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LXE408 is a novel, potent, orally bioactive and non-competitive inhibitor of kinetoplastid-selective proteasome with an IC50 of 0.04 μM for L. donovani proteasome and an EC50 of 0.04 μM for L. donovani. LXE408 has the potential for treating visceral leishmaniasis.
| Targets |
Kinetoplastid 20S proteasome (selective, non-competitive inhibitor).
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| ln Vitro |
LXE408 (compound 1) has the ability to form a ternary complex with the proteasome in order to occupy the pocket. LXE408 has a limited propensity to cross the blood-brain barrier (mouse brain/plasma AUC ratio = 0.03) and no inhibitory impact on hERG channels (IC50>30 μM) in manual patch clamp studies [1].
LXE408 (compound 1) has the ability to form a ternary complex with the proteasome to occupy the pocket, which is distinct from classic proteasome inhibitors. It has an IC50 of 0.04 microM for L. donovani proteasome and an EC50 of 0.04 microM for L. donovani amastigotes. LXE408 displays a limited ability to cross the blood-brain barrier (BBB; mouse brain/plasma AUC ratio = 0.03) and no inhibitory impact on hERG channels (IC50 >30 microM) in manual patch clamp studies, indicating a good cardiac safety profile. |
| ln Vivo |
LXE408 (Compound 1; 0.3-10 mg/kg; oral; twice daily for 8 days) substantially lowers parasite burden in the liver in a dose-dependent manner [1]. LXE408 (1, 3, 10, 20 mg/kg; oral; twice daily; for 10 days) can effectively heal skin lesions caused by parasites near the tail base of BALB/c mice infected with Le. major [1]. LXE408 (5 mg/kg IV and 20 mg/kg PO) showed a T1/2 of 3.3 hours in mice. LXE408 (3 mg/kg IV and 10 mg/kg PO) had a T1/2 of 3.8 hours, a CL of 2.1 mL/min·kg, and a Vss of 0.53 L/kg in male Sprague-Dawley rats[1]. LXE408 (0.3 mg/kg IV and 1.0 mg/kg PO) showed a T1/2 of 3.8 hours in male beagle dogs. LXE408 (0.3 mg/kg IV and 10 mg/kg PO) had a T1/2 of 9.7 hours in male cynomolgus monkeys [1].
In vivo, LXE408 (0.3-10 mg/kg; oral; twice daily for 8 days) substantially lowers parasite burden in the liver in a dose-dependent manner. Parasite burden in the liver was diminished by 95% and >99.84% at doses of 1 mg/kg and 10 mg/kg, respectively. LXE408 (1, 3, 10, 20 mg/kg; oral; twice daily for 10 days) can effectively heal skin lesions caused by parasites near the tail base of BALB/c mice infected with Leishmania major. |
| Enzyme Assay |
Assay: In vitro proteasome inhibition assay (kinetoplastid vs. host). Protocol: The 20S proteasome from L. donovani and human cells is purified. The proteasome (2 nM) is incubated with LXE408 (0-1000 nM) and a fluorogenic substrate (e.g., Suc-LLVY-AMC) in assay buffer. Release of free AMC is measured over 60 minutes using a fluorescence plate reader (excitation 360 nm, emission 460 nm). IC50 values are calculated for both enzymes to determine selectivity.
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| Cell Assay |
Cells: L. donovani-infected macrophages. Protocol: Mouse peritoneal macrophages are infected with L. donovani promastigotes (10:1 ratio) for 4 hours. After washing to remove extracellular parasites, cells are incubated with LXE408 (0.1-1000 nM) in culture medium for 48-72 hours. Cells are then fixed, stained with Giemsa, and the number of amastigotes per 100 macrophages is counted microscopically. EC50 is calculated.
