Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases

Visceral
leishmaniasis is responsible for up to 30,000 deaths every
year. Current treatments have shortcomings that include toxicity and
variable efficacy across endemic regions. Previously, we reported
the discovery of GNF6702, a selective inhibitor of the kinetoplastid
proteasome, which cleared parasites in murine models of leishmaniasis,
Chagas disease, and human African trypanosomiasis. Here, we describe
the discovery and characterization of LXE408, a structurally related
kinetoplastid-selective proteasome inhibitor currently in Phase 1
human clinical trials. Furthermore, we present high-resolution cryo-EM
structures of the Leishmania tarentolae proteasome
in complex with LXE408, which provides a compelling explanation for
the noncompetitive mode of binding of this novel class of inhibitors
of the kinetoplastid proteasome.