RIPK2

Summary

RIPK2 (receptor interacting serine/threonine kinase 2, HGNC:10020) is a protein-coding gene on chromosome 8q21.3, encoding Receptor-interacting serine/threonine-protein kinase 2 (O43353). Serine/threonine/tyrosine-protein kinase that plays an essential role in modulation of innate and adaptive immune responses.

This gene encodes a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. The encoded protein contains a C-terminal caspase activation and recruitment domain (CARD), and is a component of signaling complexes in both the innate and adaptive immune pathways. It is a potent activator of NF-kappaB and inducer of apoptosis in response to various stimuli.

Source: NCBI Gene 8767 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 74 total
• GTEx eGene: eQTL in 23 tissues, sQTL in 7 (q < 0.05)
• ChEMBL bioactivity: 64 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.95 (loss-of-function intolerant), LOEUF 0.53 (moderately constrained)
• MANE Select transcript: NM_003821
• Notable: 74 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10020
Approved symbol	RIPK2
Name	receptor interacting serine/threonine kinase 2
Location	8q21.3
Locus type	gene with protein product
Status	Approved
Aliases	RICK, RIP2, CARDIAK, CARD3
Ensembl gene	ENSG00000104312
Ensembl biotype	protein_coding
OMIM	603455
Entrez	8767

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 9 nonsense_mediated_decay, 6 protein_coding, 1 retained_intron

MANE Select: ENST00000220751

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 1, TSL 4: 1

ENST00000220751, ENST00000517696, ENST00000518673, ENST00000522965, ENST00000893222, ENST00000929530, ENST00000994612, ENST00000994613, ENST00001034718, ENST00001034719, ENST00001034720, ENST00001034721, ENST00001106108, ENST00001106109, ENST00001114859, ENST00001138555

RefSeq mRNA: 2 — MANE Select: NM_003821 NM_001375360, NM_003821

CCDS: CCDS6247

Canonical transcript exons

ENST00000220751 — 11 exons

Exon	Start	End
ENSE00000698858	89762829	89762982
ENSE00001019097	89790079	89791064
ENSE00001019100	89757816	89758233
ENSE00003459316	89769772	89769929
ENSE00003529823	89765341	89765496
ENSE00003571421	89772667	89772828
ENSE00003599613	89786593	89786686
ENSE00003608024	89780075	89780160
ENSE00003611739	89771741	89771790
ENSE00003617726	89784050	89784139
ENSE00003650154	89789321	89789482

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 94.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.4866 / max 999.2793, expressed in 1811 samples.

Highest expression (Bgee): cartilage tissue, monocyte, mononuclear cell, leukocyte, type B pancreatic cell.

Genetic regulation across tissues (GTEx eQTL / sQTL)

RIPK2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 23 tissues and its splicing (sQTL) in 7 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 30 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	3.6e-12	+0.12	8:89771370:GA:G
Breast Mammary Tissue	eqtl	3.3e-08	+0.21	8:89847469:T:C
Thyroid	eqtl	4.5e-08	+0.20	8:89808784:A:G
Brain Cerebellar Hemisphere	eqtl	1.4e-06	-0.33	8:89801900:T:C
Cells Cultured fibroblasts	sqtl	2.0e-06	+0.34	8:89805205:G:A
Skin Sun Exposed Lower leg	eqtl	3.3e-06	+0.15	8:89687131:A:G
Pancreas	eqtl	5.7e-06	+0.23	8:89709590:T:G
Adipose Subcutaneous	eqtl	3.5e-05	+0.26	8:89686893:G:A
Brain Nucleus accumbens basal ganglia	eqtl	9.1e-05	+0.28	8:89699704:GA:G
Brain Cerebellum	eqtl	9.7e-05	+0.28	8:89628493:C:T
Lung	eqtl	1.0e-04	+0.11	8:89810531:G:A
Esophagus Mucosa	eqtl	1.1e-04	+0.31	8:89771518:C:T
Colon Transverse	eqtl	1.6e-04	+0.16	8:89794504:G:A
Small Intestine Terminal Ileum	eqtl	2.1e-04	+0.21	8:89764584:A:C
Esophagus Muscularis	eqtl	3.0e-04	+0.17	8:89820440:G:A
Muscle Skeletal	eqtl	5.6e-04	+0.15	8:89797894:C:T
Stomach	eqtl	6.5e-04	+0.18	8:89709590:T:G
Brain Frontal Cortex BA9	eqtl	8.7e-04	-0.29	8:89701884:A:C
Artery Tibial	eqtl	4.2e-03	+0.18	8:89690724:C:T
Cells EBV-transformed lymphocytes	sqtl	5.0e-03	+0.24	8:89805205:G:A

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
89667	39.8291	1810
89668	2.3239	433
89669	0.9185	273
89670	0.4150	210

