EMD-15025
Leishmania tarentolae proteasome 20S subunit in complex with compound 2
EMD-15025
Single-particle2.7 Å
Deposition: 24/05/2022Map released: 28/09/2022
Last modified: 24/07/2024
Sample Organism:
Leishmania tarentolae
Sample: Proteasome
Fitted models: 7zyj (Avg. Q-score: 0.565)
Deposition Authors: Srinivas H
Sample: Proteasome
Fitted models: 7zyj (Avg. Q-score: 0.565)
Deposition Authors: Srinivas H
Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT).
Koester DC 
,
Marx VM,
Williams S,
Jiricek J,
Dauphinais M,
Rene O,
Miller SL,
Zhang L,
Patra D,
Chen YL,
Cheung H,
Gable J,
Lakshminarayana SB,
Osborne C,
Galarneau JR,
Kulkarni U,
Richmond W,
Bretz A ,
Xiao L,
Supek F,
Wiesmann C,
Honnappa S,
Be C,
Maser P ,
Kaiser M ,
Ritchie R,
Barrett MP,
Diagana TT,
Sarko C,
Rao SPS
(2022) J Med Chem , 65 , 11776 - 11787
,
Marx VM,
Williams S,
Jiricek J,
Dauphinais M,
Rene O,
Miller SL,
Zhang L,
Patra D,
Chen YL,
Cheung H,
Gable J,
Lakshminarayana SB,
Osborne C,
Galarneau JR,
Kulkarni U,
Richmond W,
Bretz A ,
Xiao L,
Supek F,
Wiesmann C,
Honnappa S,
Be C,
Maser P ,
Kaiser M ,
Ritchie R,
Barrett MP,
Diagana TT,
Sarko C,
Rao SPS
(2022) J Med Chem , 65 , 11776 - 11787
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.
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.