| Structural highlights
9dhg 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 1.386Å |
| 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
DHODH inhibition represents an attractive approach to overcome differentiation blockade for the treatment of AML. In a previous communication, we described our efforts leading to the discovery of compound 3 (JNJ-74856665), an orally bioavailable, potent, and selective DHODH inhibitor for clinical development. Guided by the co-crystal structures bound to human DHODH, other fused six-membered constructs were explored as isosteric replacements of the isoquinolinone central core. The correct positioning of the nitrogen in these core systems proved to be essential in modulating potency. Herein is described the synthesis of these complexly functionalized cores and their profiling, leading to DHODH inhibitors that possess favorable properties suitable for further development.
Identification of isoquinolinone DHODH inhibitor isosteres.,DeRatt LG, Zhang Z, Pietsch EC, Cisar J, Wang A, Wang CY, Tanner A, Shaffer P, Jacoby E, Kazmi F, Shukla N, Philippar U, Attar RM, Edwards JP, Kuduk SD Bioorg Med Chem Lett. 2024 Sep 14;113:129965. doi: 10.1016/j.bmcl.2024.129965. PMID:39284456[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 EC, Cisar J, Wang A, Wang CY, Tanner A, Shaffer P, Jacoby E, Kazmi F, Shukla N, Philippar U, Attar RM, Edwards JP, Kuduk SD. Identification of isoquinolinone DHODH inhibitor isosteres. Bioorg Med Chem Lett. 2024 Sep 14;113:129965. PMID:39284456 doi:10.1016/j.bmcl.2024.129965
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