Nagle, Advait, Biggart, Agnes, Be, Celine, Srinivas, Honnappa, Hein, Andreas, caridha, Diana, Sciotti, Richard, Pybus, Brandon, Kreishman-Deitrick, Mara, Bursulaya, Badry, Lai, Yin, Gao, Mu-Yun, Liang, Fang, Mathison, Casey, Liu, Xiaodong, Yeh, Vince, Smith, Jeffrey, Isabelle, Isabelle, Xie, Yongping, Chianelli, Donatella, Gibney, Michael, Berman, Ashley, Chen, Yen-Liang, Jiricek, Jan, Davis, Lauren, Liu, Xianzhong, Ballard, Jaime, Khare, Shilpi, Eggimann, Fabian, Luneau, Alexandre, Groessl, Todd, Shapiro, Michael, Richmond, Wendy, Johnson, Kevin, Rudewicz, Patrick, Rao, Srinivasa, Thompson, Christopher, Tuntland, Tove, Spraggon, Glen, Glynne, Richard, Supek, Frantisek, Wiesmann, Christian and Molteni, Valentina (2020) Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases. Journal of Medicinal Chemistry. ISSN 0022-26231520-4804

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 trypamomiasis. Here, we describe the discovery and characterization of LXE408, a structurally related kinetoplastid-selective proteasome inhibitor currently in Phase 1 human clinical trials. In addition, we present high-resolution cryo-EM structures of the Leishmania tarentolae proteasome in complex with LXE408, which provides an explanation for the non-competitive mode of binding of this novel class of inhibitors to the kinetoplastid proteasome.

Item Type:	Article
Date Deposited:	12 Aug 2020 00:45
Last Modified:	12 Aug 2020 00:45
URI:	https://oak.novartis.com/id/eprint/42342