| Structural highlights
9bkn is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.3Å |
| Ligands: | , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
PYRD_HUMAN Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:263750; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.[1]
Function
PYRD_HUMAN Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
Publication Abstract from PubMed
Acute myelogenous leukemia (AML), a heterogeneous disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway and preclinical findings demonstrated that DHODH is a metabolic vulnerability in AML as inhibitors can induce differentiation across multiple AML subtypes. As a result of virtual screening and structure-based drug design approaches, a novel series of isoquinolinone DHODH inhibitors was identified. Further lead optimization afforded JNJ-74856665 as an orally bioavailable, potent, and selective DHODH inhibitor with favorable physicochemical properties selected for clinical development in patients with AML and myelodysplastic syndromes (MDS).
Discovery of JNJ-74856665: A Novel Isoquinolinone DHODH Inhibitor for the Treatment of AML.,DeRatt LG, Zhang Z, Pietsch C, Cisar JS, Zhang X, Wang W, Tanner A, Matico R, Shaffer P, Jacoby E, Kazmi F, Shukla N, Bush TL, Patrick A, Philippar U, Attar R, Edwards JP, Kuduk SD J Med Chem. 2024 Jun 18. doi: 10.1021/acs.jmedchem.4c00809. PMID:38889244[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010 Jan;42(1):30-5. doi: 10.1038/ng.499. Epub 2009 Nov 13. PMID:19915526 doi:10.1038/ng.499
- ↑ DeRatt LG, Zhang Z, Pietsch C, Cisar JS, Zhang X, Wang W, Tanner A, Matico R, Shaffer P, Jacoby E, Kazmi F, Shukla N, Bush TL, Patrick A, Philippar U, Attar R, Edwards JP, Kuduk SD. Discovery of JNJ-74856665: A Novel Isoquinolinone DHODH Inhibitor for the Treatment of AML. J Med Chem. 2024 Jun 18. PMID:38889244 doi:10.1021/acs.jmedchem.4c00809
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