Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome
Abstract 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. P...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2024-12-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s44321-024-00181-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594479050129408 |
|---|---|
| author | Rosalie Matico Karolien Grauwen Dhruv Chauhan Xiaodi Yu Irini Abdiaj Suraj Adhikary Ine Adriaensen Garcia Molina Aranzazu Jesus Alcázar Michela Bassi Ellen Brisse Santiago Cañellas Shubhra Chaudhuri Francisca Delgado Alejandro Diéguez-Vázquez Marc Du Jardin Victoria Eastham Michael Finley Tom Jacobs Ken Keustermans Robert Kuhn Josep Llaveria Jos Leenaerts Maria Lourdes Linares Maria Luz Martín Rosa Martín-Pérez Carlos Martínez Robyn Miller Frances M Muñoz Michael E Muratore Amber Nooyens Laura Perez-Benito Mathieu Perrier Beth Pietrak Jef Serré Sujata Sharma Marijke Somers Javier Suarez Gary Tresadern Andres A Trabanco Dries Van den Bulck Michiel Van Gool Filip Van Hauwermeiren Teena Varghese Juan Antonio Vega Sameh A Youssef Matthew J Edwards Daniel Oehlrich Nina Van Opdenbosch |
| author_facet | Rosalie Matico Karolien Grauwen Dhruv Chauhan Xiaodi Yu Irini Abdiaj Suraj Adhikary Ine Adriaensen Garcia Molina Aranzazu Jesus Alcázar Michela Bassi Ellen Brisse Santiago Cañellas Shubhra Chaudhuri Francisca Delgado Alejandro Diéguez-Vázquez Marc Du Jardin Victoria Eastham Michael Finley Tom Jacobs Ken Keustermans Robert Kuhn Josep Llaveria Jos Leenaerts Maria Lourdes Linares Maria Luz Martín Rosa Martín-Pérez Carlos Martínez Robyn Miller Frances M Muñoz Michael E Muratore Amber Nooyens Laura Perez-Benito Mathieu Perrier Beth Pietrak Jef Serré Sujata Sharma Marijke Somers Javier Suarez Gary Tresadern Andres A Trabanco Dries Van den Bulck Michiel Van Gool Filip Van Hauwermeiren Teena Varghese Juan Antonio Vega Sameh A Youssef Matthew J Edwards Daniel Oehlrich Nina Van Opdenbosch |
| author_sort | Rosalie Matico |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-5709e3f7f42e4d508855aaf3a1778b40 |
| institution | Kabale University |
| issn | 1757-4684 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-5709e3f7f42e4d508855aaf3a1778b402025-01-19T12:34:36ZengSpringer NatureEMBO Molecular Medicine1757-46842024-12-01171548410.1038/s44321-024-00181-4Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasomeRosalie Matico0Karolien Grauwen1Dhruv Chauhan2Xiaodi Yu3Irini Abdiaj4Suraj Adhikary5Ine Adriaensen6Garcia Molina Aranzazu7Jesus Alcázar8Michela Bassi9Ellen Brisse10Santiago Cañellas11Shubhra Chaudhuri12Francisca Delgado13Alejandro Diéguez-Vázquez14Marc Du Jardin15Victoria Eastham16Michael Finley17Tom Jacobs18Ken Keustermans19Robert Kuhn20Josep Llaveria21Jos Leenaerts22Maria Lourdes Linares23Maria Luz Martín24Rosa Martín-Pérez25Carlos Martínez26Robyn Miller27Frances M Muñoz28Michael E Muratore29Amber Nooyens30Laura Perez-Benito31Mathieu Perrier32Beth Pietrak33Jef Serré34Sujata Sharma35Marijke Somers36Javier Suarez37Gary Tresadern38Andres A Trabanco39Dries Van den Bulck40Michiel Van Gool41Filip Van Hauwermeiren42Teena Varghese43Juan Antonio Vega44Sameh A Youssef45Matthew J Edwards46Daniel Oehlrich47Nina Van Opdenbosch48Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP)Janssen Interventional OncologyJanssen Interventional OncologyJanssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP)Janssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP)Janssen Research & Development, LLC, In Vivo Sciences (IVS)Janssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Interventional OncologyJanssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Research & Development, LLC, Preclinical Sciences and Translational Safety (PSTS)Janssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Research & Development, LLC, Discovery PharmaceuticsJanssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP)Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP)Janssen Research & Development, LLC, Preclinical Sciences and Translational Safety (PSTS)Charles River LaboratoriesJanssen Interventional OncologyJanssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Interventional OncologyJanssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP)Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP)Janssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Interventional OncologyJanssen Research & Development, LLC, Therapeutic DiscoveryJanssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP)Janssen Interventional OncologyJanssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP)Janssen Research & Development, LLC, Drug Metabolism and Phamacokinetcs (DMPK)Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP)Janssen Research & Development, LLC, Therapeutic DiscoveryJanssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP)Janssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Interventional OncologyJanssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP)Janssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Research & Development, LLC, Preclinical Sciences and Translational Safety (PSTS)Janssen Interventional OncologyJanssen Research & Development, LLC, Global Discovery Chemistry (GDC)Janssen Interventional OncologyAbstract 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.https://doi.org/10.1038/s44321-024-00181-4Novel InhibitorNLRP3IL-1βInflammasomeClinical Candidate |
