Discovery of novel quinoline-based proteasome inhibitors for Human African Trypanosomiasis (HAT)

Koester, D. C. and Marx, V. M. and Williams, S. and Jiricek, J. and Dauphinais, M. and René, O. and Miller, S. L. and Zhang, L. and Patra, D. and Chen, Y. L. and Cheung, H. and Gable, J. and Lakshminarayana, S. B. and Osborne, C. and Galarneau, J. R. and Kulkarni, U. and Richmond, W. and Bretz, A. and Xiao, L. and Supek, F. and Wiesmann, C. and Honnappa, S. and Be, C. and Mäser, P. and Kaiser, M. and Ritchie, R. and Barrett, M. P. and Diagana, T. T. and Sarko, C. and Rao, S. P. S.. (2022) Discovery of novel quinoline-based proteasome inhibitors for Human African Trypanosomiasis (HAT). Journal of medicinal chemistry, 65. 11776−11787.

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Official URL: https://edoc.unibas.ch/90592/

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
UniBasel Contributors:Mäser, Pascal and Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:27 Dec 2022 10:40
Deposited On:27 Dec 2022 10:40

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