Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome

被引：4

作者：

Matico, Rosalie ^{[1
]}

Grauwen, Karolien ^{[2
]}

Chauhan, Dhruv ^{[2
]}

Yu, Xiaodi ^{[1
]}

Abdiaj, Irini ^{[3
]}

Adhikary, Suraj ^{[1
]}

Adriaensen, Ine ^{[4
]}

Aranzazu, Garcia Molina ^{[3
]}

Alcazar, Jesus ^{[3
]}

Bassi, Michela ^{[5
]}

Brisse, Ellen ^{[2
]}

Canellas, Santiago ^{[3
]}

Chaudhuri, Shubhra ^{[6
]}

Delgado, Francisca ^{[3
]}

Dieguez-Vazquez, Alejandro ^{[3
]}

Du Jardin, Marc ^{[7
]}

Eastham, Victoria ^{[1
]}

Finley, Michael ^{[1
]}

Jacobs, Tom ^{[8
]}

Keustermans, Ken ^{[9
]}

Kuhn, Robert ^{[10
]}

Llaveria, Josep ^{[3
]}

Leenaerts, Jos ^{[5
]}

Linares, Maria Lourdes ^{[3
]}

Martin, Maria Luz ^{[3
]}

Martin-Perez, Rosa ^{[2
]}

Martinez, Carlos ^{[3
]}

Miller, Robyn ^{[1
]}

Munoz, Frances M. ^{[1
]}

Muratore, Michael E. ^{[5
]}

Nooyens, Amber ^{[2
]}

Perez-Benito, Laura ^{[11
]}

Perrier, Mathieu ^{[5
]}

Pietrak, Beth ^{[1
]}

Serre, Jef ^{[2
]}

Sharma, Sujata ^{[1
]}

Somers, Marijke ^{[12
]}

Suarez, Javier ^{[1
]}

Tresadern, Gary ^{[11
]}

Trabanco, Andres A. ^{[3
]}

van den Bulck, Dries ^{[1
]}

Van Gool, Michiel ^{[5
]}

Van Hauwermeiren, Filip ^{[2
]}

Varghese, Teena ^{[1
]}

Vega, Juan Antonio ^{[3
]}

Youssef, Sameh A. ^{[8
]}

Edwards, Matthew J. ^{[2
]}

Oehlrich, Daniel ^{[5
]}

Van Opdenbosch, Nina ^{[2
]}

机构：

[1] Janssen Res & Dev LLC, Discovery Technol & Mol Pharmacol DTMP, Spring House, PA 19044 USA

[2] Janssen Pharmaceut, Turnhoutseweg 30, B-2340 Beerse, Belgium

[3] Janssen Res & Dev LLC, Global Discovery Chem GDC, C Rio Jarama,75, E-45007 Toledo, Spain

[4] Janssen Res & Dev LLC, In Vivo Sci IVS, Turnhoutseweg 30, B-2340 Beerse, Belgium

[5] Janssen Res & Dev LLC, Global Discovery Chem GDC, Turnhoutseweg 30, B-2340 Beerse, Belgium

[6] Janssen Res & Dev LLC, Preclin Sci & Translat Safety PSTS, Spring House, PA 19044 USA

[7] Janssen Res & Dev LLC, Discovery Pharmaceut, Turnhoutseweg 30, B-2340 Beerse, Belgium

[8] Janssen Res & Dev LLC, Preclin Sci & Translat Safety PSTS, Turnhoutseweg 30, B-2340 Beerse, Belgium

[9] Charles River Labs, Turnhoutseweg 30, B-2340 Beerse, Belgium

[10] Janssen Intervent Oncol, Spring House, PA 19044 USA

[11] Janssen Res & Dev LLC, Therapeut Discovery, Turnhoutseweg 30, B-2340 Beerse, Belgium

[12] Janssen Res & Dev LLC, Drug Metab & Phamacokinetcs DMPK, Turnhoutseweg 30, B-2340 Beerse, Belgium

来源：

EMBO MOLECULAR MEDICINE | 2025年 / 17卷 / 01期

关键词：

Novel Inhibitor; NLRP3; IL-1; beta; Inflammasome; Clinical Candidate; AIM2; INFLAMMASOME; ACTIVATION; INHIBITOR;

