YM311 / Astellas, FibroGen - LARVOL DELTA

Recent advance of hypoxia-inducible factor prolyl hydroxylases inhibitors for anemia therapy. (PubMed, Eur J Med Chem) - "Early inhibitors, such as FG-2216, demonstrated proof-of-concept but faced safety concerns, prompting structural optimization to enhance selectivity and pharmacokinetic profiles. Subsequent generations, exemplified by roxadustat, incorporated modifications to reduce off-target effects and improve oral bioavailability, achieving clinical efficacy in renal anemia...The iterative discovery-to-optimization process underscores the value of PHD inhibitors as templates for novel therapies targeting hypoxia-responsive diseases, while ongoing research addresses challenges in long-term safety and patient-specific response variability. This progress solidifies PHD inhibitors as pivotal tools for anemia management and broader therapeutic innovation."

Journal • Anemia • Hematological Disorders

Discovery of DS44470011: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia. (PubMed, Bioorg Med Chem Lett) - "We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. 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."

Journal • Anemia • Hematological Disorders

Identification of EPZ004777 and FG2216 as inhibitors of TGF-β1 induced Treg cells by screening a library of epigenetic compounds. (PubMed, Life Sci) - "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."

Journal • Immunology • CD4 • FOXP3 • IFNG • TGFB1

Sensing an Oxygen Sensor: Development and Application of Activity-Based Assays Directly Monitoring HIF Heterodimerization. (PubMed, Anal Chem) - "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."

Journal • EPAS1 • HIF1A

A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats. (PubMed, PLoS One) - "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 • Preclinical • Cardiomyopathy • Cardiovascular • Fibrosis • Genetic Disorders • Glomerulonephritis • Hematological Disorders • Hypertension • Immunology • Metabolic Disorders • Nephrology • Obesity • Renal Disease

Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors induce autophagy and have a protective effect in an in-vitro ischaemia model. (PubMed, Sci Rep) - "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."

Journal • Preclinical • Cardiovascular • Ischemic stroke

Inhibition of firefly luciferase activity by a HIF prolyl hydroxylase inhibitor. (PubMed, J Photochem Photobiol B) - "In contrast, the PHIs FG-4592 (roxadustat) and FG-2216 (ICA, BIQ, IOX3, YM 311) did not affect firefly luciferase. 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 • Gene Therapies • Hematological Disorders • Immunology • Ischemic stroke • Nephrology • Renal Disease • Reperfusion Injury

UPLC-MS-Based Procedures to Detect Prolyl-hydroxylase Inhibitors of HIF in Urine. (PubMed, J Anal Toxicol) - "This article presents newly developed screening and confirmation analytical procedures to detect the misuse of nine prolyl-hydroxylase inhibitors of the hypoxia-inducible factor: daprodustat, desidustat, FG2216, IOX2, IOX4, JNJ-42041935, molidustat, roxadustat and vadadustat, targeting either the parent drugs and/or their main metabolite(s). 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."

Journal

Five New Guaiane Sesquiterpenes from the Endophytic Fungus Xylaria sp. YM 311647 of Azadirachta indica. (PubMed) - "The structures of these compounds were elucidated on the basis of spectroscopic analyses, and their inhibitory activities against five pathogenic fungi were evaluated. All guaiane sesquiterpenes showed moderate or weak antifungal activities in a broth microdilution assay."

Journal • Biosimilar