Related Experiment Video

Updated: Feb 20, 2026

Investigating Target Gene Function in a CD40 Agonistic Antibody-induced Colitis Model using CRISPR/Cas9-based Technologies
09:08

Investigating Target Gene Function in a CD40 Agonistic Antibody-induced Colitis Model using CRISPR/Cas9-based Technologies

Published on: June 2, 2021

2.1K

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

Elizaveta S Leshchiner1,2, Jason S Rush3, Michael A Durney3

  • 1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138.

Proceedings of the National Academy of Sciences of the United States of America
|October 27, 2017
PubMed

Insights

Small molecules targeting CARD9 (caspase recruitment domain-containing protein 9) offer a new therapeutic strategy for inflammatory bowel disease (IBD). These compounds disrupt key protein interactions, showing promise for treating this complex heritable disease.

Area of Science:

  • Genetics and Molecular Biology
  • Immunology
  • Drug Discovery

Background:

  • Advances in human genetics have improved understanding of complex heritable diseases.
  • Genome-wide association studies identified CARD9 variants associated with inflammatory bowel disease (IBD) risk.
  • Predisposing CARD9 variants increase NF-κB cytokine production; protective variants lack TRIM62 recruitment.

Purpose of the Study:

  • To develop a blueprint for IBD therapeutics based on CARD9 variant biochemical insights.
  • To recapitulate the protective mechanism of CARD9 variants using small molecules.
  • To identify compounds that disrupt the CARD9-TRIM62 interaction.

Main Methods:

  • Biochemical analysis of CARD9 variant proteins.
  • Development of multiplexed bead-based technology for compound screening.
  • Screening for compounds disrupting CARD9-TRIM62 interaction and CARD9 ubiquitination.

Main Results:

  • Identified compounds that directly and selectively bind CARD9.
  • Discovered compounds that disrupt TRIM62 recruitment to CARD9.
  • Demonstrated cellular activity and selectivity of compounds in CARD9-dependent pathways.

Conclusions:

  • Small molecules targeting CARD9 represent a potential therapeutic avenue for IBD.
  • Disruption of CARD9-TRIM62 interaction is a viable strategy for IBD treatment.
  • Targeting CARD9 offers a path toward improved IBD therapeutics.

Keywords:
CARD9inflammatory bowel diseasesmall moleculestherapeutics

More Related Videos

Evaluating Therapeutic Interventions in the SHIP-deficient Mouse Model of Crohn Disease-like Ileitis and Fibrosis09:44

Evaluating Therapeutic Interventions in the SHIP-deficient Mouse Model of Crohn Disease-like Ileitis and Fibrosis

Published on: October 14, 2025

504
In Vivo Augmentation of Gut-Homing Regulatory T Cell Induction08:02

In Vivo Augmentation of Gut-Homing Regulatory T Cell Induction

Published on: January 22, 2020

6.0K

Related Concept Videos

Drugs for Treatment of Crohn's Disease in IBD Using Biologic Agents: Anti-TNF01:24

Drugs for Treatment of Crohn's Disease in IBD Using Biologic Agents: Anti-TNF

Tumor Necrosis Factor (TNF), a proinflammatory cytokine, contributes significantly to the inflammation seen in Crohn's disease. It exists as soluble TNF and membrane-bound TNF, with actions mediated through TNF receptors (TNFR). TNFR activation leads to the release of proinflammatory cytokines, T-cell activation, collagen production, and leukocyte migration, all contributing to inflammation in Crohn's disease. Anti-TNF monoclonal antibodies, namely infliximab (Remicade), adalimumab...
607
Drugs for Treatment of Crohn's Disease in IBD Using Immunomodulatory Agents01:29

Drugs for Treatment of Crohn's Disease in IBD Using Immunomodulatory Agents

Crohn's disease is an inflammatory bowel disorder marked by chronic inflammation of the GI tract. Various treatment strategies for Crohn's disease are employed, such as immunomodulatory agents, glucocorticoids, and biologics or anti-TNF therapy. Azathioprine (Imuran), a commonly used immunomodulatory drug for Crohn's disease, is converted in the body to mercaptopurine, which inhibits purine biosynthesis and cell proliferation. Both are utilized in severe cases of Inflammatory Bowel...
574
Inflammatory Bowel Disease IV: Pharmacological Management01:29

Inflammatory Bowel Disease IV: Pharmacological Management

Upon diagnosis, managing Inflammatory Bowel Disease (IBD) involves addressing several crucial aspects. The primary goals include resting the bowel, correcting malnutrition, and providing symptomatic relief. Resting the bowel may consist of medications to reduce inflammation and promote healing. Correcting malnutrition is essential, often requiring dietary adjustments and nutritional supplements. Symptomatic relief aims to ease pain, diarrhea, and other discomforts in IBD.
Pharmacologic...
817
Drugs for Treatment of Ulcerative Colitis in IBD01:29

Drugs for Treatment of Ulcerative Colitis in IBD

Ulcerative colitis is a chronic inflammatory condition primarily affecting the colon and rectum. The primary drugs used in the treatment of ulcerative colitis are aminosalicylates. They exhibit anti-inflammatory and immunosuppressive properties. They modulate inflammatory mediators and inhibit the activity of nuclear factor κB (NF-κB). Aminosalicylates also reduce inflammation by inhibiting prostaglandin and leukotriene production and decreasing neutrophil chemotaxis and superoxide...
549
Drugs for Treatment of Crohn's Disease in IBD Using Glucocorticoids01:21

Drugs for Treatment of Crohn's Disease in IBD Using Glucocorticoids

Glucocorticoids, a class of anti-inflammatory drugs, are pivotal in treating moderate to severe Crohn's disease by inducing remission. They exhibit their anti-inflammatory action by inhibiting the production of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and chemokines like IL-8. In addition, they reduce the expression of inflammatory cell adhesion molecules and inhibit gene transcription of nitric oxide synthase, phospholipase A2, cyclooxygenase-2...
542
Inflammatory Bowel Disease II: Crohn's Disease01:30

Inflammatory Bowel Disease II: Crohn's Disease

Introduction
Inflammatory bowel disease, commonly known as IBD, refers to a collection of disorders that lead to persistent inflammation of the gastrointestinal tract. The two types of IBD are ulcerative colitis, which impacts the colon, and Crohn's disease, which can involve any part of the gastrointestinal segment.
Crohn's disease
Crohn's disease is a chronic, systemic inflammatory bowel disease (IBD) that predominantly affects the gastrointestinal tract. It is marked by...
1.3K