ASLAN003

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

ASLAN003 是一种口服有效的 DHODH（人二氢乳清酸脱氢酶）抑制剂，具有抗肿瘤活性。

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.

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.Cell Proliferation Assay Cell Line:THP-1, MOLM-14 and KG-1 cells Concentration:0.01, 0.1, 1, 10, 100 μM Incubation Time:For 48 hours Result:Inhibited leukemic cell proliferation of THP-1, MOLM-14 and KG-1 with IC50 values of 152 nM, 582 nM, and 382 nM, respectively.Western Blot Analysis Cell Line:KG-1 and MOLM-14 cells Concentration:0.5, 1 μM Incubation Time:For 48 hours Result:Significantly increased cleaved caspase 8, increased leakage of cytochrome c from mitochondria into the cytosol and induced cleaved caspase-3 and -7.

Farudodstat (50 mg/kg; oral gavage; once daily; from the day 3 to 30) substantially reduces the number of disseminated tumors and prolongs survival. Animal Model:Female NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ, NGS mice (4-6 weeks old) with MOLM-14 cells Dosage:50 mg/kg Administration:Oral gavage; once daily; from the day 3 to 30 Result:Substantially reduced the number of disseminated tumors and the size of these tumors. Survival was significantly prolonged.

——

Metabolic Enzyme/Protease

Dehydrogenase

DHODH

Cancer

Acute Myeloid Leukemia

1035688-66-4

356.32

C19H14F2N2O3

>98% (HPLC)

DMSO:120 mg/mL (336.78 mM; Need ultrasonic)

O=C(C1=CC=CN=C1NC2=C(F)C=C(C3=CC=CC(OC)=C3)C=C2F)O

——

(-20℃)

With Ice Pack

≥ 2 years