Fumarate Prodrugs as a Novel Therapeutic Approach in Acute Myeloid Leukaemia

Abstract

Fumarate Prodrugs as a Novel Therapeutic Approach in Acute Myeloid Leukemia Haematopoiesis occurs in the hypoxic bone marrow (BM) microenvironment, where multipotent haematopoietic stem and progenitor cells (HSPC) differentiate and renew blood cells (1). Acute myeloid leukaemia (AML) is a haematological disorder characterised by clonal proliferation of the HSPC compartment, leading to an increased number of blast cells (myeloid progenitors) in the bone marrow and peripheral blood, causing bone marrow failure and a decrease in erythropoiesis. AML is the most common type of acute leukaemia, accounting for approximately 80% of acute leukemic cases in adults (2). The response to the low oxygen conditions in the BM is orchestrated by the hypoxia inducible factors (HIFs). These factors play a central role in gene expression, controlling cell cycle and cell growth, metabolism, oxygen homeostasis, apoptosis, and autophagy. Previous research in our lab (published, UK patent filed) demonstrated that stabilising HIFs through inhibition of their negative regulators the HIF-PHDs (HIF-prolyl hydroxylase domain enzymes) has potent anti-leukemic effects in vitro and in vivo (3). As such, we explored the potential of therapeutic targeting of fumarate, a natural PHDs inhibitor, involved in the citric acid cycle (TCA) and energy production. Notably, fumarate is highly druggable with fumarate prodrugs dimethyl fumarate (DMF) and diroximel fumarate (DRF) currently used to treat multiple sclerosis and psoriasis (4). Our group is the first to investigate the potential of these FDA-approved fumarate prodrugs for the treatment of AML. Our data shows that both fumarate prodrugs (DMF and DRF) have significant anti-leukaemic effects in vitro. Moreover, combination therapy with either fumarate prodrug plus venetoclax, now a gold standard of AML therapy, shows promising in vitro efficacy. To further exploit the therapeutic potential of fumarate prodrugs, our recent investigations have explored replacing the N-Succinimide group of DRF with hydroxamic acid (IOX-6). Significantly, these chemical alterations increased the anti-leukaemic effect of DRF, opening up the potential of further improving fumarate prodrugs for the treatment of AML.