Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT) PMID: 35993839

ADC Targets in Oncology

2026-04-10

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

J Med Chem. 2022 Sep 8;65(17):11776-11787. doi: 10.1021/acs.jmedchem.2c00791.

Dennis C Koester ¹ , Vanessa M Marx ¹ , Sarah Williams ¹ , Jan Jiricek ¹ , Maxime Dauphinais ¹ , Olivier René ¹ , Sarah L Miller ¹ , Lei Zhang ¹ , Debjani Patra ² , Yen-Liang Chen ³ , Harry Cheung ³ , Jonathan Gable ³ , Suresh B Lakshminarayana ⁴ , Colin Osborne ⁵ , Jean-Rene Galarneau ⁶ , Upendra Kulkarni ⁷ , Wendy Richmond ⁸ , Angela Bretz ⁸ , Linda Xiao ⁹ , Frantisek Supek ¹⁰ , Christian Wiesmann ¹¹ , Srinivas Honnappa ¹¹ , Celine Be ¹¹ , Pascal Mäser ¹² ¹³ , Marcel Kaiser ¹² ¹³ , Ryan Ritchie ¹⁴ , Michael P Barrett ¹⁴ , Thierry T Diagana ² , Christopher Sarko ¹ , Srinivasa P S Rao ²

Affiliations

1. Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Emeryville, California 94608, United States.
2. Novartis Institutes for Tropical Diseases, Emeryville, California 94608, United States.
3. Lead Discovery, Novartis Institutes for Tropical Diseases, Emeryville, California 94608, United States.
4. Pharmacokinetic Sciences, Novartis Institutes for Tropical Diseases, Emeryville, California 94608, United States.
5. Pharmacokinetic Sciences, Pharmacology and Comparative Medicine, Novartis Institutes for Tropical Diseases, Emeryville, California 94608, United States.
6. Preclinical Safety, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, United States.
7. Chemical and Pharmaceutical Profiling, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, United States.
8. Global Discovery Chemistry, Novartis Institutes for Biomedical Research, San Diego, California 92121, United States.
9. Pharmacology, Novartis Institutes for Tropical Diseases, Emeryville, California 94608, United States.
10. Novartis Institutes for Biomedical Research, San Diego, California 92121, United States.
11. Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
12. Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123 Allschwil, Switzerland.
13. University of Basel, CH 4000 Basel, Switzerland.
14. University of Glasgow, University Place, Glasgow G12 8TA, U.K.

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 K_p 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 (K_p,uu) to cure a CNS disease such as HAT.