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

Abstract

Differentiation therapies achieve remarkable success in acute promyelocytic leukemia, a subtype of acute myeloid leukemia. However, excluding acute promyelocytic leukemia, clinical benefits of differentiation therapies are negligible in acute myeloid leukemia except for mutant isocitrate dehydrogenase 1/2. Dihydroorotate dehydrogenase catalyses the fourth step of the de novo pyrimidine synthesis pathway. ASLAN003 is a highly potent dihydroorotate dehydrogenase inhibitor that induces differentiation, as well as reduces cell proliferation and viability, of acute myeloid leukemia cell lines and primary acute myeloid leukemia blasts including in chemo-resistant cells. Apoptotic pathways are triggered by ASLAN003, and it also significantly inhibits protein synthesis and activates AP-1 transcription, contributing to its differentiation promoting capacity. Finally, ASLAN003 substantially reduces leukemic burden and prolongs survival in acute myeloid leukemia xenograft mice and acute myeloid leukemia patient-derived xenograft models. Notably, the drug has no evident effect on normal hematopoietic cells and exhibits excellent safety profiles in mice, even after a prolonged period of administration. Our results, therefore, suggest that ASLAN003 is an agent targeting dihydroorotate dehydrogenase with potential in the treatment of acute myeloid leukemia. ASLAN003 is currently being evaluated in phase 2a clinical trial in acute myeloid leukemia patients. Article Summary 1. ASLAN003, a novel, potent dihydroorotate dehydrogenase inhibitor, induces differentiation of acute myeloid leukemia cells in vitro and in vivo. 2. ASLAN003 triggers apoptosis, inhibits protein synthesis and activates AP-1 transcription.

The Synergism Between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia

“…From this seminal discovery, several academic and industrial research groups, including ours, have designed new and more potent DHODH inhibitors, confirming original results and extending the knowledge about this topic [2,3,4,5]. Transcriptome analyses revealed that leukemic cells treated with DHODH inhibitors upregulate genes related to apoptosis and differentiation, and downregulate protein translation-related genes, impairing protein synthesis [4,5]. However, the exact mechanisms triggered by DHODH inhibitors that eventually affect differentiation and apoptosis have not been fully elucidated [6], probably because DHODH is involved in multiple cellular pathways, and its inhibition has very wide consequences.…”

“…The inhibition of Dihydroorotate Dehydrogenase (DHODH) has recently been found to induce differentiation in several models of Acute Myeloid Leukemia (AML), both in vitro and in vivo [1]. From this seminal discovery, several academic and industrial research groups, including ours, have designed new and more potent DHODH inhibitors, confirming original results and extending the knowledge about this topic [2,3,4,5]. Transcriptome analyses revealed that leukemic cells treated with DHODH inhibitors upregulate genes related to apoptosis and differentiation, and downregulate protein translation-related genes, impairing protein synthesis [4,5].…”

5-aminoimidazole-4-carboxamide ribonucleoside induces differentiation in a subset of primary acute myeloid leukemia blasts

“…Ribotide AICAR was shown to interfere with pyrimidine synthesis by inhibiting UMP-synthase, which is a step downstream of DHODH; AICAr and the DHODH inhibitor brequinar had similar effects on differentiation and S-phase arrest, and the effects of both drugs depended on the activation of the DNA damage response ATR/Chk1 pathway [13]. In last couple of years, multiple agents have been identified as potent inhibitors of DHODH that trigger some differentiation of AML cell lines [14][15][16][17][18][19], patient AML cells ex vivo [19] or patient-derived xenografts in vivo [18,19], and four clinical trials are underway in order to establish their safety and efficiency in AML patients [20].…”

Mysteries of partial dihydroorotate dehydrogenase inhibition and leukemia terminal differentiation

“…t is reasonable to wonder why inhibiting dihydroorotate dehydrogenase (DHODH), a protean and vital metabolic enzyme, would be expected to solve, not exacerbate, prevalent oncotherapy problems of toxicity and resistance. Yet, in addition to ASLAN003, described in this issue of Haematologica, 1 at least four other DHODH inhibitors are being developed for oncotherapy. 2 DHODH is the sole mitochondrial enzyme in the pathway of de novo pyrimidine synthesis, which makes pyrimidine nucleobases from glutamine and aspartate.…”

“…(A) The 1,000 genes most significantly up-or down-regulated upon addition of ASLAN003 to KG1 or MOLM14 acute myeloid leukemia (AML) cells were examined for their expression pattern in normal hematopoietic stem cells (HSC), multipotent progenitors (MPP), common myeloid progenitors (CMP), granulocyte-monocyte progenitors (GMP), granulocytes (gran) and monocytes (mono) (data from BloodPool 15 ), and found to be genes normally up-or down-regulated with terminal granulocyte or monocyte differentiation. Experimental details of ASLAN003 treatment are described by Zhou et al, 1 gene expression by RNA-sequencing Geo Database GSE128950. (B) Proliferation and lineage differentiation are coupled through mitochondrial metabolism.…”