ASLAN003

ASLAN003 is an orally active and potent inhibitor of DHODH (Human Dihydroorotate Dehydrogenase) with antitumor activity. It has the potential to be a first-in-class candidate in AML.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.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. 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. (In Vitro) :Farudodstat (0.01-100 μM; for 48 hours) inhibits leukemic cell proliferation. The cell viability is maintained at ~50% at Farudodstat 1 μM and higher.Farudodstat (0.5, 1 μM; for 48 hours) significantly increases cleaved caspase 8.Farudodstat (2, 4 μM; for 96 hours) decreases viability and induces differentiation in primary acute myeloid leukemia blasts and myelodysplastic syndrome samples.Farudodstat (1, 2 μM; pretreatment 1 h before OPP for 1 h) inhibits protein synthesis, as demonstrated by the reduced incorporation of O-propargyl-puromycin (OPP) at protein translation sites in both MOLM-14 and KG-1 cells. Farudodstat causes the downregulation of EIF4B, and RPL6 proteins. (In Vivo) :Farudodstat (50 mg/kg; oral gavage; once daily; from the day 3 to 30) substantially reduces the number of disseminated tumors and prolongs survival.