LXE408 is an Orally Active Proteasome Inhibitor with Anti-leishmaniasis Activity

LXE408 is an Orally Active Proteasome Inhibitor with Anti-leishmaniasis Activity

Proteasomes are protein complexes that degrade unwanted or damaged proteins by proteolysis, which can destroy peptide bonds. Specifically, proteasomes are part of the main mechanism by which cells regulate the concentration of specific proteins and degrade misfolded proteins. Besides, proteasomes is in all eukaryotes, archaea and some bacteria. In eukaryotes, proteasomes are located both in the nucleus and in the cytoplasm. The whole system of ubiquitination and proteasome degradation is called the ubiquitin-proteasome system. Moreover, proteasome degradation pathway is essential for many cellular processes, including cell cycle, regulation of gene expression, and response to oxidative stress. Furthermore, proteasome inhibitors have effective antitumor activity in cell culture, induce apoptosis by destroying the regulation, and degradation of growth-promoting cell cycle proteins. Ischemic leishmaniasis (VL) is an infectious disease. LXE408 is an orally active, non-competitive, and kinetoplastid-selective proteasome inhibitor.

LXE408 is an Orally Active Proteasome Inhibitor with Anti leishmaniasis Activity 2020 08 22 - LXE408 is an Orally Active Proteasome Inhibitor with Anti-leishmaniasis Activity

LXE408 is an orally active, non-competitive, and kinetoplastid-selective proteasome inhibitor with anti-leishmaniasis activity.

How does LXE408 work on the target? Let’s study it together. In the beginning, LXE408 is an orally active, non-competitive, and kinetoplastid-selective proteasome inhibitor. Meanwhile, LXE408 has an IC50 of 0.04 μM for L. donovani proteasome and an EC50 of 0.04 μM for L. donovani. Nonetheless, LXE408 has the potential for visceral leishmaniasis (VL) research.

In the second place, LXE408 potently reduces the parasite burden in the liver in a dose-dependent manner with 0.3-10 mg/kg. Importantly, LXE408 effects the robust healing of parasite-induced skin lesions at the base of the tail in BALB/c mice infected with L. major with 1-20 mg/kg. Particularly, LXE408 has a T1/2 of 3.3 hours for mouse. LXE408 has a T1/2 of 3.8 hours, a CL of 2.1 mL/min•kg, and a Vss of 0.53 L/kg for male Sprague-Dawley rat. By the way, LXE408 has a T1/2 of 3.8, 9.7 hours for male beagle dogs and male cynomolgus monkey.

All in all, LXE408 is an orally active, non-competitive, and kinetoplastid-selective proteasome inhibitor.

References:

Advait Nagle, et al. J Med Chem. 2020 Jul 15.

 

 

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