6QU7

Crystal structure of human DHODH in complex with BAY 2402234

6QU7 の概要

• エントリーDOI: 10.2210/pdb6qu7/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, OROTIC ACID, FLAVIN MONONUCLEOTIDE, ... (7 entities in total)
• 機能のキーワード: dhodh, oxidoreductase
• 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: 41286.92

構造登録者

Friberg, A.,Gradl, S. (登録日: 2019-02-26, 公開日: 2019-06-05, 最終更新日: 2024-05-15)

主引用文献

Christian, S.,Merz, C.,Evans, L.,Gradl, S.,Seidel, H.,Friberg, A.,Eheim, A.,Lejeune, P.,Brzezinka, K.,Zimmermann, K.,Ferrara, S.,Meyer, H.,Lesche, R.,Stoeckigt, D.,Bauser, M.,Haegebarth, A.,Sykes, D.B.,Scadden, D.T.,Losman, J.A.,Janzer, A.
The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies.
Leukemia, 33:2403-2415, 2019

PubMed Abstract: Acute myeloid leukemia (AML) is a devastating disease, with the majority of patients dying within a year of diagnosis. For patients with relapsed/refractory AML, the prognosis is particularly poor with currently available treatments. Although genetically heterogeneous, AML subtypes share a common differentiation arrest at hematopoietic progenitor stages. Overcoming this differentiation arrest has the potential to improve the long-term survival of patients, as is the case in acute promyelocytic leukemia (APL), which is characterized by a chromosomal translocation involving the retinoic acid receptor alpha gene. Treatment of APL with all-trans retinoic acid (ATRA) induces terminal differentiation and apoptosis of leukemic promyelocytes, resulting in cure rates of over 80%. Unfortunately, similarly efficacious differentiation therapies have, to date, been lacking outside of APL. Inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine synthesis pathway, was recently reported to induce differentiation of diverse AML subtypes. In this report we describe the discovery and characterization of BAY 2402234 - a novel, potent, selective and orally bioavailable DHODH inhibitor that shows monotherapy efficacy and differentiation induction across multiple AML subtypes. Herein, we present the preclinical data that led to initiation of a phase I evaluation of this inhibitor in myeloid malignancies.

PubMed: 30940908
DOI: 10.1038/s41375-019-0461-5

実験手法

X-RAY DIFFRACTION (1.52 Å)