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DOI 10.1021/acs.jmedchem.0c00499

Медицинская библиотека · Journal of medicinal chemistry · 2020

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

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

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Аннотация

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.

Для цитирования: 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. Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases.. Journal of medicinal chemistry. 2020. DOI: 10.1021/acs.jmedchem.0c00499.

Предметные рубрики MeSH

AnimalsAntiprotozoal AgentsDogsHumansLeishmania donovaniLeishmania majorLeishmaniasis, VisceralLiverMacaca fascicularisMiceMice, Inbred BALB COxazolesProteasome InhibitorsPyrimidinesRatsRats, Sprague-DawleyTriazoles
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