A combined AI and cell biology approach surfaces targets and mechanistically distinct Inflammasome inhibitors
Summary: Inflammasomes are protein complexes that mediate innate immune responses whose dysregulation has been linked to a spectrum of acute and chronic human conditions, which dictates therapeutic development that is aligned with disease variability. We designed a scalable, physiologic high-content...
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| Language: | English |
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Elsevier
2024-12-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224026294 |
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| author | Daniel Chen Tempest Plott Michael Wiest Will Van Trump Ben Komalo Dat Nguyen Charlie Marsh Jarred Heinrich Colin J. Fuller Lauren Nicolaisen Elisa Cambronero An Nguyen Christian Elabd Francesco Rubbo Rachel DeVay Jacobson |
| author_facet | Daniel Chen Tempest Plott Michael Wiest Will Van Trump Ben Komalo Dat Nguyen Charlie Marsh Jarred Heinrich Colin J. Fuller Lauren Nicolaisen Elisa Cambronero An Nguyen Christian Elabd Francesco Rubbo Rachel DeVay Jacobson |
| author_sort | Daniel Chen |
| collection | DOAJ |
| description | Summary: Inflammasomes are protein complexes that mediate innate immune responses whose dysregulation has been linked to a spectrum of acute and chronic human conditions, which dictates therapeutic development that is aligned with disease variability. We designed a scalable, physiologic high-content imaging assay in human PBMCs that we analyzed using a combination of machine-learning and cell biology methods. This resulted in a set of biologically interpretable readouts that can resolve a spectrum of cellular states associated with inflammasome activation and inhibition. These methods were applied to a phenotypic screen that surfaced mechanistically distinct inflammasome inhibitors from an annotated 12,000 compound library. A set of over 100 inhibitors, including an array of Raf-pathway inhibitors, were validated in downstream functional assays. This approach demonstrates how complementary machine learning-based methods can be used to generate profiles of cellular states associated with different stages of complex biological pathways and yield compound and target discovery. |
| format | Article |
| id | doaj-art-01cb3490251649b8b5df12f29f5f035a |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-01cb3490251649b8b5df12f29f5f035a2024-12-22T05:29:15ZengElsevieriScience2589-00422024-12-012712111404A combined AI and cell biology approach surfaces targets and mechanistically distinct Inflammasome inhibitorsDaniel Chen0Tempest Plott1Michael Wiest2Will Van Trump3Ben Komalo4Dat Nguyen5Charlie Marsh6Jarred Heinrich7Colin J. Fuller8Lauren Nicolaisen9Elisa Cambronero10An Nguyen11Christian Elabd12Francesco Rubbo13Rachel DeVay Jacobson14Spring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USASpring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USASpring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USASpring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USASpring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USASpring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USASpring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USASpring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USASpring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USASpring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USASpring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USASpring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USASpring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USASpring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USA; Corresponding authorSpring Discovery, Inc., 1125 Industrial Road, San Carlos, CA 94070, USA; Corresponding authorSummary: Inflammasomes are protein complexes that mediate innate immune responses whose dysregulation has been linked to a spectrum of acute and chronic human conditions, which dictates therapeutic development that is aligned with disease variability. We designed a scalable, physiologic high-content imaging assay in human PBMCs that we analyzed using a combination of machine-learning and cell biology methods. This resulted in a set of biologically interpretable readouts that can resolve a spectrum of cellular states associated with inflammasome activation and inhibition. These methods were applied to a phenotypic screen that surfaced mechanistically distinct inflammasome inhibitors from an annotated 12,000 compound library. A set of over 100 inhibitors, including an array of Raf-pathway inhibitors, were validated in downstream functional assays. This approach demonstrates how complementary machine learning-based methods can be used to generate profiles of cellular states associated with different stages of complex biological pathways and yield compound and target discovery.http://www.sciencedirect.com/science/article/pii/S2589004224026294Cell biologyData analysisMachine learning |
| spellingShingle | Daniel Chen Tempest Plott Michael Wiest Will Van Trump Ben Komalo Dat Nguyen Charlie Marsh Jarred Heinrich Colin J. Fuller Lauren Nicolaisen Elisa Cambronero An Nguyen Christian Elabd Francesco Rubbo Rachel DeVay Jacobson A combined AI and cell biology approach surfaces targets and mechanistically distinct Inflammasome inhibitors iScience Cell biology Data analysis Machine learning |
| title | A combined AI and cell biology approach surfaces targets and mechanistically distinct Inflammasome inhibitors |
| title_full | A combined AI and cell biology approach surfaces targets and mechanistically distinct Inflammasome inhibitors |
| title_fullStr | A combined AI and cell biology approach surfaces targets and mechanistically distinct Inflammasome inhibitors |
| title_full_unstemmed | A combined AI and cell biology approach surfaces targets and mechanistically distinct Inflammasome inhibitors |
| title_short | A combined AI and cell biology approach surfaces targets and mechanistically distinct Inflammasome inhibitors |
| title_sort | combined ai and cell biology approach surfaces targets and mechanistically distinct inflammasome inhibitors |
| topic | Cell biology Data analysis Machine learning |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224026294 |
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