Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases
A. S. Nagle, Agnes Biggart, C. Be, Honnappa Srinivas, Andreas Hein, Diana Caridha, Richard J. Sciotti, Brandon Pybus, Mara Kreishman-Deitrick, Badry Bursulaya, Yin Hwa Lai, Mu-Yun Gao, Fang Liang, Casey J. N. Mathison, Xiaodong Liu, Vince S. C. Yeh, Jeffrey W. Smith, Isabelle K. Lerario, Yongping Xie, D. CHIANELLI, Michael J. Gibney, Ashley Berman, Yen‐Liang Chen, Jan Jiřiček, Lauren Davis, Xianzhong Liu, Jaime Ballard, Shilpi Khare, Fabian Eggimann, Alexandre Luneau, Todd Groessl, Michael Shapiro, Wendy Richmond, Kevin C. Johnson, Patrick J. Rudewicz, Srinivasa P. S. Rao, Christopher Thompson, Tove Tuntland, Glen Spraggon, Richard Glynne, František Supek, Christian Wiesmann, Valentina Molteni
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.