D O I：

10.1038/s44321-024-00181-4

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

The NLRP3 inflammasome plays a pivotal role in host defense and drives inflammation against microbial threats, crystals, and danger-associated molecular patterns (DAMPs). Dysregulation of NLRP3 activity is associated with various human diseases, making it an attractive therapeutic target. Patients with NLRP3 mutations suffer from Cryopyrin-Associated Periodic Syndrome (CAPS) emphasizing the clinical significance of modulating NLRP3. In this study, we present the identification of a novel chemical class exhibiting selective and potent inhibition of the NLRP3 inflammasome. Through a comprehensive structure-activity relationship (SAR) campaign, we optimized the lead molecule, compound A, for in vivo applications. Extensive in vitro and in vivo characterization of compound A confirmed the high selectivity and potency positioning compound A as a promising clinical candidate for diseases associated with aberrant NLRP3 activity. This research contributes to the ongoing efforts in developing targeted therapies for conditions involving NLRP3-mediated inflammation, opening avenues for further preclinical and clinical investigations.

引用

页码：54 / 84

页数：31

共 63 条

[1] Real-space refinement in PHENIX for cryo-EM and crystallography [J].

Afonine, Pavel V. ;

Poon, Billy K. ;

Read, Randy J. ;

Sobolev, Oleg V. ;

Terwilliger, Thomas C. ;

Urzhumtsev, Alexandre ;

Adams, Paul D. .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2018, 74 :531-544

[2] Cutting Edge: NF-κB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 Expression [J].

Bauernfeind, Franz G. ;

Horvath, Gabor ;

Stutz, Andrea ;

Alnemri, Emad S. ;

MacDonald, Kelly ;

Speert, David ;

Fernandes-Alnemri, Teresa ;

Wu, Jianghong ;

Monks, Brian G. ;

Fitzgerald, Katherine A. ;

Hornung, Veit ;

Latz, Eicke .

JOURNAL OF IMMUNOLOGY, 2009, 183 (02) :787-791

[3]

Bowers K. J., 2006, SCALABLE ALGORITHMS

[4] Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin [J].

Boyden, ED ;

Dietrich, WF .

NATURE GENETICS, 2006, 38 (02) :240-244

[5] Differential Requirement for Caspase-1 Autoproteolysis in Pathogen-Induced Cell Death and Cytokine Processing [J].

Broz, Petr ;

von Moltke, Jakob ;

Jones, Jonathan W. ;

Vance, Russell E. ;

Monack, Denise M. .

CELL HOST & MICROBE, 2010, 8 (06) :471-483

[6] Mechanisms of NLRP3 inflammasome- mediated hepatic stellate cell activation: Therapeutic potential for liver fibrosis [J].

Charan, Harsh Vardhan ;

Dwivedi, Durgesh Kumar ;

Khan, Sabbir ;

Jena, Gopabandhu .

GENES & DISEASES, 2023, 10 (02) :480-494

[7] RRx-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor [J].

Chen, Yun ;

He, Hongbin ;

Lin, Bolong ;

Chen, Yun ;

Deng, Xianming ;

Jiang, Wei ;

Zhou, Rongbin .

CELLULAR & MOLECULAR IMMUNOLOGY, 2021, 18 (06) :1425-1436

[8] NLRP3 and pyroptosis blockers for treating inflammatory diseases [J].

Coll, Rebecca C. ;

Schroder, Kate ;

Pelegrin, Pablo .

TRENDS IN PHARMACOLOGICAL SCIENCES, 2022, 43 (08) :653-668

[9] MCC950 directly targets the NLRP3 ATP- hydrolysis motif for inflammasome inhibition [J].

Coll, Rebecca C. ;

Hill, James R. ;

Day, Christopher J. ;

Zamoshnikova, Alina ;

Boucher, Dave ;

Massey, Nicholas L. ;

Chitty, Jessica L. ;

Fraser, James A. ;

Jennings, Michael P. ;

Robertson, Avril A. B. ;

Schroder, Kate .

NATURE CHEMICAL BIOLOGY, 2019, 15 (06) :556-+

[10] A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases [J].

Coll, Rebecca C. ;

Robertson, Avril A. B. ;

Chae, Jae Jin ;

Higgins, Sarah C. ;

Munoz-Planillo, Raul ;

Inserra, Marco C. ;

Vetter, Irina ;

Dungan, Lara S. ;

Monks, Brian G. ;

Stutz, Andrea ;

Croker, Daniel E. ;

Butler, Mark S. ;

Haneklaus, Moritz ;

Sutton, Caroline E. ;

Nunez, Gabriel ;

Latz, Eicke ;

Kastner, Daniel L. ;

Mills, Kingston H. G. ;

Masters, Seth L. ;

Schroder, Kate ;

Cooper, Matthew A. ;

O'Neill, Luke A. J. .

NATURE MEDICINE, 2015, 21 (03) :248-+

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