8Z35

Crystal Structure of HIF-PHD2 in complex with compound 7 (DS44470011)

This is a non-PDB format compatible entry.

Summary for 8Z35

• Entry DOI: 10.2210/pdb8z35/pdb
• Related: 8Z31 8Z32 8Z33
• Descriptor: Egl nine homolog 1, FE (II) ION, SULFATE ION, ... (6 entities in total)
• Functional Keywords: renal anemia, inhibitor, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 26032.70

Authors

Ito, S.,Baba, D.,Fukuda, T.,Tanaka, N. (deposition date: 2024-04-14, release date: 2025-02-26)

Primary citation

Fukuda, T.,Kuribayashi, T.,Takano, R.,Sasaki, K.,Tsuji, T.,Niitsu, Y.,Ishii, K.,Hashimoto, M.,Baba, D.,Ito, S.,Tanaka, N.
Discovery of DS44470011: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.
Bioorg.Med.Chem.Lett., 108:129799-129799, 2024

PubMed Abstract: Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. 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.

PubMed: 38754564
DOI: 10.1016/j.bmcl.2024.129799

Experimental method

X-RAY DIFFRACTION (2 Å)