Top tissues by expression

showing 100 of 285 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	94.59	gold quality
monocyte	CL:0000576	91.40	gold quality
mononuclear cell	CL:0000842	90.72	gold quality
leukocyte	CL:0000738	90.52	gold quality
type B pancreatic cell	CL:0000169	89.65	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.81	gold quality
vena cava	UBERON:0004087	87.69	gold quality
bone marrow	UBERON:0002371	87.32	gold quality
stromal cell of endometrium	CL:0002255	87.31	gold quality
granulocyte	CL:0000094	86.84	gold quality
gall bladder	UBERON:0002110	86.60	gold quality
oocyte	CL:0000023	86.52	gold quality
upper arm skin	UBERON:0004263	86.52	silver quality
smooth muscle tissue	UBERON:0001135	86.04	gold quality
islet of Langerhans	UBERON:0000006	85.62	gold quality
blood	UBERON:0000178	85.55	gold quality
endometrium	UBERON:0001295	85.43	gold quality
pericardium	UBERON:0002407	85.33	gold quality
mucosa of urinary bladder	UBERON:0001259	84.57	gold quality
bone marrow cell	CL:0002092	84.51	gold quality
secondary oocyte	CL:0000655	84.35	gold quality
heart right ventricle	UBERON:0002080	83.49	gold quality
vermiform appendix	UBERON:0001154	83.48	gold quality
olfactory bulb	UBERON:0002264	83.45	gold quality
synovial joint	UBERON:0002217	83.21	gold quality
upper lobe of left lung	UBERON:0008952	82.84	gold quality
caecum	UBERON:0001153	82.82	gold quality
mammary duct	UBERON:0001765	82.77	silver quality
epithelial cell of pancreas	CL:0000083	82.65	silver quality
cervix epithelium	UBERON:0004801	82.58	silver quality
skin of leg	UBERON:0001511	82.55	gold quality
superficial temporal artery	UBERON:0001614	82.26	silver quality
epithelium of mammary gland	UBERON:0003244	82.24	silver quality
lymph node	UBERON:0000029	82.21	gold quality
upper lobe of lung	UBERON:0008948	82.01	gold quality
uterus	UBERON:0000995	81.95	gold quality
tibial artery	UBERON:0007610	81.89	gold quality
popliteal artery	UBERON:0002250	81.88	gold quality
zone of skin	UBERON:0000014	81.74	gold quality
skin of abdomen	UBERON:0001416	81.66	gold quality
artery	UBERON:0001637	81.66	gold quality
pancreas	UBERON:0001264	81.61	gold quality
right lung	UBERON:0002167	81.59	gold quality
descending thoracic aorta	UBERON:0002345	81.48	gold quality
omental fat pad	UBERON:0010414	81.46	gold quality
peritoneum	UBERON:0002358	81.44	gold quality
placenta	UBERON:0001987	81.40	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	81.39	gold quality
spinal cord	UBERON:0002240	81.30	gold quality
aorta	UBERON:0000947	81.25	gold quality
lung	UBERON:0002048	80.99	gold quality
parotid gland	UBERON:0001831	80.94	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.92	gold quality
oviduct epithelium	UBERON:0004804	80.57	gold quality
calcaneal tendon	UBERON:0003701	80.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.52	gold quality
ascending aorta	UBERON:0001496	80.48	gold quality
thoracic aorta	UBERON:0001515	80.47	gold quality
mucosa of stomach	UBERON:0001199	80.44	gold quality
left coronary artery	UBERON:0001626	80.35	gold quality
coronary artery	UBERON:0001621	80.14	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	80.03	gold quality
layer of synovial tissue	UBERON:0007616	79.90	silver quality
skin of hip	UBERON:0001554	79.87	gold quality
tonsil	UBERON:0002372	79.87	gold quality
cardia of stomach	UBERON:0001162	79.83	silver quality
body of pancreas	UBERON:0001150	79.78	gold quality
right atrium auricular region	UBERON:0006631	79.69	gold quality
tibial nerve	UBERON:0001323	79.66	gold quality
urinary bladder	UBERON:0001255	79.65	gold quality
myometrium	UBERON:0001296	79.48	gold quality
muscle layer of sigmoid colon	UBERON:0035805	79.41	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	79.40	gold quality
right coronary artery	UBERON:0001625	79.35	gold quality
cardiac atrium	UBERON:0002081	79.31	gold quality
subcutaneous adipose tissue	UBERON:0002190	79.30	gold quality
cardiac ventricle	UBERON:0002082	79.27	gold quality
heart	UBERON:0000948	79.26	gold quality
uterine cervix	UBERON:0000002	79.21	gold quality
heart left ventricle	UBERON:0002084	79.21	gold quality
upper leg skin	UBERON:0004262	79.19	gold quality
lower esophagus muscularis layer	UBERON:0035833	79.19	gold quality
lower esophagus	UBERON:0013473	79.18	gold quality
female reproductive system	UBERON:0000474	79.11	gold quality
cervix squamous epithelium	UBERON:0006922	79.10	gold quality
saliva-secreting gland	UBERON:0001044	78.99	gold quality
lower esophagus mucosa	UBERON:0035834	78.83	gold quality
oral cavity	UBERON:0000167	78.69	silver quality
minor salivary gland	UBERON:0001830	78.69	gold quality
amniotic fluid	UBERON:0000173	78.67	gold quality
prostate gland	UBERON:0002367	78.49	gold quality
left uterine tube	UBERON:0001303	78.48	gold quality
connective tissue	UBERON:0002384	78.45	gold quality
adipose tissue	UBERON:0001013	78.35	gold quality
fallopian tube	UBERON:0003889	78.34	gold quality
ectocervix	UBERON:0012249	78.19	gold quality
mouth mucosa	UBERON:0003729	78.10	gold quality
body of uterus	UBERON:0009853	78.09	gold quality
spleen	UBERON:0002106	78.02	gold quality
sigmoid colon	UBERON:0001159	77.99	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-7052	yes	839.83
E-HCAD-4	yes	46.57
E-GEOD-70580	no	1508.08
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Cerebral cortex	tissue	12.6	low
Motor cortex	tissue	12.6
Pons	tissue	12.3
Cerebellum	tissue	12.0	not detected
Prefrontal cortex	tissue	11.9
Retrosplenial cortex	tissue	11.9
Midbrain	tissue	11.5
Thalamus	tissue	11.5
Hippocampal formation	tissue	11.4
Entorhinal cortex	tissue	11.4
Retrosplenial and cingulate cortex	tissue	11.3
Occipital cortex	tissue	11.3
Hypothalamus	tissue	11.1
Septum	tissue	11.1
Somatosensory cortex	tissue	11.1
Insular cortex	tissue	11.1
Substantia nigra	tissue	10.8
Putamen	tissue	10.5
Medulla oblongata	tissue	10.3
Superior colliculi	tissue	10.2
Periaqueductal gray	tissue	10.2
Amygdala	tissue	10.0
Temporal cortex	tissue	10.0
Spinal cord	tissue	9.9
Corpus callosum	tissue	9.8
Ventral forebrain	tissue	9.7
Olfactory bulb	tissue	9.6
Basal ganglia	tissue	9.1	medium
Urinary bladder	tissue	8.8	medium
Gallbladder	tissue	8.8	high
Bone marrow	tissue	8.4	not detected
Tonsil	tissue	6.3	medium
Lymph node	tissue	6.1	medium
Lung	tissue	5.7	medium
Smooth muscle	tissue	5.3	low
Appendix	tissue	5.3	low
Endometrium 1	tissue	5.2	high
Liver	tissue	5.2	low
Prostate	tissue	5.0	medium
Breast	tissue	4.7	high
Salivary gland	tissue	4.7	medium
Placenta	tissue	4.5	high
Spleen	tissue	4.5	low
Cervix	tissue	4.4	medium
Heart muscle	tissue	4.1	medium
Skin 1	tissue	3.9	not detected
Adipose tissue	tissue	3.9	not detected
Parathyroid gland	tissue	3.9	medium
Thyroid gland	tissue	3.9	medium
Pancreas	tissue	3.7	medium
Hippocampus	tissue	3.7	low
Kidney	tissue	3.4	medium
Nucleus accumbens	tissue	3.1
Locus coeruleus	tissue	3.1
Esophagus	tissue	2.8	not detected
Testis	tissue	2.7	medium
Stomach 1	tissue	2.7	low
Rectum	tissue	2.7	medium
Colon	tissue	2.7	medium
Vagina	tissue	2.6	not detected

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Subiculum (11.4), Dorsal hippocampus (11.0), Ventral hippocampus (10.3), Ventral spinal cord (9.9), White matter (9.8).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets:

Target	Regulation
IL12B	Activation

Upstream regulators (CollecTRI, top): E2F4, IFNG, NFKB1, RELA, TNF

Functional genomics

gnomAD constraint: pLI 0.954, LOEUF 0.532, missense Z 1.54 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000220751 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
8:89,758,061–89,790,118	448 / 534.7	0.84	no
8:89,790,119–89,790,298	29 / 68.6	0.42	no
8:89,790,299–89,790,413	41 / 43.7	0.94	no

Literature-anchored findings (GeneRIF, showing 40)

