Abstract

Small-molecule inhibitors directly target CARD9 and mimic its protective variant in inflammatory bowel disease

Leshchiner ES1,2, Rush JS3, Durney MA3, Cao Z4,5,6, Dančík V2, Chittick B2, Wu H2, Petrone A3, Bittker JA3, Phillips A3, Perez JR3, Shamji AF2, Kaushik VK3, Daly Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11392-11397. doi: 10.1073/pnas.1705748114. Epub 2017 Oct 9. MJ7,8, Graham DB4,5,6, Schreiber SL9,2, Xavier RJ10,5,6.
 
     
Author information

1 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138. 2 Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142. 3 Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142. 4 Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. 5 Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. 6 Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142. 7 Medical and Population Genetics Program, Broad Institute, Cambridge, MA 02142. 8 Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114. 9 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138; stuart_schreiber@harvard.edu xavier@molbio.mgh.harvard.edu. 10 Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; stuart_schreiber@harvard.edu xavier@molbio.mgh.harvard.edu.

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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