PDBsum entry 6qu7

Oxidoreductase

PDB id: 6qu7

Contents

Protein chain

363 a.a.

Ligands

ORO

FMN

JJE

SO4 ×2

ACT ×4

Waters ×194

PDB id:

6qu7

Name:

Oxidoreductase

Title:

Crystal structure of human dhodh in complex with bay 2402234

Structure:

Dihydroorotate dehydrogenase (quinone), mitochondrial. Chain: a. Synonym: dhodehase,dihydroorotate oxidase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: dhodh. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.52Å R-factor: 0.152 R-free: 0.173

Authors:

A.Friberg,S.Gradl

Key ref:

S.Christian et al. (2019). The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies. Leukemia, 33, 2403-2415. PubMed id: 30940908 DOI: 10.1038/s41375-019-0461-5

Date:

26-Feb-19 Release date: 05-Jun-19

Protein chain

Q02127  (PYRD_HUMAN) -  Dihydroorotate dehydrogenase (quinone), mitochondrial from Homo sapiens

Seq: 395 a.a.

Struc: 363 a.a.

Enzyme reactions

• Enzyme class: E.C.1.3.5.2 - dihydroorotate dehydrogenase (quinone).
• Reaction: (S)-dihydroorotate + a quinone = orotate + a quinol

(S)-dihydroorotate (Bound ligand (Het Group name = ORO) corresponds exactly) + quinone = orotate + quinol

• Cofactor: FMN

FMN (Bound ligand (Het Group name = FMN) corresponds exactly)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1038/s41375-019-0461-5

Leukemia 33:2403-2415 (2019)

PubMed id: 30940908

The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies.

S.Christian, C.Merz, L.Evans, S.Gradl, H.Seidel, A.Friberg, A.Eheim, P.Lejeune, K.Brzezinka, K.Zimmermann, S.Ferrara, H.Meyer, R.Lesche, D.Stoeckigt, M.Bauser, A.Haegebarth, D.B.Sykes, D.T.Scadden, J.A.Losman, A.Janzer.

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.