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

  • J Med Chem. 2020 Oct 8;63(19):10773-10781. doi: 10.1021/acs.jmedchem.0c00499.
Advait Nagle  1 ,  Agnes Biggart  1 ,  Celine Be  2 ,  Honnappa Srinivas  2 ,  Andreas Hein  2 ,  Diana Caridha  3 ,  Richard J Sciotti  3 ,  Brandon Pybus  3 ,  Mara Kreishman-Deitrick  3 ,  Badry Bursulaya  1 ,  Yin H Lai  1 ,  Mu-Yun Gao  1 ,  Fang Liang  1 ,  Casey J N Mathison  1 ,  Xiaodong Liu  1 ,  Vince Yeh  1 ,  Jeffrey Smith  1 ,  Isabelle Lerario  1 ,  Yongping Xie  1 ,  Donatella Chianelli  1 ,  Michael Gibney  1 ,  Ashley Berman  1 ,  Yen-Liang Chen  4 ,  Jan Jiricek  4 ,  Lauren C Davis  1 ,  Xianzhong Liu  1 ,  Jaime Ballard  1 ,  Shilpi Khare  1 ,  Fabian Kurt Eggimann  2 ,  Alexandre Luneau  2 ,  Todd Groessl  1 ,  Michael Shapiro  1 ,  Wendy Richmond  1 ,  Kevin Johnson  1 ,  Patrick J Rudewicz  4 ,  Srinivasa P S Rao  4 ,  Christopher Thompson  5 ,  Tove Tuntland  1 ,  Glen Spraggon  1 ,  Richard J Glynne  1 ,  Frantisek Supek  1 ,  Christian Wiesmann  2 ,  Valentina Molteni  1
Affiliations
  • 1. Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
  • 2. Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland.
  • 3. Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.
  • 4. Novartis Institute of Tropical Diseases, Emeryville, California 94608, United States.
  • 5. Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, United States.
PMID: 32667203 DOI: 10.1021/acs.jmedchem.0c00499
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.

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