• Involvement of receptor-interacting protein 2 in innate and adaptive immune responses (PMID:11894097)
• Rip2 transduces signals from both innate and adaptive immune responses. Functions downstream of the TLR2/3/4, IL-1 and IL-18 receptors. (PMID:11894098)
• These results implicate RIP2 in a previously unrecognized role: a checkpoint for myogenic proliferation and differentiation. (PMID:12138198)
• equilibrium and kinetic folding of a unique protein domain, caspase recruitment domain (CARD), of the RIP-like interacting CLARP kinase (RICK) (RICK-CARD), which adopts a alpha-helical Greek key fold (PMID:12755636)
• role in CARD6 modulation of NF-kappa B activation (PMID:12775719)
• Rip2 has an important role in TCR-induced NF-kappaB activation and T-cell function (PMID:14638696)
• NOD2-dependent ubiquitinylation of NEMO (a key component of the NF-kB signaling complex) is dependent on the scaffolding protein kinase RIP2. (PMID:15620648)
• Caspase-1-mediated cell death is regulated, at least in part, by the balance of Rip2 and Cop; alterations of this balance may contribute to aberrant caspase-1-mediated pathogenesis in Huntington’s disease. (PMID:16354923)
• CARD6 is a regulator of NF-kappaB activation that modulates the functions of RICK protein (PMID:16418290)
• NOD2-S interacts with both, NOD2 and receptor-interacting protein kinase 2 and inhibits the “nodosome” assembly by interfering with the oligomerization of NOD2 (PMID:16492792)
• review of the regulation of interactions of CARD6 with RICK and microtubules [review] (PMID:16582588)
• Results indicate that S176 is a regulatory autophosphorylation site for RIP2 and that S176 phosphorylation can be used to monitor the activation state of RIP2. (PMID:16824733)
• Cop inhibition of cell death, at least to a certain extent, results from its interference with the activation of caspase-1 and caspase-4. (PMID:16920334)
• mutational analysis shows that interaction of NOD1 with RICK is critically dependent on 3 acidic residues on NOD1 CARD & 3 basic residues on RICK CARD & is likely to have a strong electrostatic component (PMID:17054981)
• Although polymorphisms in RIP2 are not likely to be associated with the development of asthma, the genetic variants might contribute to asthma severity in the Japanese population (PMID:17075290)
• NOD2 is responsible for the membrane recruitment of RICK to induce a regulated NF-kappaB signaling and production of proinflammatory cytokines. (PMID:17355968)
• RIPK2 is a marker for resolution of peritoneal dialysis-associated peritonitis. (PMID:17851464)
• Data show that RICK polyubiquitination links TAK1 to IKK complexes, a critical step in Nod1/Nod2-mediated NF-kappaB activation. (PMID:18079694)
• The encapsulation efficiency of RIPK2 is reported. (PMID:18359207)
• We conclude that the endogenous IL-8 response induced by C. trachomatis infection is dependent upon NOD1 signaling through RIP2 as part of a signal system requiring multiple inputs for optimal IL-8 induction. (PMID:18426885)
• upregulation of RIP2 expression is required for rapid resolution of peritonitis (PMID:18566542)
• alternative mRNA splicing may be involved in the regulation of RIP2 actions, underlying the complexity of RIP2-dependent pathways regulating stress signaling and apoptosis. (PMID:19121870)
• detected on all female reproductive tract tissues (PMID:19406482)
• Data suggest a role for XIAP in regulating innate immune responses by interacting with NOD1 and NOD2 through interaction with RIP2. (PMID:19667203)
• Elevated RIP-2 protein levels promote NF-kappaB function via interaction with IKK gamma (PMID:19693652)
• the NOD2/RIP2 pathway has a role in recognition of Yersinia, but caspase-12 does not modulate innate host defense against Y. pestis (PMID:19721713)
• MS80 inhibits CD40-NF-kappaB pathway via targeting RIP2. (PMID:19911254)
• Data suggest that inhibition of rip2 upregulation after wounding might contribute to the reduced and delayed wound re-epithelialization phenotype seen in glucocorticoid-treated patients. (PMID:20025869)
• RIP2 polymorphisms are not associated with inflammatory bowel diseases. (PMID:20645315)
• RIP2 undergoes autophosphorylation on Tyr 474 and this event is necessary for effective NOD2 signaling (PMID:21123652)
• Tri-DAP interacts directly with the LRR domain of NOD1 and consequently increases RICK/NOD1 association and RICK phosphorylation activity (PMID:21757725)
• the CARD of procaspase-1 is differently involved in the formation of procaspase-1 activating platforms and procaspase-1-mediated, RIP2-dependent NF-kappaB activation. (PMID:21862576)
• GEF-H1 mediated the activation of Rip2 during signaling by NOD2, but not in the presence of the 3020insC variant of NOD2 associated with Crohn’s disease. GEF-H1 functioned downstream of NOD2 as part of Rip2-containing signaling complexes. (PMID:21887730)
• RIP2 gene polymorphisms may be associated with susceptibility to systemic lupus erythematosus in the Chinese population. (PMID:22075569)
• IL-4 failed to up-regulate expression of RP105 at the cell surface. In conclusion, the anti-inflammatory actions of IL-4 occur independently of IL-10, RP105, and the kinase activity of RIPK2 (PMID:22484241)
• Association has been found between RIPK2 (rs42490) and cancer risk. (PMID:22504414)
• These findings mechanisms whereby HBeAg modulates intracellular signaling pathways by targeting RIPK2, supporting the concept that HBeAg could impair both innate and adaptive immune responses to promote chronic HBV infection. (PMID:22615316)
• RIP2 tyrosine kinase activity is not only required for NOD2-dependent autophagy but plays a dual role in this process. (PMID:22665475)
• we demonstrate that Porphyromonas gingivalis infection of human aortic endothelial cells resulted in the rapid cleavage of RIPK1 and RIPK2 (PMID:22685397)
• inositol phosphatase SHIP-1 inhibits NOD2-induced NF-kappaB activation by disturbing the interaction of XIAP with RIP2 (PMID:22815893)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ripk2	ENSDARG00000104290
danio_rerio		ENSDARG00000112870
mus_musculus	Ripk2	ENSMUSG00000041135
rattus_norvegicus	Ripk2	ENSRNOG00000009389

Paralogs (23): MAP3K9 (ENSG00000006432), TESK2 (ENSG00000070759), MAP3K13 (ENSG00000073803), ARAF (ENSG00000078061), MAP3K20 (ENSG00000091436), LIMK1 (ENSG00000106683), TESK1 (ENSG00000107140), TNNI3K (ENSG00000116783), RIPK3 (ENSG00000129465), MAP3K10 (ENSG00000130758), RAF1 (ENSG00000132155), RIPK1 (ENSG00000137275), MAP3K12 (ENSG00000139625), KSR1 (ENSG00000141068), MAP3K21 (ENSG00000143674), BRAF (ENSG00000157764), ILK (ENSG00000166333), MLKL (ENSG00000168404), KSR2 (ENSG00000171435), MOS (ENSG00000172680), MAP3K11 (ENSG00000173327), LIMK2 (ENSG00000182541), LRRK2 (ENSG00000188906)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1891456) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 10 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal macrophage physiology	2
decreased T cell proliferation	2
decreased tumor necrosis factor secretion	2
decreased interleukin-6 secretion	2
increased susceptibility to infection	1
abnormal cytokine secretion	1
abnormal T-helper 1 physiology	1
decreased IgG2a level	1
decreased interferon-gamma secretion	1
decreased tumor incidence following infection	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q3SZJ2	87.2%	Diamond
Gallus gallus	Q90999	73.1%	Diamond
Arabidopsis thaliana	Q9SIZ4	63.9%	Diamond
Dictyostelium discoideum	Q8SSS9	54.1%	Diamond
Caenorhabditis elegans	Q09488	40.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PARAIL	ncRNA	101929709
OSGIN2	protein-coding	734
NBN	protein-coding	4683
DECR1	protein-coding	1666

Protein

Protein identifiers

Receptor-interacting serine/threonine-protein kinase 2 — O43353 (reviewed: O43353)

Alternative names: CARD-containing interleukin-1 beta-converting enzyme-associated kinase, RIP-like-interacting CLARP kinase, Receptor-interacting protein 2, Tyrosine-protein kinase RIPK2

All UniProt accessions (4): O43353, A0A0S2Z4Z8, E5RGK6, E7ERW9

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine/tyrosine-protein kinase that plays an essential role in modulation of innate and adaptive immune responses. Acts as a key effector of NOD1 and NOD2 signaling pathways: upon activation by bacterial peptidoglycans, NOD1 and NOD2 oligomerize and recruit RIPK2 via CARD-CARD domains, leading to the formation of RIPK2 filaments. Once recruited, RIPK2 autophosphorylates and undergoes ‘Lys-63’-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3, as well as ‘Met-1’-linked (linear) polyubiquitination by the LUBAC complex, becoming a scaffolding protein for downstream effectors. ‘Met-1’-linked polyubiquitin chains attached to RIPK2 recruit IKBKG/NEMO, which undergoes ‘Lys-63’-linked polyubiquitination in a RIPK2-dependent process. ‘Lys-63’-linked polyubiquitin chains attached to RIPK2 serve as docking sites for TAB2 and TAB3 and mediate the recruitment of MAP3K7/TAK1 to IKBKG/NEMO, inducing subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. The protein kinase activity is dispensable for the NOD1 and NOD2 signaling pathways. Contributes to the tyrosine phosphorylation of the guanine exchange factor ARHGEF2 through Src tyrosine kinase leading to NF-kappa-B activation by NOD2. Also involved in adaptive immunity: plays a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation. Plays a role in the inactivation of RHOA in response to NGFR signaling.

Subunit / interactions. Interacts (via CARD domain) with NOD2 (via CARD domain). Interacts (via CARD domain) with NOD1 (via CARD domain). Homooligomer; following interaction with NOD1 or NOD2, homooligomerizes via its CARD domain and forms long filaments named RIPosomes. Found in a signaling complex consisting of at least ARHGEF2, NOD2 and RIPK2. Interacts with ARHGEF2; the interaction mediates tyrosine phosphorylation of RIPK2 by Src kinase CSK. Interacts with MAP3K4; this interaction sequesters RIPK2 from the NOD2 signaling pathway. Interacts with IKBKG/NEMO. The polyubiquitinated protein interacts with MAP3K7/TAK1; interaction is indirect and is mediated by TAB2 and TAB3 that bind to polyubiquitin chains attached to RIPK2. Binds to CFLAR/CLARP and CASP1 via their CARD domains. Binds to BIRC3/c-IAP1 and BIRC2/c-IAP2, TRAF1, TRAF2, TRAF5 and TRAF6. Interacts with NLRP10. Interacts with CARD9. Interacts with INAVA; the interaction takes place upon PRR stimulation. Interacts (via CARD domain) with NGFR (via death domain). Interacts with IRGM; promoting RIPK2 degradation.

