8z32
From Proteopedia
Crystal Structure of HIF-PHD2 in complex with compound 3
Structural highlights
DiseaseEGLN1_HUMAN Defects in EGLN1 are the cause of familial erythrocytosis type 3 (ECYT3) [MIM:609820. ECYT3 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels.[1] [2] FunctionEGLN1_HUMAN Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality.[3] [4] [5] [6] [7] Publication Abstract from PubMedInhibition 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. Discovery of DS44470011: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.,Fukuda T, Kuribayashi T, Takano R, Sasaki K, Tsuji T, Niitsu Y, Ishii K, Hashimoto M, Baba D, Ito S, Tanaka N Bioorg Med Chem Lett. 2024 Aug 1;108:129799. doi: 10.1016/j.bmcl.2024.129799. , Epub 2024 May 15. PMID:38754564[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
Categories: Homo sapiens | Large Structures | Baba D | Fukuda T | Ito S | Tanaka N
