PXD070429

PXD070429 is an original dataset announced via ProteomeXchange.

Title	Human genetics guides the discovery of novel CARD9 inhibitors with in vitro and in vivo anti-inflammatory activity
Description	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 NFκB 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.
HostingRepository	PRIDE
AnnounceDate	2026-01-09
AnnouncementXML	Submission_2026-01-08_17:14:47.125.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD070429
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Amanda Del Rosario
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2025-11-06 18:07:10	ID requested
⏵ 1	2026-01-08 17:14:47	announced

10.1016/J.CELL.2025.12.013;

10.6019/PXD070429;

submitter keyword: LC-MSMS, PAL,CARD9

Amanda Del Rosario
contact affiliation	Johnson & Johnson
contact email	adelros1@its.jnj.com
lab head
Amanda Del Rosario
contact affiliation	Johnson & Johnson
contact email	adelros1@its.jnj.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD070429
     1. Label: PRIDE project
     2. Name: Human genetics guides the discovery of novel CARD9 inhibitors with in vitro and in vivo anti-inflammatory activity