Subcellular location. Cytoplasm. Cell membrane. Endoplasmic reticulum.

Tissue specificity. Detected in heart, brain, placenta, lung, peripheral blood leukocytes, spleen, kidney, testis, prostate, pancreas and lymph node.

Post-translational modifications. Polyubiquitinated via both ‘Lys-63’- and ‘Met-1’-linked polyubiquitin following recruitment by NOD1 or NOD2, creating docking sites for downstream effectors, triggering activation of the NF-kappa-B and MAP kinases signaling. ‘Lys-63’-linked polyubiquitination by XIAP is essential for NOD2 signaling and promotes recruitment of the LUBAC complex. Also polyubiquitinated with ‘Lys-63’-linked chains by PELI3, BIRC2/c-IAP1 and BIRC3/c-IAP2. Ubiquitinated on Lys-209 via ‘Lys-63’-linked by ITCH. Undergoes ‘Lys-63’-linked deubiquitination by MYSM1 to attenuate NOD2-mediated inflammation and tissue damage. Polyubiquitinated with ‘Lys-63’-linked chains in response to Shigella infection, promoting its SQSTM1/p62-dependent autophagic degradation. Undergoes ‘Met-1’-linked polyubiquitination; the head-to-tail linear polyubiquitination is mediated by the LUBAC complex in response to NOD2 stimulation ‘Met-1’-linked polyubiquitination. ‘Lys-63’-linked polyubiquitination by XIAP is required for recruitment of the LUBAC complex and subsequent. Linear polyubiquitination is restricted by FAM105B/otulin, probably to limit NOD2-dependent pro-inflammatory signaling activation of NF-kappa-B. Ubiquitination at Lys-503 by ZNRF4 via ‘Lys-48’-linked polyubiquitination promotes RIPK2 degradation by the proteasome; ubiquitination by ZNRF4 takes place during both acute and NOD2 tolerance conditions. Autophosphorylated. Phosphorylated at Ser-176, either via autophosphorylation or by LRRK2, enhancing activity. Autophosphorylation at Tyr-474 is required for effective NOD2 signaling. Autophosphorylation is however not essential for NOD2 signaling. Phosphorylation at Tyr-381 by Src kinase CSK occurs in a ARHGEF2-dependent manner and is required for NOD2-dependent innate immune activation. Degraded via selective autophagy following interaction with IRGM. IRGM promotes NOD1/NOD2-RIPK2 RIPosome recruitment to autophagosome membranes. RIPK2 biquitinated via ‘Lys-63’-linked chains is then recognized by SQSTM1/p62, leading to the SQSTM1/p62-dependent autophagic degradation of the NOD1/NOD2-RIPK2 RIPosome. (Microbial infection) Acetylation of Ser-174, Ser-176 and Ser-178 by Yersinia YopJ prevents phosphorylation and activation, thereby promoting cell death.

Activity regulation. In the inactive state, the helix alphaC is packed against the helical, non-phosphorylated activation segment (AS). Upon activation, helix alphaC is displaced and the phosphorylated AS becomes disordered. Specifically inhibited by GSK583, which blocks NOD2 signaling by interfering with XIAP binding to RIPK2. Specifically inhibited by CSLP37 and CSLP43, which blocks NOD2 signaling by interfering with XIAP binding to RIPK2.

Domain organisation. Contains an N-terminal kinase domain and a C-terminal caspase activation and recruitment domain (CARD) that mediates the recruitment of CARD-containing proteins.

Similarity. Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
O43353-1	1	yes
O43353-2	2

RefSeq proteins (2): NP_001362289, NP_003812* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001315	CARD	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR017322	Rcpt-int_Ser/Thr_kinase-2	Family
IPR042149	CARD_RIP2	Domain
IPR051681	Ser/Thr_Kinases-Pseudokinases	Family

Pfam: PF00619, PF07714

Enzyme classification (BRENDA)

• EC 2.7.10.2 — non-specific protein-tyrosine kinase (BRENDA: 41 organisms, 396 substrates, 479 inhibitors, 43 Km, 32 kcat entries)
• EC 2.7.11.30 — receptor protein serine/threonine kinase (BRENDA: 8 organisms, 67 substrates, 81 inhibitors, 4 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.014–17.64	12
[KDSRC KINASE]-L-TYROSINE	0.0057–0.24	12
POLY(GLU4-TYR)	0.018–0.659	10
ATP	0.0057–0.0088	2
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO	0.057	1
S1 PEPTIDE	0.037	1
KKVLTQMGSPSIRCS(P)SVS	0.26	1
KVLTQMGSPSVRCS(P)SMS	0.331	1
EEEEY	—	0

Catalyzed reactions (Rhea)

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)
• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (124 total): mutagenesis site 38, modified residue 24, helix 23, strand 12, turn 7, cross-link 4, region of interest 3, sequence variant 3, domain 2, binding site 2, sequence conflict 2, chain 1, splice variant 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

showing 30 of 33 structures by resolution:

PDB	Title	Method	Resolution (Å)
7OBS	Crystal structure of 14-3-3 sigma in complex with RIPK2 phosphopeptide	X-RAY DIFFRACTION	1.8
9F3V	RIP2K kinase domain dimer with bound compound 37 (N399), a speific NOD1 pathway inhibitor	X-RAY DIFFRACTION	1.94
5NG0	Structure of RIP2K(L294F) with bound AMPPCP	X-RAY DIFFRACTION	2
8X2O	RIPK2 in complex with K252	X-RAY DIFFRACTION	2.26
7OBT	Crystal structure of 14-3-3 sigma in complex with RIPK2 phosphopeptide and stabilizer …	X-RAY DIFFRACTION	2.3
6ES0	Crystal structure of the kinase domain of human RIPK2 in complex with the activation loop …	X-RAY DIFFRACTION	2.38
5AR2	RIP2 Kinase Catalytic Domain (1 - 310)	X-RAY DIFFRACTION	2.44
5J7B	The identification and pharmacological characterization of …	X-RAY DIFFRACTION	2.53
6HMX	RIP2 Kinase Catalytic Domain complex with …	X-RAY DIFFRACTION	2.53
6SZJ	RIP2 Kinase Catalytic Domain complex with 5amino1tertbutyl3(3methoxyphenyl)1H …	X-RAY DIFFRACTION	2.53
5NG3	Structure of inactive kinase RIP2K(K47R)	X-RAY DIFFRACTION	2.6
6RNA	RIP2 Kinase Catalytic Domain complex with …	X-RAY DIFFRACTION	2.62
5AR5	RIP2 Kinase Catalytic Domain (1 - 310) complex with Benzimidazole	X-RAY DIFFRACTION	2.66
6UL8	RIP2 kinase catalytic domain complex with …	X-RAY DIFFRACTION	2.68
5J79	The identification and pharmacological characterization of …	X-RAY DIFFRACTION	2.69
6RN8	RIP2 Kinase Catalytic Domain complex with …	X-RAY DIFFRACTION	2.69
5AR4	RIP2 Kinase Catalytic Domain (1 - 310) complex with SB-203580	X-RAY DIFFRACTION	2.7
5AR7	RIP2 Kinase Catalytic Domain (1 - 310) complex with Biaryl Urea	X-RAY DIFFRACTION	2.71
4C8B	Structure of the kinase domain of human RIPK2 in complex with ponatinib	X-RAY DIFFRACTION	2.75
5AR8	RIP2 Kinase Catalytic Domain (1 - 310) complex with Biphenylsulfonamide	X-RAY DIFFRACTION	2.79
5NG2	Structure of RIP2K(D146N) with bound Staurosporine	X-RAY DIFFRACTION	2.8
5W5J	Identification of potent and selective RIPK2 inhibitors for the treatment of inflammatory …	X-RAY DIFFRACTION	2.85
5W5O	Identification of potent and selective RIPK2 inhibitors for the treatment of inflammatory …	X-RAY DIFFRACTION	2.89
6SZE	RIP2 Kinase Catalytic Domain complex with 5-Amino-1-Phenylpyrazole-4-Carboxamide.	X-RAY DIFFRACTION	2.94
6S1F	Structure of the kinase domain of human RIPK2 in complex with the inhibitor CSLP3	X-RAY DIFFRACTION	3.11
8AZA	Structure of RIP2K dimer bound to the XIAP BIR2 domain	ELECTRON MICROSCOPY	3.15
5AR3	RIP2 Kinase Catalytic Domain (1 - 310) complex with AMP-PCP	X-RAY DIFFRACTION	3.23
6FU5	Structure of the kinase domain of human RIPK2 in complex with the inhibitor CSLP18	X-RAY DIFFRACTION	3.26
6GFJ	Structure of RIP2 CARD domain fused to crystallisable MBP tag	X-RAY DIFFRACTION	3.3
6GGS	Structure of RIP2 CARD filament	ELECTRON MICROSCOPY	3.94

