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LXE408 is an oral antileishmanarial compound that selectively targets the kinetoplastid proteosome vs. the mammalian proteosome. The prior candidate, GNF6702, had solubility-limited oral absorption, which could have been addressed with a specialized formulation but would have increased the cost and limited use in developing countries. A single methyl group dramatically improved the dissolution properties without compromising activity, leading to LXE408. Interestingly, a 3.4A cryo-EM structure was obtained of LXE408 with the kinetoplastid proteosome showing its non-competitive mode of binding in contrast to mammalian proteosome inhibitors like bortezomib.