ASLAN003 is a novel, potent and orally bioavailable inhibitor of DHODH (Human Dihydroorotate Dehydrogenase) which has the potential to be first-in-class in AML (Acute Myelogenous Leukemia). ASLAN003 has antitumor activity.
Physicochemical Properties
| Molecular Formula | C19H14F2N2O3 |
| Molecular Weight | 356.322871685028 |
| Exact Mass | 356.097 |
| CAS # | 1035688-66-4 |
| PubChem CID | 24986824 |
| Appearance | White to off-white solid powder |
| LogP | 4.6 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 26 |
| Complexity | 470 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | FC1C=C(C=C(C=1NC1C(C(=O)O)=CC=CN=1)F)C1C=CC=C(C=1)OC |
| InChi Key | OMPATGZMNFWVOH-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C19H14F2N2O3/c1-26-13-5-2-4-11(8-13)12-9-15(20)17(16(21)10-12)23-18-14(19(24)25)6-3-7-22-18/h2-10H,1H3,(H,22,23)(H,24,25) |
| Chemical Name | 2-((3,5-difluoro-3'-methoxy-[1,1'-biphenyl]-4-yl)amino)nicotinic acid |
| Synonyms | ASLAN003 ASLAN 003 ASLAN-003 Aslan-003. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | For 48 hours, farudodstat (0.01-100 μM) suppresses the growth of leukemia cells. 50% or more of the cell viability is maintained at concentrations of Farudodstat [1]. Cleaved caspase 8 is considerably increased by farudodstat (0.5, 1 μM) for 48 hours [1]. Farudodstat (2, 4 μM; for 96 hours) decreases viability and causes differentiation in myelodysplastic syndrome samples and primary acute myeloid leukemia blasts [1]. It was demonstrated that in MOLM-14 and KG-1 cells, fardodstat (1, 2 μM; 1 hour pretreatment before OPP, 1 hour on) slows protein synthesis and decreases incorporation of O-propargylpuromycin (OPP) into protein translation sites. RPL6 and EIF4B protein downregulation is brought on by farudodstat [1]. |
| ln Vivo | The number of disseminated tumors is significantly decreased and survival is prolonged when farudstat (50 mg/kg; oral gavage; once daily; days 3 to 30) is administered [1]. |
| Cell Assay |
Cell Proliferation Assay[1] Cell Types: THP-1, MOLM-14 and KG-1 Cell Tested Concentrations: 0.01, 0.1, 1, 10, 100 μM Incubation Duration: 48 hrs (hours) Experimental Results: THP-1, MOLM-14 and KG- 1 Cell Inhibition of Leukemia Cell Proliferation The IC50 values of MOLM-14 and KG-1 are 152 nM, 582 nM and 382 nM respectively. Western Blot Analysis[1] Cell Types: KG-1 and MOLM-14 Cell Tested Concentrations: 0.5, 1 μM Incubation Duration: 48 hrs (hours) Experimental Results: Significant increase in cleaved caspase 8 and leakage of cytochrome c from mitochondria into the cytosol and induces cleavage of caspase-3 and -7. |
| Animal Protocol |
Animal/Disease Models: Female NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ, NGS mice (4-6 weeks old) with MOLM-14 cells [1] Doses: 50 mg/kg Route of Administration: po (oral gavage); one time/day; Results from day 3 to day 30: The number of disseminated tumors and tumor size were Dramatically diminished. Survival period was Dramatically prolonged. |
| References |
[1]. ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia. Haematologica. 2019 Nov7;haematol.2019.230482. [2]. Human Dihydroorotate Dehydrogenase (hDHODH) as a new target on Acute Myelogenous Leukemia (AML): Targeting Myeloid Differentiation using Potent and Innovative hDHODH Inhibitors. 23rd Swedish Conference on Macromolecular Structure an. |
| Additional Infomation |
Farudodstat (ASLAN003) is under investigation in clinical trial NCT03451084 (A Dose Optimisation Study of ASLAN003 in Acute Myeloid Leukemia). Farudodstat is an orally available inhibitor of dihydroorotate dehydrogenase (DHODH), with potential antineoplastic activity. Upon administration, farudodstat specifically targets, binds to and prevents the activation of DHODH, thereby preventing the fourth enzymatic step in de novo pyrimidine synthesis. This prevents uridine monophosphate (UMP) formation, DNA synthesis, cell division and cellular proliferation, causes reactive oxygen species (ROS) formation, enables differentiation and induces apoptosis in susceptible tumor cells. DHODH, a mitochondrial enzyme, catalyzes the conversion of dihydroorotate (DHO) to orotate in the endogenous synthesis of UMP. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~125 mg/mL (~350.81 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.17 mg/mL (6.09 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.17 mg/mL (6.09 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8065 mL | 14.0323 mL | 28.0647 mL | |
| 5 mM | 0.5613 mL | 2.8065 mL | 5.6129 mL | |
| 10 mM | 0.2806 mL | 1.4032 mL | 2.8065 mL |