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| Animal Protocol |
Animal/Disease Models: Female balb/c (Bagg ALBino) mouse (6-8 weeks old) infected with Lactobacillus donovani [1]
Doses: 0.3, 1, 3, 10 mg/kg Route of Administration: Oral; twice (two times) daily for 8 days Experimental Results: Parasite burden in the liver was diminished by 95% and >99.84% at doses of 1 mg/kg and 10 mg/kg. Animal/Disease Models: balb/c (Bagg ALBino) mouse [1] Doses: 5 mg/kg IV and 20 mg/kg PO (pharmacokinetic/PK/PK analysis) Route of Administration: IV or PO Experimental Results: T1/2 was 3.3 hrs (hrs (hours)), CL was 2.3 mL /min •kg, the Vss of mice is 0.63L/kg. Animal Model: BALB/c mice infected with L. donovani or L. major. Protocol: For VL model: female BALB/c mice (6-8 weeks) are infected intravenously with 2x10^7 L. donovani amastigotes. LXE408 is administered orally (0.3-10 mg/kg) twice daily for 8 days. Liver parasite burden is determined by limiting dilution culture or qPCR of parasite DNA. For cutaneous model: mice are injected subcutaneously in the tail base with L. major. LXE408 is given orally twice daily for 10 days; lesion size is measured weekly. |
| ADME/Pharmacokinetics |
After IV administration (5 mg/kg) in mice, LXE408 showed a T1/2 of 3.3 hours. In male Sprague-Dawley rats (3 mg/kg IV), it had a T1/2 of 3.8 hours, a CL of 2.1 mL/min·kg, and a Vss of 0.53 L/kg. In male beagle dogs (0.3 mg/kg IV), T1/2 was 3.8 hours. In male cynomolgus monkeys (0.3 mg/kg IV), T1/2 was 9.7 hours. Oral bioavailability varies by species.
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| Toxicity/Toxicokinetics |
LXE408 shows no inhibitory impact on hERG channels (IC50 >30 microM) in manual patch clamp studies, suggesting a good cardiac safety profile. No other specific toxicity data was reported, but as a proteasome inhibitor, there is potential for some class-specific effects. The compound has a low propensity to cross the BBB (AUC ratio 0.03), which may reduce CNS side effects but could be a limitation for treating CNS-localized disease.
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| References | |
| Additional Infomation |
LXE408 represents a novel therapeutic agent for visceral leishmaniasis. It is unique because it targets the kinetoplastid proteasome in a non-competitive manner, binding to a pocket distinct from the active site of classic proteasome inhibitors like bortezomib. This selective binding explains its lack of activity against the human proteasome and its selectivity for the parasite. The compound has shown efficacy in mouse models of both visceral and cutaneous leishmaniasis.
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| Molecular Formula |
C23H18FN7O2
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|---|---|
| Molecular Weight |
443.4331
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| Exact Mass |
443.15
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| CAS # |
1799330-15-6
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| PubChem CID |
118162630
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
3.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
33
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| Complexity |
702
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C([H])=C([H])C(=C([H])C=1C1N=C2N=C([H])C(C3=C(C([H])([H])[H])C([H])=C([H])C([H])=N3)=C([H])N2N=1)N([H])C(C1=C(C([H])([H])[H])N=C(C([H])([H])[H])O1)=O
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| InChi Key |
GNVVPYCWVLCWKV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H18FN7O2/c1-12-5-4-8-25-19(12)15-10-26-23-29-21(30-31(23)11-15)17-9-16(6-7-18(17)24)28-22(32)20-13(2)27-14(3)33-20/h4-11H,1-3H3,(H,28,32)
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| Chemical Name |
N-[4-fluoro-3-[6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]phenyl]-2,4-dimethyl-1,3-oxazole-5-carboxamide
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO : ~16.67 mg/mL (~37.59 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.62 mg/mL (1.40 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 6.2 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: ≥ 0.62 mg/mL (1.40 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 6.2 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 0.62 mg/mL (1.40 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2551 mL | 11.2757 mL | 22.5515 mL | |
| 5 mM | 0.4510 mL | 2.2551 mL | 4.5103 mL | |
| 10 mM | 0.2255 mL | 1.1276 mL | 2.2551 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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