established via applying hypoxia mimetic CoCl, iron chelator desferrioxamine, proteasome inhibitor MG-132, and 2-OG mimetic dimethyloxalylglycine on the assays, indicating concentration-dependent effects.
- | Evrenzo (roxadustat) / Astellas, AstraZeneca, FibroGen, YM311 / Astellas, FibroGen
Journal: Inhibition of firefly luciferase activity by a HIF prolyl hydroxylase inhibitor. (Pubmed Central) - Apr 7, 2021
D-luciferin did not inhibit the PHDs, despite its structural similarity to JNJ-1935. This study provides insights into a previously unknown JNJ-1935 off-target effect as well as into the chemical requirements for firefly luciferase and PHD inhibitors and may inform the development of novel compounds targeting these enzymes.
- | Journal: UPLC-MS-Based Procedures to Detect Prolyl-hydroxylase Inhibitors of HIF in Urine. (Pubmed Central) - Mar 9, 2021
The applicability of the newly developed methods was verified by the analysis of urine samples containing molidustat, roxadustat or daprodustat. The developed procedures enabled to detect the compounds under investigation and their main metabolites.
- | Preclinical, Journal: Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors induce autophagy and have a protective effect in an in-vitro ischaemia model. (Pubmed Central) - Nov 19, 2020
The new class of PHD inhibitors (FG4592, FG2216, GSK1278863, Bay85-3934) have the higher potency than DMOG. The interplay between autophagy, HIF stabilisation and neuroprotection in ischaemic stroke merits further investigation.