9DHH

DHODH in complex with Compound 8

これはPDB形式変換不可エントリーです。

9DHH の概要

• エントリーDOI: 10.2210/pdb9dhh/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, LAURYL DIMETHYLAMINE-N-OXIDE, FLAVIN MONONUCLEOTIDE, ... (11 entities in total)
• 機能のキーワード: dihydroorotate dehydrogenase, dhodh, oxidoreductase, inhibitor, oxidoreductase-inhibitor complex, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42346.67

構造登録者

Shaffer, P.L. (登録日: 2024-09-03, 公開日: 2024-10-09, 最終更新日: 2024-10-16)

主引用文献

DeRatt, L.G.,Zhang, Z.,Pietsch, E.C.,Cisar, J.,Wang, A.,Wang, C.Y.,Tanner, A.,Shaffer, P.,Jacoby, E.,Kazmi, F.,Shukla, N.,Philippar, U.,Attar, R.M.,Edwards, J.P.,Kuduk, S.D.
Identification of isoquinolinone DHODH inhibitor isosteres.
Bioorg.Med.Chem.Lett., 113:129965-129965, 2024

PubMed Abstract: 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.

PubMed: 39284456
DOI: 10.1016/j.bmcl.2024.129965

実験手法

X-RAY DIFFRACTION (1.49 Å)