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43353-F1	76.99	0.54

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, TKL Ser/Thr protein kinases, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH approved · IF enhanced

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
146	proton acceptor

Ligand- & substrate-binding residues (2)

Position	Role
24–32	ATP
47	ATP

Post-translational modifications (28)

Type	Positions
(microbial infection) o-acetylthreonine	149, 189, 397
Phosphoserine	168, 174, 176, 178, 180, 181, 363, 393, 527, 529, 531, 539
(microbial infection) o-acetylserine	174, 176, 178, 181, 183, 363, 423
Phosphotyrosine	381, 474
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in ubiquitin)	209, 410, 503, 538

Mutagenesis-validated functional residues (38)

Position	Phenotype
47	abolishes protein-kinase activity without preventing ability to activate nf-kappa-b downstream of nod2.
47	abolishes protein-kinase activity. reduces fas-mediated apoptosis.
95	abolished ability to activate nf-kappa-b downstream of nod2.
146	abolishes protein-kinase activity without preventing ability to activate nf-kappa-b downstream of nod2.
176	decreased phosphorylation and activation. abolished phosphorylation by lrrk2.
209	decreased polyubiquitination.
381	prevents phosphorylation. reduces serine and threonine phosphorylation of arhgef2.
410	reduced ubiquitination by xiap and activation of nf-kappa-b; when associated with r-538.
437	decreased interaction with ngfr.
444	abolishes interaction with nod1. abolished activation of nf-kappa-b.
445	strongly decreased activation of nf-kappa-b. does not affect activation of nf-kappa-b; when associated with e-458.
449	strongly decreased activation of nf-kappa-b.
450	increased activation of nf-kappa-b.
452	impaired interaction with nod2 and decreased homooligomerization and ability to transmit nod2 signaling.
453	decreased homooligomerization and ability to transmit nod2 signaling.
455	decreased homooligomerization and ability to transmit nod2 signaling.
458	strongly decreased activation of nf-kappa-b. does not affect activation of nf-kappa-b; when associated with r-445.
461	abolished activation of nf-kappa-b.
467	decreased interaction with ngfr.
470	decreased homooligomerization and ability to transmit nod2 signaling.
471	abolished activation of nf-kappa-b.
471	decreased interaction with ngfr.
472	abolished activation of nf-kappa-b.
474	decreases interaction with nod2.
474	abolished activation of nf-kappa-b.

Function

Pathways and Gene Ontology

Reactome pathways

8 curated (TAS) of 48; 7 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

48 pathways:

ID	Pathway	Evidence
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses ⚕	curated
R-HSA-202424	Downstream TCR signaling	curated
R-HSA-9020702	Interleukin-1 signaling	curated
R-HSA-450321	JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	curated
R-HSA-5689896	Ovarian tumor domain proteases	curated
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation	curated
R-HSA-450302	activated TAK1 mediates p38 MAPK activation	curated
R-HSA-209543	p75NTR recruits signalling complexes	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663205	Infectious disease ⚕	—
R-HSA-9679506	SARS-CoV Infections ⚕	—
R-HSA-9694516	SARS-CoV-2 Infection ⚕	—
R-HSA-9705683	SARS-CoV-2-host interactions ⚕	—
R-HSA-9824446	Viral Infection Pathways ⚕	—
R-HSA-1280218	Adaptive Immune System	—
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-73887	Death Receptor Signaling	—
R-HSA-5688426	Deubiquitination	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-446652	Interleukin-1 family signaling	—
R-HSA-448424	Interleukin-17 signaling	—
R-HSA-450294	MAP kinase activation	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-975871	MyD88 cascade initiated on plasma membrane	—
R-HSA-975155	MyD88 dependent cascade initiated on endosome	—
R-HSA-166166	MyD88-independent TLR4 cascade	—
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane	—
R-HSA-168638	NOD1/2 Signaling Pathway	electronic
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-162582	Signal Transduction	—
R-HSA-449147	Signaling by Interleukins	—
R-HSA-202403	TCR signaling	—
R-HSA-975138	TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	—
R-HSA-937061	TRIF (TICAM1)-mediated TLR4 signaling	—
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade	—
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade	—
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade	—
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade	—
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade	—
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade	—
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade	—
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade	—
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade	—
R-HSA-168898	Toll-like Receptor Cascades	—
R-HSA-193704	p75 NTR receptor-mediated signalling	—
R-HSA-193639	p75NTR signals via NF-kB	—

MSigDB gene sets: 511 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, REACTOME_NOD1_2_SIGNALING_PATHWAY, GOBP_REGULATION_OF_STRESS_ACTIVATED_PROTEIN_KINASE_SIGNALING_CASCADE, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM

GO Biological Process (31): adaptive immune response (GO:0002250), apoptotic process (GO:0006915), inflammatory response (GO:0006954), signal transduction (GO:0007165), canonical NF-kappaB signal transduction (GO:0007249), positive regulation of protein ubiquitination (GO:0031398), positive regulation of interferon-alpha production (GO:0032727), positive regulation of interferon-beta production (GO:0032728), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), toll-like receptor 2 signaling pathway (GO:0034134), defense response to bacterium (GO:0042742), positive regulation of apoptotic process (GO:0043065), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), innate immune response (GO:0045087), positive regulation of transcription by RNA polymerase II (GO:0045944), T cell receptor signaling pathway (GO:0050852), protein homooligomerization (GO:0051260), nucleotide-binding oligomerization domain containing 1 signaling pathway (GO:0070427), nucleotide-binding oligomerization domain containing 2 signaling pathway (GO:0070431), cellular response to muramyl dipeptide (GO:0071225), positive regulation of protein K63-linked ubiquitination (GO:1902523), MAPK cascade (GO:0000165), positive regulation of cytokine production (GO:0001819), immune system process (GO:0002376), protein phosphorylation (GO:0006468), regulation of apoptotic process (GO:0042981), regulation of primary metabolic process (GO:0080090), cell surface toll-like receptor signaling pathway (GO:0140895)

GO Molecular Function (18): protein serine/threonine kinase activity (GO:0004674), JUN kinase kinase kinase activity (GO:0004706), non-membrane spanning protein tyrosine kinase activity (GO:0004715), signaling receptor binding (GO:0005102), ATP binding (GO:0005524), LIM domain binding (GO:0030274), signaling adaptor activity (GO:0035591), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), CARD domain binding (GO:0050700), caspase binding (GO:0089720), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein tyrosine kinase activity (GO:0004713), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (7): cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), vesicle (GO:0031982), protein-containing complex (GO:0032991)

Reactome top-level categories

18 top-level categories:

Category	Pathways
Toll-like Receptor Cascades	5
MAP kinase activation	2
Immune System	2
Toll Like Receptor 4 (TLR4) Cascade	2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
TCR signaling	1
p75NTR signals via NF-kB	1
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1
Toll Like Receptor 3 (TLR3) Cascade	1
Interleukin-1 signaling	1
TRIF (TICAM1)-mediated TLR4 signaling	1
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1
MyD88 cascade initiated on plasma membrane	1
Deubiquitination	1
Interleukin-1 family signaling	1
SARS-CoV-2-host interactions	1
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1

GO top-level categories

showing 60 of 74 GO namespaces:

Category	Terms
protein kinase activity	3
immune response	2
defense response	2
positive regulation of type I interferon production	2
positive regulation of cytokine production	2
protein binding	2
protein domain specific binding	2
cellular anatomical structure	2
cytoplasm	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular signaling cassette	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
interferon-alpha production	1
regulation of interferon-alpha production	1
interferon-beta production	1
regulation of interferon-beta production	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
interleukin-12 production	1
regulation of interleukin-12 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
cell surface toll-like receptor signaling pathway	1
response to bacterium	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
defense response to symbiont	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
antigen receptor-mediated signaling pathway	1
protein complex oligomerization	1
MAP kinase kinase kinase activity	1
protein tyrosine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
protein-macromolecule adaptor activity	1
identical protein binding	1
protein dimerization activity	1
protease binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 25 of 56 annotations. The rest are phylogenetic / computational / electronic (IEA).

