Discovery of novel quinoline-based proteasome inhibitors for human African trypanosomiasis (HAT)

Koester, D. C. et al. (2022) Discovery of novel quinoline-based proteasome inhibitors for human African trypanosomiasis (HAT). Journal of Medicinal Chemistry, 65(17), pp. 11776-11787. (doi: 10.1021/acs.jmedchem.2c00791) (PMID:35993839) (PMCID:PMC9469205)

Abstract

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.

• Item Type: Articles
• Additional Information: NITD thanks the Wellcome Trust (fund IDs WT-103024MA and WT-104976) for financial support of this project.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Barrett, Professor Michael and Ritchie, Mr Ryan
• Authors: Koester, D. C., Marx, V. M., Williams, S., Jiricek, J., Dauphinais, M., René, O., Miller, S. L., Zhang, L., Patra, D., Chen, Y.-L., Cheung, H., Gable, J., Lakshminarayana, S. B., Osborne, C., Galarneau, J.-R., Kulkarni, U., Richmond, W., Bretz, A., Xiao, L., Supek, F., Wiesmann, C., Honnappa, S., Be, C., Mäser, P., Kaiser, M., Ritchie, R., Barrett, M. P., Diagana, T. T., Sarko, C., and Rao, S. P. S.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Medicinal Chemistry
• Publisher: American Chemical Society
• ISSN: 0022-2623
• ISSN (Online): 1520-4804
• Published Online: 22 August 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Journal of Medicinal Chemistry 65(17): 11776-11787
• Publisher Policy: Reproduced under a Creative Commons License