Small-molecule inhibitors directly target CARD9 and mimic its protective variant in inflammatory bowel disease
Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an allelic series of CARD9 variants associated with increased risk of or protection from inflammatory bowel disease (IBD). The predisposing variant o...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 43; pp. 11392 - 11397 |
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| Main Authors | , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
24.10.2017
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0027-8424 1091-6490 1091-6490 |
| DOI | 10.1073/pnas.1705748114 |
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| Abstract | Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an allelic series of CARD9 variants associated with increased risk of or protection from inflammatory bowel disease (IBD). The predisposing variant of CARD9 is associated with increased NF-κB–mediated cytokine production. Conversely, the protective variant lacks a functional C-terminal domain and is unable to recruit the E3 ubiquitin ligase TRIM62. Here, we used biochemical insights into CARD9 variant proteins to create a blueprint for IBD therapeutics and recapitulated the mechanism of the CARD9 protective variant using small molecules. We developed a multiplexed bead-based technology to screen compounds for disruption of the CARD9–TRIM62 interaction. We identified compounds that directly and selectively bind CARD9, disrupt TRIM62 recruitment, inhibit TRIM62-mediated ubiquitinylation of CARD9, and demonstrate cellular activity and selectivity in CARD9-dependent pathways. Taken together, small molecules targeting CARD9 illustrate a path toward improved IBD therapeutics. |
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| AbstractList | Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an allelic series of CARD9 variants associated with increased risk of or protection from inflammatory bowel disease (IBD). The predisposing variant of CARD9 is associated with increased NF-κB-mediated cytokine production. Conversely, the protective variant lacks a functional C-terminal domain and is unable to recruit the E3 ubiquitin ligase TRIM62. Here, we used biochemical insights into CARD9 variant proteins to create a blueprint for IBD therapeutics and recapitulated the mechanism of the CARD9 protective variant using small molecules. We developed a multiplexed bead-based technology to screen compounds for disruption of the CARD9-TRIM62 interaction. We identified compounds that directly and selectively bind CARD9, disrupt TRIM62 recruitment, inhibit TRIM62-mediated ubiquitinylation of CARD9, and demonstrate cellular activity and selectivity in CARD9-dependent pathways. Taken together, small molecules targeting CARD9 illustrate a path toward improved IBD therapeutics.Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an allelic series of CARD9 variants associated with increased risk of or protection from inflammatory bowel disease (IBD). The predisposing variant of CARD9 is associated with increased NF-κB-mediated cytokine production. Conversely, the protective variant lacks a functional C-terminal domain and is unable to recruit the E3 ubiquitin ligase TRIM62. Here, we used biochemical insights into CARD9 variant proteins to create a blueprint for IBD therapeutics and recapitulated the mechanism of the CARD9 protective variant using small molecules. We developed a multiplexed bead-based technology to screen compounds for disruption of the CARD9-TRIM62 interaction. We identified compounds that directly and selectively bind CARD9, disrupt TRIM62 recruitment, inhibit TRIM62-mediated ubiquitinylation of CARD9, and demonstrate cellular activity and selectivity in CARD9-dependent pathways. Taken together, small molecules targeting CARD9 illustrate a path toward improved IBD therapeutics. Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an allelic series of variants associated with increased risk of or protection from inflammatory bowel disease (IBD). The predisposing variant of CARD9 is associated with increased NF-κB-mediated cytokine production. Conversely, the protective variant lacks a functional C-terminal domain and is unable to recruit the E3 ubiquitin ligase TRIM62. Here, we used biochemical insights into CARD9 variant proteins to create a blueprint for IBD therapeutics and recapitulated the mechanism of the CARD9 protective variant using small molecules. We developed a multiplexed bead-based technology to screen compounds for disruption of the CARD9-TRIM62 interaction. We identified compounds that directly and selectively bind CARD9, disrupt TRIM62 recruitment, inhibit TRIM62-mediated ubiquitinylation of CARD9, and demonstrate cellular activity and selectivity in CARD9-dependent pathways. Taken together, small molecules targeting CARD9 illustrate a path toward improved IBD therapeutics. Understanding the genetic basis of human disease can reveal mechanisms of disease pathology and guide the design of novel treatment strategies. Here, we leverage insights from genetic studies to create a blueprint for treatment of inflammatory bowel disease (IBD). We demonstrate the feasibility of using small-molecule inhibitors to recapitulate the antiinflammatory function of CARD9 mutations associated with protection from IBD. Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an allelic series of CARD9 variants associated with increased risk of or protection from inflammatory bowel disease (IBD). The predisposing variant of CARD9 is associated with increased NF-κB–mediated cytokine production. Conversely, the protective variant lacks a functional C-terminal domain and is unable to recruit the E3 ubiquitin ligase TRIM62. Here, we used biochemical insights into CARD9 variant proteins to create a blueprint for IBD therapeutics and recapitulated the mechanism of the CARD9 protective variant using small molecules. We developed a multiplexed bead-based technology to screen compounds for disruption of the CARD9–TRIM62 interaction. We identified compounds that directly and selectively bind CARD9, disrupt TRIM62 recruitment, inhibit TRIM62-mediated ubiquitinylation of CARD9, and demonstrate cellular activity and selectivity in CARD9-dependent pathways. Taken together, small molecules targeting CARD9 illustrate a path toward improved IBD therapeutics. Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an allelic series of CARD9 variants associated with increased risk of or protection from inflammatory bowel disease (IBD). The predisposing variant of CARD9 is associated with increased NF-κB-mediated cytokine production. Conversely, the protective variant lacks a functional C-terminal domain and is unable to recruit the E3 ubiquitin ligase TRIM62. Here, we used biochemical insights into CARD9 variant proteins to create a blueprint for IBD therapeutics and recapitulated the mechanism of the CARD9 protective variant using small molecules. We developed a multiplexed bead-based technology to screen compounds for disruption of the CARD9-TRIM62 interaction. We identified compounds that directly and selectively bind CARD9, disrupt TRIM62 recruitment, inhibit TRIM62-mediated ubiquitinylation of CARD9, and demonstrate cellular activity and selectivity in CARD9-dependent pathways. Taken together, small molecules targeting CARD9 illustrate a path toward improved IBD therapeutics. |
| Author | Petrone, Adam Rush, Jason S. Durney, Michael A. Phillips, Andrew Shamji, Alykhan F. Perez, Jose R. Dančík, Vlado Daly, Mark J. Cao, Zhifang Kaushik, Virendar K. Chittick, Benjamin Wu, Huixian Bittker, Joshua A. Graham, Daniel B. Xavier, Ramnik J. Schreiber, Stuart L. Leshchiner, Elizaveta S. |
| Author_xml | – sequence: 1 givenname: Elizaveta S. surname: Leshchiner fullname: Leshchiner, Elizaveta S. organization: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138 – sequence: 2 givenname: Jason S. surname: Rush fullname: Rush, Jason S. organization: Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142 – sequence: 3 givenname: Michael A. surname: Durney fullname: Durney, Michael A. organization: Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142 – sequence: 4 givenname: Zhifang surname: Cao fullname: Cao, Zhifang organization: Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142 – sequence: 5 givenname: Vlado surname: Dančík fullname: Dančík, Vlado organization: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142 – sequence: 6 givenname: Benjamin surname: Chittick fullname: Chittick, Benjamin organization: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142 – sequence: 7 givenname: Huixian surname: Wu fullname: Wu, Huixian organization: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142 – sequence: 8 givenname: Adam surname: Petrone fullname: Petrone, Adam organization: Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142 – sequence: 9 givenname: Joshua A. surname: Bittker fullname: Bittker, Joshua A. organization: Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142 – sequence: 10 givenname: Andrew surname: Phillips fullname: Phillips, Andrew organization: Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142 – sequence: 11 givenname: Jose R. surname: Perez fullname: Perez, Jose R. organization: Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142 – sequence: 12 givenname: Alykhan F. surname: Shamji fullname: Shamji, Alykhan F. organization: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142 – sequence: 13 givenname: Virendar K. surname: Kaushik fullname: Kaushik, Virendar K. organization: Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142 – sequence: 14 givenname: Mark J. surname: Daly fullname: Daly, Mark J. organization: Medical and Population Genetics Program, Broad Institute, Cambridge, MA 02142 – sequence: 15 givenname: Daniel B. surname: Graham fullname: Graham, Daniel B. organization: Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142 – sequence: 16 givenname: Stuart L. surname: Schreiber fullname: Schreiber, Stuart L. organization: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138 – sequence: 17 givenname: Ramnik J. surname: Xavier fullname: Xavier, Ramnik J. organization: Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29073062$$D View this record in MEDLINE/PubMed |
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| Keywords | therapeutics inflammatory bowel disease small molecules CARD9 |
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| Notes | SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 Reviewers: B.F.C., The Scripps Research Institute; and K.M.S., University of California, San Francisco. Contributed by Stuart L. Schreiber, September 7, 2017 (sent for review April 19, 2017; reviewed by Benjamin F. Cravatt and Kevan M. Shokat) Author contributions: E.S.L., J.S.R., M.A.D., A. Phillips, J.P., A.F.S., V.K.K., M.J.D., D.B.G., S.L.S., and R.J.X. designed research; E.S.L., J.S.R., M.A.D., Z.C., and A. Petrone performed research; E.S.L., J.S.R., Z.C., V.D., B.C., and H.W. contributed new reagents/analytic tools; E.S.L., M.A.D., Z.C., V.D., B.C., J.B., V.K.K., D.B.G., S.L.S., and R.J.X. analyzed data; E.S.L., D.B.G., S.L.S., and R.J.X. wrote the paper; and J.P. contributed to discussions and data interpretation. |
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| Snippet | Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an... Understanding the genetic basis of human disease can reveal mechanisms of disease pathology and guide the design of novel treatment strategies. Here, we... |
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| SubjectTerms | Biochemistry Biological Sciences CARD Signaling Adaptor Proteins - antagonists & inhibitors CARD Signaling Adaptor Proteins - genetics Cytokines Drug Evaluation, Preclinical Enzyme-Linked Immunosorbent Assay - methods Genetic Markers Genetic Variation Genetics Genome-wide association studies Genomes High-Throughput Screening Assays Humans Inflammatory bowel disease Inflammatory bowel diseases Inflammatory Bowel Diseases - drug therapy Inflammatory Bowel Diseases - genetics Intestine Multiplexing NF-κB protein Protein Binding Proteins Recruitment Sensitivity and Specificity Tripartite Motif Proteins - antagonists & inhibitors Tripartite Motif Proteins - genetics Ubiquitin Ubiquitin-protein ligase Ubiquitin-Protein Ligases - antagonists & inhibitors Ubiquitin-Protein Ligases - genetics |
| Title | Small-molecule inhibitors directly target CARD9 and mimic its protective variant in inflammatory bowel disease |
| URI | https://www.jstor.org/stable/26488594 https://www.ncbi.nlm.nih.gov/pubmed/29073062 https://www.proquest.com/docview/1981797214 https://www.proquest.com/docview/1957477290 https://pubmed.ncbi.nlm.nih.gov/PMC5664502 |
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