9bkm
DHODH in complex with Ligand 10
Structural highlights
DiseasePYRD_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] FunctionPYRD_HUMAN Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. Publication Abstract from PubMedAcute 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
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