Discovery of novel NLRP3 inhibitors enabled by a high-throughput screen

被引：0

作者：

Dorich, Stephane ^{[1
]}

Auger, Anick ^{[1
]}

Wang, Li ^{[2
]}

Burch, Jason ^{[1
]}

Pellerin, Charles ^{[1
]}

Chan, Silas ^{[2
]}

Raymond, Marianne ^{[1
]}

Zhang, Lingling ^{[2
]}

Chefson, Amandine ^{[1
]}

Germain, Marie-Anne ^{[1
]}

Jananji, Silvana ^{[1
]}

Dumais, Valerie ^{[1
]}

Gaudreault, Samuel ^{[1
]}

Caron, Alexandre ^{[1
]}

Dumas-Berube, Emilie ^{[1
]}

Crackower, Michael. A. ^{[2
]}

机构：

[1] Ventus Therapeut Inc, 4800 Rue Levy, St Laurent, PQ H4R 2P1, Canada

[2] Ventus Therapeut US Inc, 100 Beaver St,Suite 201, Waltham, MA 02453 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2025年 / 122卷

关键词：

NLRP3; inhibitors; High-throughput screen (HTS); Scintillation proximity assay (SPA); Brain penetrant; Furan; Pharmacodynamic model; INFLAMMASOME;

D O I：

10.1016/j.bmcl.2025.130184

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

NLRP3 is a key regulator of the innate immune system involved in sensing a variety of pathogen and danger signals. Priming and activation of NLRP3 leads to the release and maturation of pro-inflammatory cytokines, as well as gasdermin D-mediated cell death. Inhibition of dysregulated NLRP3 activity has been associated with promising therapeutic opportunities for a variety of systemic and neurological diseases including atherosclerosis and Parkinson's disease. Herein, we discuss how a high-throughput screen (HTS) allowed us to discover new chemical scaffolds that specifically bind to NLRP3 and inhibit its function in a selective manner. We also describe how an enantiomer of HTS hit 5, compound 11, demonstrated in vivo inhibition of NLRP3.

引用

页数：7

共 50 条

[1] A phenotypic high-content, high-throughput screen identifies inhibitors of NLRP3 inflammasome activation
Sohaib Nizami
Val Millar
Kanisa Arunasalam
Tryfon Zarganes-Tzitzikas
David Brough
Gary Tresadern
Paul E. Brennan
John B. Davis
Daniel Ebner
Elena Di Daniel
Scientific Reports, 11
[2] A phenotypic high-content, high-throughput screen identifies inhibitors of NLRP3 inflammasome activation
Nizami, Sohaib
Millar, Val
Arunasalam, Kanisa
Zarganes-Tzitzikas, Tryfon
Brough, David
Tresadern, Gary
Brennan, Paul E.
Davis, John B.
Ebner, Daniel
Di Daniel, Elena
SCIENTIFIC REPORTS, 2021, 11 (01)
[3] Discovery of novel androgen receptor coactivator binding inhibitors through high-throughput screen
Josan, Jatinder
Parent, Alexander
Mayne, Christopher
Zhang, Chen
Norris, John
McDonnell, Donald
Katzenellenbogen, John
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2012, 244
[4] A high-throughput screen to identify novel calcineurin inhibitors
Margassery, Lekha Menon
Kennedy, Jonathan
O'Gara, Fergal
Dobson, Alan D.
Morrissey, John P.
JOURNAL OF MICROBIOLOGICAL METHODS, 2012, 88 (01) : 63 - 66
[5] The discovery of novel and potent indazole NLRP3 inhibitors enabled by DNA-encoded library screening
Hartman, George
Humphries, Paul
Hughes, Robert
Ho, Andrew
Montgomery, Rusty
Deshpande, Aditi
Mahanta, Maitriyee
Tronnes, Sarah
Cowdin, Samantha
He, Xu
Liu, Fangchao
Zhang, Lifang
Liu, Chuan
Dou, Dengfeng
Li, Jin
Spasic, Aleksander
Coll, Rebecca
Marleaux, Michael
Hochheiser, Inga V.
Geyer, Matthias
Rubin, Paul
Fortney, Kristen
Wilhelmsen, Kevin
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2024, 102
[6] High-Throughput drug discovery of novel inhibitors of secretion.
Satoh, A.
Suzuki, H.
Honjo, Y.
Nishina, Y.
MOLECULAR BIOLOGY OF THE CELL, 2014, 25
[7] Discovery of Two Novel Oxidases Using a High-Throughput Activity Screen
Rembeza, Elzbieta
Boverio, Alessandro
Fraaije, Marco W.
Engqvist, Martin K. M.
CHEMBIOCHEM, 2022, 23 (02)
[8] A High-Throughput Screen for Antibiotic Drug Discovery
Scanlon, Thomas C.
Dostal, Sarah M.
Griswold, Karl E.
BIOTECHNOLOGY AND BIOENGINEERING, 2014, 111 (02) : 232 - 243
[9] Novel Macrocyclic NLRP3 Inhibitors
Mesch, Stefanie
Shannon, Jonathan
Miller, David
Macleod, Angus
Bouche, Lea
Johnston, Heather J.
Matthews, Kim
Paehler, Axel
Best, Stuart
Guba, Wolfgang
Alanine, Thomas
Halai, Reena
Charge, Lorna
Garside, Samantha
Thom, Stephen
Incerti-Pradillos, Celia
Mcpherson, Christopher
Carrillo, Jokin
St-Gallay, Steve
Rigo, Pierre
Schlicht, Sonja
Hendrick, Alan G.
Lerner, Christian
Piali, Luca
Blaising, Julie
Mracsko, Eva Z.
Jaeschke, Georg
Cooper, Matthew A.
JOURNAL OF MEDICINAL CHEMISTRY, 2024, 67 (23) : 20911 - 20932
[10] Novel inhibitors of the NLRP3 inflammasome
Fulp, Jacob
He, Liu
Jiang, Yuqi
Zhang, Shijun
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2017, 254

← 1 2 3 4 5 →