Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT)

Human African Trypanosomiasis (HAT) is a vector-borne
disease caused
by kinetoplastid parasites of the Trypanosoma 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 7 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 in silico model to predict the brain-to-plasma
partition coefficient Kp 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 (Kp,uu) to cure a CNS disease such as HAT.