ArticleJournal of medicinal chemistry2020
Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases.
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Article in Journal of medicinal chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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58 citing papers in PubMed, 111 citations in OpenAlex.
- Safety and pharmacokinetics of GSK3494245, a highly selective Leishmaniasis kinetoplastid proteasome inhibitor for the treatment of visceral leishmaniasis: A Phase 1, randomized, single ascending dose escalation study in healthy participants.PLoS neglected tropical diseases · 2026Trial
- Safety, tolerability and pharmacokinetics of DNDI-6148, a novel agent for leishmaniasis: A randomized, controlled, single ascending dose study in healthy participants.British journal of clinical pharmacology · 2026Trial
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- Five-layer systems analysis ofeLife · 2026Article
- Integrating Molecular Similarity and AlphaFold-Based Structural Alignment for Target Discovery inPharmaceuticals (Basel, Switzerland) · 2026Article
- Multi-drug tolerance in Leishmania persister-like cells.Communications biology · 2026Article
- ExploringAntimicrobial agents and chemotherapy · 2026Article
- Decoding efficacy and resistance space at a drug binding site.Nature communications · 2026Article
- Pathogenic Significance of Trypanosomatids: Progress in Drug Resistance, Control Strategies, and Artificial Intelligence.Interdisciplinary perspectives on infectious diseases · 2026Review
- Trypanosomatid parasites, translational research in a One Health, One World environment.Frontiers in chemistry · 2026Review
- Recent advances in triazole hybrid molecules for the therapeutic management of neglected tropical diseases.RSC medicinal chemistry · 2025Review
- Optimization of Species-Selective Reversible Proteasome Inhibitors for the Treatment of Malaria.Journal of medicinal chemistry · 2025Article
- Challenges of Aufheben to Promote Druglikeness: Chemical Modification Strategies to Improve Aqueous Solubility and Permeability.Journal of medicinal chemistry · 2025Review
- Pyrazole-Imidazoline Derivative Prevents Cardiac Damage and Mortality in AcutePharmaceuticals (Basel, Switzerland) · 2025Article
- Interventions for Neglected Diseases Caused by Kinetoplastid Parasites: A One Health Approach to Drug Discovery, Development, and Deployment.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Structure-activity relationships of 1,5-dihydro-2RSC medicinal chemistry · 2025Article
- Exploring theAntimicrobial agents and chemotherapy · 2025Article
- Structure and activity of the essential UCH family deubiquitinase DUB16 from Leishmania donovani.The Biochemical journal · 2025Article
- Enhancing schistosomiasis drug discovery approaches with optimized proteasome substrates.Protein science : a publication of the Protein Society · 2025Article
- Identification of Substituted 4-Aminocinnolines as Broad-Spectrum Antiparasitic Agents.ACS infectious diseases · 2025Article
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Authors and funding
43 authors at 4 institutions in 2 countries.
Advait NagleGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.ORCID 0000-0002-9347-8542
Agnes BiggartGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Celine BeNovartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland.
Honnappa SrinivasNovartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland.
Andreas HeinNovartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland.
Diana CaridhaExperimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.
Richard J SciottiExperimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.
Brandon PybusExperimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.
Mara Kreishman-DeitrickExperimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.
Badry BursulayaGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Yin H LaiGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Mu-Yun GaoGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Fang LiangGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Casey J N MathisonGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.ORCID 0000-0002-1310-826X
Xiaodong LiuGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Vince YehGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Jeffrey SmithGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Isabelle LerarioGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Yongping XieGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Donatella ChianelliGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Michael GibneyGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Ashley BermanGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Yen-Liang ChenNovartis Institute of Tropical Diseases, Emeryville, California 94608, United States.
Jan JiricekNovartis Institute of Tropical Diseases, Emeryville, California 94608, United States.
Lauren C DavisGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Xianzhong LiuGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Jaime BallardGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Shilpi KhareGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Fabian Kurt EggimannNovartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland.
Alexandre LuneauNovartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland.
Todd GroesslGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Michael ShapiroGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Wendy RichmondGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Kevin JohnsonGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Patrick J RudewiczNovartis Institute of Tropical Diseases, Emeryville, California 94608, United States.
Srinivasa P S RaoNovartis Institute of Tropical Diseases, Emeryville, California 94608, United States.ORCID 0000-0002-7156-5725
Christopher ThompsonNovartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, United States.
Tove TuntlandGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Glen SpraggonGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Richard J GlynneGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Frantisek SupekGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
Christian WiesmannNovartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland.
Valentina MolteniGenomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.ORCID 0000-0002-5387-6036
Genomics Institute of the Novartis Research Foundation · USNovartis (Switzerland) · CHNovartis (United States) · USWalter Reed Army Institute of Research · US
Funding
Wellcome Trust 091038/Z/09/Z
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
Indexed as
AnimalsAntiprotozoal AgentsDogsHumansLeishmania donovaniLeishmania majorLeishmaniasis, VisceralLiverMacaca fascicularisMiceMice, Inbred BALB COxazolesProteasome InhibitorsPyrimidinesRatsRats, Sprague-DawleyAntiprotozoal AgentsGNF6702LXE408OxazolesProteasome InhibitorsPyrimidinesTriazoles
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.