25 experimentally-supported GO terms:

GO term	NS	Evidence
apoptotic process	BP	direct assay
cellular response to muramyl dipeptide	BP	direct assay
defense response to bacterium	BP	direct assay
innate immune response	BP	direct assay
nucleotide-binding oligomerization domain containing 1 signaling pathway	BP	direct assay
nucleotide-binding oligomerization domain containing 2 signaling pathway	BP	direct assay
positive regulation of canonical NF-kappaB signal transduction	BP	direct assay
positive regulation of interleukin-1 beta production	BP	direct assay
positive regulation of protein K63-linked ubiquitination	BP	direct assay
positive regulation of protein ubiquitination	BP	mutant phenotype
protein homooligomerization	BP	direct assay
toll-like receptor 2 signaling pathway	BP	direct assay
cytoplasm	CC	direct assay
cytoskeleton	CC	direct assay
cytosol	CC	direct assay
plasma membrane	CC	direct assay
protein-containing complex	CC	direct assay
vesicle	CC	direct assay
CARD domain binding	MF	direct assay
LIM domain binding	MF	physical interaction
caspase binding	MF	physical interaction
identical protein binding	MF	physical interaction
protein homodimerization activity	MF	direct assay
signaling adaptor activity	MF	direct assay
signaling receptor binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,548 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RIPK2	NOD2	Q9HC29	942
RIPK2	NOD1	Q9Y239	941
RIPK2	CASP1	P29466	770
RIPK2	NLRC4	Q9NPP4	737
RIPK2	CCDC122	Q5T0U0	728
RIPK2	CARD6	Q9BX69	726
RIPK2	ATG16L1	Q676U5	720
RIPK2	NLRP3	Q96P20	718
RIPK2	NFKB1	P19838	714
RIPK2	NLRP1	Q9C000	702
RIPK2	IL1B	P01584	682
RIPK2	LACC1	Q8IV20	682
RIPK2	TLR4	O00206	681
RIPK2	TLR2	O60603	681
RIPK2	BIRC2	Q13490	674

IntAct

Human interaction partners of RIPK2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 64 partners by confidence:

Partner	Interaction type	MIscore	Records
XIAP	physical association	0.950	21
NOD2	physical association	0.870	11
NOD1	proximity	0.760	6
TRAF3	physical association	0.720	5
TRAF2	physical association	0.690	2
BIRC2	physical association	0.600	3
BIRC3	physical association	0.600	3
MAVS	association	0.580	3
OTUD1	physical association	0.460	3
CARD6	physical association	0.400	2
YWHAE	physical association	0.400	2
CASP1	physical association	0.400	1
IKBKG	physical association	0.400	1
SFN	physical association	0.400	1
TRAF1	physical association	0.400	1
KDM3A	physical association	0.370	1
PRMT2	physical association	0.370	1
UBE2I	physical association	0.370	1
YWHAG	physical association	0.370	1
CIB2	association	0.350	1
CNOT1	association	0.350	1
GMFB	association	0.350	1
PPP1R8	association	0.350	1
CEP43	proximity	0.270	1
ACTG1	physical association	0.000	1
ATP5F1D	physical association	0.000	1
CALM1	physical association	0.000	1
ECHS1	physical association	0.000	1
ENO1	physical association	0.000	1
EZR	physical association	0.000	1

BioGRID (197 interactions; top human partners by supporting records): XIAP (Two-hybrid; 23 records), NOD2 (Affinity Capture-Western; 14 records), BIRC2 (Reconstituted Complex; 11 records), BIRC3 (Affinity Capture-Western; 8 records), MAP3K7 (Affinity Capture-Western; 5 records), SQSTM1 (Proximity Label-MS; 5 records), TRAF3 (Affinity Capture-MS; 5 records), ERLIN2 (Affinity Capture-MS; 4 records), IRGM (Affinity Capture-Western; 4 records), NOD1 (Reconstituted Complex; 4 records), ATG16L1 (Affinity Capture-Western; 3 records), ERLIN1 (Affinity Capture-MS; 3 records), IRF4 (Affinity Capture-Western; 3 records), PELI3 (Affinity Capture-Western; 3 records), TRAF2 (Affinity Capture-Western; 3 records)

SIGNOR signaling

showing 20 of 21 signaling interactions:

A	Effect	B	Mechanism
RIPK2	up-regulates	IRF5	phosphorylation
RIPK2	“up-regulates activity”	RIPK2	phosphorylation
NOD2	“up-regulates activity”	RIPK2	binding
TNF	“up-regulates quantity by expression”	RIPK2	“transcriptional regulation”
IFNG	“up-regulates quantity by expression”	RIPK2	“transcriptional regulation”
RIPK2	“up-regulates activity”	IKBKG
BIRC2	“up-regulates activity”	RIPK2	polyubiquitination
BIRC3	“up-regulates activity”	RIPK2	polyubiquitination
ZNRF4	“down-regulates quantity by destabilization”	RIPK2	ubiquitination
LRRK2	“up-regulates activity”	RIPK2	phosphorylation
RIPK2	“up-regulates activity”	MAPK1	phosphorylation
RIPK2	“up-regulates activity”	MAP2K7	phosphorylation
XIAP	“up-regulates activity”	RIPK2	ubiquitination
LUBAC	“up-regulates activity”	RIPK2	polyubiquitination
PELI3	“up-regulates activity”	RIPK2	ubiquitination
IRF4	“down-regulates activity”	RIPK2	binding
RIPK2	“up-regulates activity”	TRAF6	binding
ATG16L1	“down-regulates activity”	RIPK2	binding
ITCH	“up-regulates activity”	RIPK2	binding
hsa-miR-150-5p	“down-regulates quantity by repression”	RIPK2	“post transcriptional regulation”

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ NOD2-RIPK2 complex	2	NOD2, RIPK2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 64 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Gap junction trafficking and regulation	5	42.5×	3e-06
Gap junction trafficking	5	42.5×	3e-06
TNFR1-induced NF-kappa-B signaling pathway	7	42.0×	3e-08
TNFR1-induced proapoptotic signaling	5	39.2×	4e-06
Regulation of necroptotic cell death	5	39.2×	4e-06
RHO GTPases activate IQGAPs	6	37.1×	7e-07
Attenuation phase	5	36.4×	6e-06
NOD1/2 Signaling Pathway	6	34.0×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein refolding	5	50.3×	1e-05
positive regulation of type I interferon production	5	34.0×	8e-05
canonical NF-kappaB signal transduction	5	29.5×	8e-05
tumor necrosis factor-mediated signaling pathway	5	26.6×	1e-04
response to unfolded protein	5	24.3×	1e-04
cellular response to type II interferon	5	16.8×	7e-04
regulation of inflammatory response	6	16.3×	1e-04
positive regulation of canonical NF-kappaB signal transduction	12	14.1×	3e-08

Disease & clinical

Genetic variants

Variant evidence for RIPK2: 74 ClinVar records (0 pathogenic / likely pathogenic); 8 GWAS associations.

