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Human genetics guides the discovery of CARD9 inhibitors with anti-inflammatory activity
Jason S Rush1, Joshua D Wertheimer2, Steven D Goldberg3
1Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Insights
Researchers developed novel inhibitors targeting the CARD9 protein to reduce inflammation. This approach leverages genetic insights for Crohn's disease to create new therapeutic strategies for inflammatory conditions.
Area of Science:
- Immunology
- Genetics
- Chemical Biology
Background:
- Human genetic studies identify disease-associated genes, but targets are often undruggable.
- A protective variant of CARD9 (a scaffold protein) against Crohn's disease suggests therapeutic potential.
Purpose of the Study:
- To develop inhibitors for CARD9 to modulate innate inflammatory responses.
- To explore a strategy for targeting challenging proteins identified through genetic associations.
Main Methods:
- Identified a ligandable site on CARD9 using a DNA-encoded library and X-ray crystallography.
- Screened for ligands that inhibit CARD9 scaffold assembly and NF-κB signaling.
- Tested inhibitors in dendritic cells and a humanized CARD9 mouse model.
Main Results:
- A druggable site on CARD9 was identified and characterized.
- Novel inhibitors were discovered that prevent CARD9 assembly and NF-κB induction.
- Inhibitors suppressed inflammatory cytokine production in cellular and animal models.
Conclusions:
- This study demonstrates a viable strategy for targeting genetically validated but challenging proteins.
- Chemical biology approaches can be used to develop novel anti-inflammatory agents.
- Targeting CARD9 offers a potential therapeutic avenue for inflammatory diseases.
Abstract:
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.
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