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

• Published in: Journal of medicinal chemistry Vol. 63; no. 19; pp. 10773 - 10781
• Main Authors: Nagle, Advait, Biggart, Agnes, Be, Celine, Srinivas, Honnappa, Hein, Andreas, Caridha, Diana, Sciotti, Richard J, Pybus, Brandon, Kreishman-Deitrick, Mara, Bursulaya, Badry, Lai, Yin H, Gao, Mu-Yun, Liang, Fang, Mathison, Casey J. N, Liu, Xiaodong, Yeh, Vince, Smith, Jeffrey, Lerario, Isabelle, Xie, Yongping, Chianelli, Donatella, Gibney, Michael, Berman, Ashley, Chen, Yen-Liang, Jiricek, Jan, Davis, Lauren C, Liu, Xianzhong, Ballard, Jaime, Khare, Shilpi, Eggimann, Fabian Kurt, Luneau, Alexandre, Groessl, Todd, Shapiro, Michael, Richmond, Wendy, Johnson, Kevin, Rudewicz, Patrick J, Rao, Srinivasa P. S, Thompson, Christopher, Tuntland, Tove, Spraggon, Glen, Glynne, Richard J, Supek, Frantisek, Wiesmann, Christian, Molteni, Valentina
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.10.2020; Amer Chemical Soc
• Subjects: Animals; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Antiprotozoal Agents - therapeutic use; Chemistry, Medicinal; Dogs; Drug Annotation; Humans; Leishmania donovani - drug effects; Leishmania donovani - isolation & purification; Leishmania major - drug effects; Leishmania major - isolation & purification; Leishmaniasis, Visceral - drug therapy; Leishmaniasis, Visceral - parasitology; Life Sciences & Biomedicine; Liver - parasitology; Macaca fascicularis; Mice; Mice, Inbred BALB C; Oxazoles - chemistry; Oxazoles - pharmacology; Oxazoles - therapeutic use; Pharmacology & Pharmacy; Proteasome Inhibitors - chemistry; Proteasome Inhibitors - pharmacology; Proteasome Inhibitors - therapeutic use; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rats; Rats, Sprague-Dawley; Science & Technology; Triazoles - chemistry; SUPERSATURATION; AMPHOTERICIN-B; BORTEZOMIB
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c00499

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.