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

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.

Replication and ribosomal stress induced by targeting pyrimidine synthesis and cellular checkpoints suppress p53-deficient tumors

“…We have recently demonstrated the crucial importance of DHODH-dependent de novo pyrimidine synthesis for the ability of cancer cells to proliferate and form tumors 20 . Similarly, administration of leflunomide in mice reduced tumor growth in this report, in agreement with the findings of others 6,33 .…”

“…Indeed, despite high expectations, targeting DHODH was shown to be therapeutically effective only in some types of cancer. For example, such intervention was successful in patients with TNBC, where inhibition of de novo pyrimidine synthesis sensitized the tumors to genotoxic therapy 8 , similar as reported for patients with acute myeloid leukemia 9,33 or multiple myeloma 34 . Better understanding of molecular mechanisms sensitizing to DHODH inhibition may therefore help to translate DHODH-directed therapy into more efficient clinical outcomes.…”

ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia

“…28 A novel DHODH inhibitor, BAY 2402234, induces differentiation and proliferation inhibition in multiple AML subtypes and is currently evaluated in phase I trial in myeloid malignancies. 29 In this study, we comprehensively characterise ASLAN003, a novel, potent DHODH Consistently, our RNA-seq data revealed a large family of genes associated with protein translation initiation was the top and the largest class downregulated by ASLAN003 treatment. We further experimentally validated that ASLAN003 inhibits protein synthesis in AML cells.…”

Metabolic dependencies and vulnerabilities in leukemia

“…New antimetabolite drugs are actively being incorporated in the antileukemic armamentarium targeting these pathways. Recently, dihydroorotate dehydrogenase (DHODH), an enzyme mediating the fourth step in de novo pyrimidine biosynthesis (Löffler et al 1997), has been proposed as a target in AML, where depletion of the pyrimidine pool not only abrogates proliferation, but also induces a HOXA9-dependent differentiation block, triggering myeloid differentiation and suppressing leukemia-initiating cell activity (Sykes et al 2016;Christian et al 2019). In addition, nucleotide degradation pathways have started to gain attention with the realization of important dependencies mediated by the clearance of endogenous and drug-generated toxic nucleotide metabolic byproducts.…”