| spellingShingle | Rosalie Matico Karolien Grauwen Dhruv Chauhan Xiaodi Yu Irini Abdiaj Suraj Adhikary Ine Adriaensen Garcia Molina Aranzazu Jesus Alcázar Michela Bassi Ellen Brisse Santiago Cañellas Shubhra Chaudhuri Francisca Delgado Alejandro Diéguez-Vázquez Marc Du Jardin Victoria Eastham Michael Finley Tom Jacobs Ken Keustermans Robert Kuhn Josep Llaveria Jos Leenaerts Maria Lourdes Linares Maria Luz Martín Rosa Martín-Pérez Carlos Martínez Robyn Miller Frances M Muñoz Michael E Muratore Amber Nooyens Laura Perez-Benito Mathieu Perrier Beth Pietrak Jef Serré Sujata Sharma Marijke Somers Javier Suarez Gary Tresadern Andres A Trabanco Dries Van den Bulck Michiel Van Gool Filip Van Hauwermeiren Teena Varghese Juan Antonio Vega Sameh A Youssef Matthew J Edwards Daniel Oehlrich Nina Van Opdenbosch Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome EMBO Molecular Medicine Novel Inhibitor NLRP3 IL-1β Inflammasome Clinical Candidate |
| title | Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome |
| title_full | Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome |
| title_fullStr | Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome |
| title_full_unstemmed | Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome |
| title_short | Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome |
| title_sort | navigating from cellular phenotypic screen to clinical candidate selective targeting of the nlrp3 inflammasome |
| topic | Novel Inhibitor NLRP3 IL-1β Inflammasome Clinical Candidate |
| url | https://doi.org/10.1038/s44321-024-00181-4 |
| work_keys_str_mv | AT rosaliematico navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT karoliengrauwen navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT dhruvchauhan navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT xiaodiyu navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT iriniabdiaj navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT surajadhikary navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT ineadriaensen navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT garciamolinaaranzazu navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT jesusalcazar navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT michelabassi navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT ellenbrisse navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT santiagocanellas navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT shubhrachaudhuri navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT franciscadelgado navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT alejandrodieguezvazquez navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT marcdujardin navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT victoriaeastham navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT michaelfinley navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT tomjacobs navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT kenkeustermans navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT robertkuhn navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT josepllaveria navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT josleenaerts navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT marialourdeslinares navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT marialuzmartin navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT rosamartinperez navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT carlosmartinez navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT robynmiller navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT francesmmunoz navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT michaelemuratore navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT ambernooyens navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT lauraperezbenito navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT mathieuperrier navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT bethpietrak navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT jefserre navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT sujatasharma navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT marijkesomers navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT javiersuarez navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT garytresadern navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT andresatrabanco navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT driesvandenbulck navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT michielvangool navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT filipvanhauwermeiren navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT teenavarghese navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT juanantoniovega navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT samehayoussef navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT matthewjedwards navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT danieloehlrich navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome AT ninavanopdenbosch navigatingfromcellularphenotypicscreentoclinicalcandidateselectivetargetingofthenlrp3inflammasome |