ClinVar

74 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	5
Benign	4

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 25 predictions of 848):

Position(s)	Effect	Δscore	Sites
8:89758234–89758235	donor_loss	1.0000	4
8:89762984	donor_loss	1.0000	2
8:89765328	acceptor_loss	1.0000
8:89765330	acceptor_gain	1.0000
8:89765332	acceptor_loss	1.0000
8:89765334	acceptor_gain	1.0000
8:89765339–89765340	acceptor_loss	1.0000	4
8:89765492	donor_gain	1.0000
8:89765497–89765498	donor_loss	1.0000	4
8:89769770–89769771	acceptor_loss	1.0000	6

AlphaMissense

1,226 missense substitutions predicted likely pathogenic (of 3,555 scored), across 283 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M98	9	0.887	0.993
M451	9	0.849	0.992
M193	9	0.845	0.963
D146	8	0.999	1.000
N151	8	0.999	1.000
D164	8	0.999	1.000
D211	8	0.998	0.999
H144	8	0.997	1.000
F165	8	0.997	1.000
H136	8	0.994	0.998
H37	8	0.981	0.997
D461	8	0.976	0.988
D155	8	0.958	0.998
F283	8	0.955	0.993
F75	8	0.949	0.999
S214	8	0.943	0.998
H159	8	0.919	0.991
D492	8	0.879	0.960
E66	7	0.996	0.997
F229	7	0.993	0.997

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

6 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	unfavorable	2.21e-06
Glioblastoma Multiforme (validation)	favorable	0.000205
Lung Adenocarcinoma (TCGA)	unfavorable	0.000255
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.000393
Kidney Renal Clear Cell Carcinoma (validation)	unfavorable	0.000576
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	unfavorable	0.000906

Disease associations

OMIM: gene MIM:603455 | disease phenotypes:

GWAS associations

8 associations:

Study	Trait	p-value
GCST002772_19	Leprosy	2e-35
GCST002772_6	Leprosy	1e-21
GCST000546_6	Leprosy	1e-16
GCST000546_5	Leprosy	1e-12
GCST001729_14	Crohn’s disease	1e-8
GCST004009_11	Leprosy	5e-8
GCST003073_5	Cerebral amyloid deposition (PET imaging)	7e-7
GCST000579_57	Cognitive performance	3e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0007707	cerebral amyloid deposition measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL4296139 (PROTEIN-PROTEIN INTERACTION), CHEMBL4879529 (PROTEIN-PROTEIN INTERACTION), CHEMBL4888447 (PROTEIN-PROTEIN INTERACTION), CHEMBL5014 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 465,020 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

showing 60 of 64 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1173655	AFATINIB	4	15,878
CHEMBL1289926	AXITINIB	4	16,510
CHEMBL288441	BOSUTINIB	4	12,869
CHEMBL2105717	CABOZANTINIB	4	11,799
CHEMBL601719	CRIZOTINIB	4	15,133
CHEMBL2028663	DABRAFENIB	4	13,060
CHEMBL2110732	DACOMITINIB ANHYDROUS	4	6,949
CHEMBL5416410	DASATINIB	4	674
CHEMBL3301612	ENCORAFENIB	4	4,898
CHEMBL553	ERLOTINIB	4	109,860
CHEMBL1287853	FEDRATINIB	4	3,770
CHEMBL939	GEFITINIB	4	119,425
CHEMBL3301622	GILTERITINIB	4	2,542
CHEMBL1873475	IBRUTINIB	4	8,363
CHEMBL554	LAPATINIB	4	70,425
CHEMBL1289601	LENVATINIB	4	9,224
CHEMBL477772	PAZOPANIB	4	16,241
CHEMBL1171837	PONATINIB	4	9,435
CHEMBL576982	QUIZARTINIB	4	4,647
CHEMBL1946170	REGORAFENIB	4	13,318
CHEMBL1336	SORAFENIB	4
CHEMBL1289494	TIVOZANIB	4
CHEMBL24828	VANDETANIB	4
CHEMBL1229517	VEMURAFENIB	4
CHEMBL415049	BARASERTIB	3
CHEMBL377300	BRIVANIB	3
CHEMBL31965	CANERTINIB	3
CHEMBL491473	CEDIRANIB	3
CHEMBL2105728	CRENOLANIB	3
CHEMBL2087361	ICOTINIB	3
CHEMBL603469	LESTAURTINIB	3
CHEMBL1091644	LINSITINIB	3
CHEMBL572881	MOTESANIB	3
CHEMBL3545154	POZIOTINIB	3
CHEMBL217092	SARACATINIB	3
CHEMBL3544983	TESEVATINIB	3
CHEMBL206834	BAFETINIB	2
CHEMBL2029988	CEP-32496	2
CHEMBL215152	DEFOSBARASERTIB	2
CHEMBL103667	DORAMAPIMOD	2
CHEMBL3348846	FEXAGRATINIB	2
CHEMBL1230609	FORETINIB	2
CHEMBL2364611	GALUNISERTIB	2
CHEMBL3039525	GOLVATINIB	2
CHEMBL2220486	LUCITANIB	2
CHEMBL3120215	OSI-027	2
CHEMBL253969	OSI-632	2
CHEMBL475251	R-406	2
CHEMBL558752	RAF-265	2
CHEMBL2408045	SAPITINIB	2
CHEMBL2105734	SEPANTRONIUM BROMIDE	2
CHEMBL230011	TG100-115	2
CHEMBL403989	TG100-801	2
CHEMBL3260567	VACTOSERTIB	2
CHEMBL2103842	VARLITINIB	2
CHEMBL551064	AEW-541	1
CHEMBL574738	AST-487	1
CHEMBL598797	CUDC-101	1
CHEMBL482967	CYC-116	1
CHEMBL1090479	GSK-1070916	1

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Receptor interacting protein kinase (RIPK) family

Most potent curated ligand interactions (9 total), top 9:

Ligand	Action	Affinity	Parameter
RIPK2 inhibitor 8	Inhibition	8.52	pIC50
RIPK2 inhibitor 5	Inhibition	8.3	pIC50
GSK583	Inhibition	8.3	pIC50
OD36	Inhibition	8.28	pIC50
ponatinib	Inhibition	7.85	pIC50
Src kinase inhibitor I	Inhibition	7.59	pIC50
ZAK inhibitor 6p	Inhibition	7.24	pKd
WJH-C19	Inhibition	6.0	pIC50
PN10	Inhibition	5.85	pIC50

Binding affinities (BindingDB)

