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

Clicks: 344
ID: 86782
2017
Article Quality & Performance Metrics
Overall Quality
Not rated
Combines reader engagement with the AI quality analysis. This article has not been analysed, so there is no overall score — reader engagement is measured and shown alongside.
AI Quality Assessment
Not analyzed
Readership in this journal
Steady

Ranked #62 of 292 articles by views in Proceedings of the National Academy of Sciences of the United States of America

Most read Least read

Bar heights use a square-root scale. Only the 120 most-read articles are drawn; the journal has 292 in total.

Mint this article as an NFT
Not yet minted

Create a permanent, verifiable on-chain record of this article on the Scimatic Network. The NFT is held in your Journament account, and you can withdraw it to your own wallet at any time.

5 SUSD one-off · no wallet required
Sign in to mint
Abstract
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.
Reference Key
leshchiner2017smallmoleculeproceedings Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Leshchiner, Elizaveta S;Rush, Jason S;Durney, Michael A;Cao, Zhifang;Dančík, Vlado;Chittick, Benjamin;Wu, Huixian;Petrone, Adam;Bittker, Joshua A;Phillips, Andrew;Perez, Jose R;Shamji, Alykhan F;Kaushik, Virendar K;Daly, Mark J;Graham, Daniel B;Schreiber, Stuart L;Xavier, Ramnik J;
Journal Proceedings of the National Academy of Sciences of the United States of America
Year 2017
DOI
10.1073/pnas.1705748114
URL
Keywords
therapeutics inflammatory bowel disease small molecules card9

Citations

No citations found. To add a citation, contact the admin at info@scimatic.org

Comments

No comments yet. Be the first to comment on this article.