Scientists develop molecules that may treat Crohn’s disease and other chronic inflammatory disorders

Good news!

"Highlights

• Scientists developed small molecules that target a protective gene variant strongly associated with inflammatory bowel disease.
• The compounds reduced both inflammatory signaling in human immune cells and inflammation in a mouse model.
• This human genetics-to-therapeutics pipeline can be applied to other diseases and challenging drug targets.

...

But a lucky few individuals are far less likely to develop IBD because they have a rare variant of a gene called CARD9. This protective gene variant prevents the long-term digestive tract inflammation that can cause tissue damage and lead to disease.

Now, researchers ... have developed small-molecule drug candidates that mimic the effects of this rare gene variant and could potentially treat Crohn’s and other inflammatory bowel diseases. ..."

From the abstract:

"Highlights

• A Crohn’s-disease-protective CARD9 variant guided inhibitor discovery strategy

• DNA-encoded library and structural studies revealed a ligandable pocket in CARD9

• Benzodiazepine inhibitors block CARD9-dependent NF-κB activation and cytokine release

• Compounds dampen inflammation in dendritic cells and in a humanized mouse model

Summary

Human genetic association studies highlight key genes involved in disease pathology, yet targets identified by these analyses often fall outside the traditional definitions of druggability.

A rare truncated variant of the scaffold protein CARD9 is linked with protection from Crohn’s disease, prompting us to pursue the development of inhibitors that might similarly modulate innate inflammatory responses.

Using a phased approach, we first identified a ligandable site on CARD9 using a structurally diverse DNA-encoded library and defined this site in detail through X-ray crystallography.

Building upon this, a subsequent ligand displacement screen identified additional molecules that uniquely engage CARD9 and prevent its assembly into scaffolds needed to nucleate a signalosome for downstream nuclear factor κB (NF-κB) induction.

These inhibitors suppressed inflammatory cytokine production in dendritic cells and a humanized CARD9 mouse model. Collectively, this study illustrates a strategy for leveraging protective human genetic variants and chemical biology to tackle challenging targets for dampening inflammation."

Scientists develop molecules that may treat Crohn’s disease | Broad Institute "The molecules mimic a gene variant that protects against Crohn’s, demonstrating a roadmap for using genetics to develop therapies for inflammatory bowel disease and other chronic inflammatory disorders."

Human genetics guides the discovery of CARD9 inhibitors with anti-inflammatory activity (no public access)

Graphical abstract