Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases.
J Med Chem
; 63(19): 10773-10781, 2020 10 08.
Article
in En
| MEDLINE
| ID: mdl-32667203
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oxazoles
/
Pyrimidines
/
Proteasome Inhibitors
/
Leishmaniasis, Visceral
/
Antiprotozoal Agents
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2020
Document type:
Article
Affiliation country:
United States