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TitleDiscovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT).
Journal, issue, pagesJ Med Chem, Vol. 65, Issue 17, Page 11776-11787, Year 2022
Publish dateSep 8, 2022
AuthorsDennis C Koester / Vanessa M Marx / Sarah Williams / Jan Jiricek / Maxime Dauphinais / Olivier René / Sarah L Miller / Lei Zhang / Debjani Patra / Yen-Liang Chen / Harry Cheung / Jonathan Gable / Suresh B Lakshminarayana / Colin Osborne / Jean-Rene Galarneau / Upendra Kulkarni / Wendy Richmond / Angela Bretz / Linda Xiao / Frantisek Supek / Christian Wiesmann / Srinivas Honnappa / Celine Be / Pascal Mäser / Marcel Kaiser / Ryan Ritchie / Michael P Barrett / Thierry T Diagana / Christopher Sarko / Srinivasa P S Rao /
PubMed AbstractHuman African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo- ...Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an model to predict the brain-to-plasma partition coefficient as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios () to cure a CNS disease such as HAT.
External linksJ Med Chem / PubMed:35993839 / PubMed Central
MethodsEM (single particle)
Resolution2.7 Å
Structure data

15025

7zyj

EMDB-15025, PDB-7zyj:
Leishmania tarentolae proteasome 20S subunit in complex with compound 2
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-KFC:
~{N}-cyclopentyl-6-methyl-4-phenylazanyl-quinoline-2-carboxamide

Source
  • leishmania tarentolae (eukaryote)
KeywordsHYDROLASE / proteasome. Cryo-EM / Inhibitor

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