Summary for 9DHH
| Entry DOI | 10.2210/pdb9dhh/pdb |
| Descriptor | Dihydroorotate dehydrogenase (quinone), mitochondrial, LAURYL DIMETHYLAMINE-N-OXIDE, FLAVIN MONONUCLEOTIDE, ... (11 entities in total) |
| Functional Keywords | dihydroorotate dehydrogenase, dhodh, oxidoreductase, inhibitor, oxidoreductase-inhibitor complex, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 42346.67 |
| Authors | Shaffer, P.L. (deposition date: 2024-09-03, release date: 2024-10-09, Last modification date: 2024-10-16) |
| Primary citation | 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 Cited by 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: 39284456DOI: 10.1016/j.bmcl.2024.129965 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.49 Å) |
Structure validation
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