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Leukemia DOI:10.1038/s41375-019-0461-5

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

Publication TypeJournal Article
Year of Publication2019
AuthorsChristian, 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, DB, Scadden, DT, Losman, J-A, Janzer, A
JournalLeukemia
Date Published2019 Apr 02
ISSN1476-5551
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.

DOI10.1038/s41375-019-0461-5
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/30940908?dopt=Abstract

Alternate JournalLeukemia
PubMed ID30940908