Congratulations to Alok and all the authors!

@broadinstitute.org @mgbresearch.bsky.social

@broadinstitute.org
@mgbresearch.bsky.social

These studies firmly establish a foundation for development of an inhibitor of CARD9 inflammatory response. More broadly, this approach illustrates a strategy for using human genetics and chemical biology to guide small-molecule discovery against challenging immune targets. (7/7)

The optimized compound blocked CARD9-dependent NFκB activation and cytokine release in human dendritic cells and reduced inflammation in mouse model of fungal infection expressing humanized CARD9 (hCARD9), demonstrating the feasibility of pharmacological targeting of CARD9. (6/7)

Using time-resolved FRET (TR-FRET) displacement screens, surface plasmon resonance (SPR), and structure-activity relationship studies we identified a benzodiazepine compound with selective CARD9 binding and cellular activity. (5/7)

To explore pharmacological modulation of CARD9, we took a binder-first strategy: a DNA-encoded library screen and subsequent structural studies revealed a ligandable pocket in the CARD9 coiled-coil domain, guiding subsequent chemical exploration. (4/7)

In prior work, we leveraged CARD9Δ11 to study CARD9 regulation and identified the E3 ligase TRIM62 as a CARD9-interacting protein that regulates CARD9 activation through post-translational modification. (3/7)
www.sciencedirect.com/science/arti...

CARD9 is a key immune adaptor required for immune responses against fungi and bacteria and is implicated in multiple inflammatory diseases. The truncation variant CARD9Δ11 protects against Crohn’s disease, suggesting CARD9 inhibition as a strategy for therapeutic intervention. (2/7)

@mgbresearch.bsky.social

Check out their findings from paired mother/infant microbiome & disease-specific metagenomic datasets! rdcu.be/eRVYz (2/2)