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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-04-02

AUTHORS

Sven Christian, Claudia Merz, Laura Evans, Stefan Gradl, Henrik Seidel, Anders Friberg, Ashley Eheim, Pascale Lejeune, Krzysztof Brzezinka, Katja Zimmermann, Steven Ferrara, Hanna Meyer, Ralf Lesche, Detlef Stoeckigt, Marcus Bauser, Andrea Haegebarth, David B Sykes, David T Scadden, Julie-Aurore Losman, Andreas 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. More... »

PAGES

1

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41375-019-0461-5

DOI

http://dx.doi.org/10.1038/s41375-019-0461-5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1113170282

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30940908


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