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.
Highlights
These authors contributed : Sven Christian, Claudia Merz, Laura Evans
Several inhibitors of dihydroorotate dehydrogenase (DHODH) have been described previously [28], with brequinar sodium and leflunomide/teriflunomide being the most well-known agents tested in humans
Despite preclinical evidence supporting the need for continuous target engagement [32, 33], the clinical trials of brequinar in solid tumors used intermittent dosing schedules similar to those of classical chemotherapy
Summary
Mutational events in hematopoietic stem cells disrupt normal differentiation and lead to a maturation arrest, which maintains leukemic cells in an undifferentiated state with the capacity to self-renew As this differentiation block can occur at different progenitor stages in the setting of a variety of mutational events, AML is a highly heterogeneous disease [2]. Therapies have been developed that target specific oncoproteins that mediate the differentiation arrest of AML blast cells, thereby inducing blast cell differentiation These therapies, which include ATRA and arsenic trioxide (ASO) for APL and Enasidenib and Ivosidenib for IDH2- and IDH1mutated AML, respectively, are well-tolerated even in elderly patients with multiple comorbidities [3,4,5]. These very promising preclinical observations are the rationale for a clinical evaluation of BAY 2402234 in myeloid malignancies that is currently ongoing (NCT 0340726)
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