Summary for 9BKN
| Entry DOI | 10.2210/pdb9bkn/pdb |
| Descriptor | Dihydroorotate dehydrogenase (quinone), mitochondrial, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (9 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 | 41424.18 |
| Authors | Shaffer, P.L. (deposition date: 2024-04-29, release date: 2024-07-03, Last modification date: 2024-07-24) |
| Primary citation | DeRatt, L.G.,Zhang, Z.,Pietsch, C.,Cisar, J.S.,Zhang, X.,Wang, W.,Tanner, A.,Matico, R.,Shaffer, P.,Jacoby, E.,Kazmi, F.,Shukla, N.,Bush, T.L.,Patrick, A.,Philippar, U.,Attar, R.,Edwards, J.P.,Kuduk, S.D. Discovery of JNJ-74856665: A Novel Isoquinolinone DHODH Inhibitor for the Treatment of AML. J.Med.Chem., 67:11254-11272, 2024 Cited by PubMed Abstract: Acute 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). PubMed: 38889244DOI: 10.1021/acs.jmedchem.4c00809 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.3 Å) |
Structure validation
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