9dhh
DHODH in complex with Compound 8
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 PubMedDHODH 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
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