Human genetics guides the discovery of CARD9 inhibitors with anti-inflammatory activity
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 structu
Content
# Human genetics guides the discovery of CARD9 inhibitors with anti-inflammatory activity
*Published: 2026 Mar 5*
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.
DOI: 10.1016/j.cell.2025.12.013