1016 measured of 1629 human assays (1841 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide	EC50	0.05 nM
CHEMBL4531690	IC50	0.06 nM
CHEMBL4857880	IC50	0.1 nM
CHEMBL4866182	IC50	0.158 nM
CHEBI:63453	IC50	0.2 nM
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
CHEMBL6160755	IC50	0.46 nM
CHEMBL5572490	KD	0.47 nM
N-cyclopropyl-4-methyl-3-[1-[5-[(1-methylpiperidin-4-yl)amino]-3-pyridinyl]pyrazol-4-yl]benzamide	IC50	0.61 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
CHEMBL5187454	IC50	0.8 nM
BDBM303369	IC50	0.81 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
CHEMBL235851	IC50	0.84 nM
N-cyclopropyl-2-fluoro-4-methyl-5-[1-[5-[[8-(oxetan-3-yl)-8-azabicyclo[3.2.1]octan-3-yl]amino]-3-pyridinyl]pyrazol-4-yl]benzamide	IC50	0.9 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-4-methyl-3-[1-[5-[[1-(oxolan-3-yl)piperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]benzamide	IC50	0.94 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-3-[1-[5-[[1-(1,4-dioxan-2-ylmethyl)piperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]-4-methylbenzamide	IC50	0.95 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
5-[1-(2-acetamido-1,3-thiazol-5-yl)pyrazol-4-yl]-4-chloro-N-cyclopropyl-2-fluorobenzamide	IC50	0.99 nM	US-11130754: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-2-fluoro-5-[1-[5-[[1-(2-methoxyethyl)piperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]-4-methylbenzamide	IC50	1 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-5-[1-(5-cyclopropyl-3-pyridinyl)pyrazol-4-yl]-2-fluoro-4-methylbenzamide	IC50	1 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-4-methyl-3-[1-[5-[[1-(3-oxabicyclo[3.1.0]hexan-6-ylmethyl)piperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]benzamide	IC50	1 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-2-fluoro-4-methyl-5-[1-[5-[[1-(oxetan-3-yl)piperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]benzamide	IC50	1.1 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-2-fluoro-4-methyl-5-[1-[5-[(1-methylpiperidin-4-yl)amino]-3-pyridinyl]pyrazol-4-yl]benzamide	IC50	1.1 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-3-[1-[5-[[1-(4-methoxycyclohexyl)piperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]-4-methylbenzamide	IC50	1.1 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-3-[1-[5-[[1-(3-methoxyoxan-4-yl)piperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]-4-methylbenzamide	IC50	1.1 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-Cyclopropyl-5-{1-[7-ethoxy-6-(4-fluoro-1-methyl-piperidin-4-yl)-imidazo[1,2-a]pyridin-3-yl]-1H-pyrazol-4-yl}-2-fluoro-4-methyl-benzamide	IC50	1.1 nM	US-11130754: Substituted benzamides as RIPK2 inhibitors
3-[1-[5-[[1-(1-acetylpiperidin-4-yl)piperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]-N-cyclopropyl-4-methylbenzamide	IC50	1.2 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-4-methyl-3-[1-[5-[[1-(2-methyloxan-4-yl)piperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]benzamide	IC50	1.2 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
3-[1-(6-tert-butylsulfonyl-7-methoxyimidazo[1,2-a]pyridin-3-yl)pyrazol-4-yl]-N-cyclopropyl-4-methylbenzamide	IC50	1.2 nM	US-11130754: Substituted benzamides as RIPK2 inhibitors
3-[1-[2-(cyclopropanecarbonylamino)-1,3-thiazol-5-yl]pyrazol-4-yl]-N-cyclopropyl-4-methylbenzamide	IC50	1.2 nM	US-11130754: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-4-methyl-3-[1-[5-(oxan-4-ylamino)-3-pyridinyl]pyrazol-4-yl]benzamide	IC50	1.3 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-2-fluoro-5-[1-[5-[[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]-4-methylbenzamide	IC50	1.3 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
5-[1-(6-tert-butylsulfonylimidazo[1,2-a]pyridin-3-yl)pyrazol-4-yl]-4-chloro-N-cyclopropyl-2-fluorobenzamide	IC50	1.3 nM	US-11130754: Substituted benzamides as RIPK2 inhibitors
N-Cyclopropyl-5-{1-[6-(1-ethyl-4-fluoro-piperidin-4-yl)-7-methoxy-imidazo[1,2-a]pyridin-3-yl]-1H-pyrazol-4-yl}-2-fluoro-4-methyl-benzamide	IC50	1.3 nM	US-11130754: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-5-[1-[5-[4-(dimethylamino)piperidin-1-yl]-3-pyridinyl]pyrazol-4-yl]-2-fluoro-4-methylbenzamide	IC50	1.4 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-2-fluoro-5-[1-[6-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-3-yl]pyrazol-4-yl]-4-methylbenzamide	IC50	1.4 nM	US-11130754: Substituted benzamides as RIPK2 inhibitors
N-Cyclopropyl-2-fluoro-5-{1-[6-(4-fluoro-1-methylpiperidin-4-yl)-7-methoxyimidazo[1,2-a]pyridin-3-yl]-H-pyrazol-4-yl}-4-methyl-benzamide	IC50	1.4 nM	US-11130754: Substituted benzamides as RIPK2 inhibitors
N-Cyclopropyl-2-fluoro-4-methyl-5-{1-[6-((R)-1-methyl-pyrrolidin-3-yl)-imidazo[1,2-a]pyridin-3-yl]-1H-pyrazol-4-yl}-benzamide(99)	IC50	1.4 nM	US-11130754: Substituted benzamides as RIPK2 inhibitors
N-[6-dimethylphosphoryl-7-(1-piperidin-4-ylpyrazol-4-yl)quinolin-4-yl]-1,3-benzothiazol-5-amine	KD	1.4 nM	US-20240190904: Heteroaryl compounds as inhibitors of RIP2 kinase, composition and application thereof
N-cyclopropyl-4-methyl-3-[1-[5-(piperidin-4-ylamino)-3-pyridinyl]pyrazol-4-yl]benzamide	IC50	1.5 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
3-[1-[5-[(1-cyclobutylpiperidin-4-yl)amino]-3-pyridinyl]pyrazol-4-yl]-N-cyclopropyl-4-methylbenzamide	IC50	1.5 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-4-methyl-3-[1-[5-[[1-(oxan-3-yl)piperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]benzamide	IC50	1.5 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-2-fluoro-5-[1-[5-[[1-(2-fluoroethyl)piperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]-4-methylbenzamide	IC50	1.5 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-5-[1-[5-[[(4R)-3,3-difluoro-1-methylpiperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]-2-fluoro-4-methylbenzamide	IC50	1.5 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-Cyclopropyl-5-{1-[6-(1-dimethylcarbamoylmethyl-piperidin-4-yl)-imidazo[1,2-a]pyridin-3-yl]-1H-pyrazol-4-yl}-2-fluoro-4-methyl-benzamide	IC50	1.5 nM	US-11130754: Substituted benzamides as RIPK2 inhibitors
REGORAFENIB	IC50	1.5 nM
N-(7-cyclobutyloxy-6-dimethylphosphorylquinolin-4-yl)-1,3-benzothiazol-5-amine	KD	1.5 nM	US-20240190904: Heteroaryl compounds as inhibitors of RIP2 kinase, composition and application thereof
N-cyclopropyl-4-methyl-3-[1-[5-[1-(oxolan-3-yl)ethylamino]-3-pyridinyl]pyrazol-4-yl]benzamide	IC50	1.6 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-3-[1-[5-[[1-(4-hydroxybutan-2-yl)piperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]-4-methylbenzamide	IC50	1.6 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-3-[1-[5-[[1-(1-methoxypropan-2-yl)piperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]-4-methylbenzamide	IC50	1.6 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
3-[1-(5-tert-butylsulfonylpyrazolo[1,5-a]pyridin-3-yl)pyrazol-4-yl]-N-cyclopropyl-4-methylbenzamide	IC50	1.6 nM	US-11130754: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-2-fluoro-4-methyl-5-[1-(6-morpholin-4-ylsulfonylimidazo[1,2-a]pyridin-3-yl)pyrazol-4-yl]benzamide	IC50	1.6 nM	US-11130754: Substituted benzamides as RIPK2 inhibitors

ChEMBL bioactivities

1002 potent at pChembl≥5 of 1016 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.96	IC50	0.011	nM	CHEMBL4531690
10.00	IC50	0.1	nM	CHEMBL4857880
9.80	IC50	0.1585	nM	CHEMBL4866182
9.55	Kd	0.28	nM	CHEMBL5177284
9.22	IC50	0.6	nM	CHEMBL5177284
9.21	IC50	0.61	nM	CHEMBL5742848
9.19	IC50	0.65	nM	CHEMBL6161949
9.11	Kd	0.78	nM	CHEMBL4596287
9.10	IC50	0.8	nM	CHEMBL5187454
9.09	IC50	0.81	nM	CHEMBL5840021
9.05	Kd	0.9	nM	CHEMBL400402
9.05	IC50	0.9	nM	CHEMBL6002258
9.03	IC50	0.94	nM	CHEMBL5851050
9.02	IC50	0.95	nM	CHEMBL5816850
9.00	IC50	1	nM	PONATINIB
9.00	IC50	1	nM	CHEMBL5845929
9.00	IC50	1	nM	CHEMBL5951662
9.00	IC50	1	nM	CHEMBL5858920
9.00	IC50	0.99	nM	CHEMBL5768963
8.96	IC50	1.1	nM	CHEMBL6016366
8.96	IC50	1.1	nM	CHEMBL6034661
8.96	IC50	1.1	nM	CHEMBL5804402
8.96	IC50	1.1	nM	CHEMBL5983278
8.96	IC50	1.1	nM	CHEMBL5841516
8.92	IC50	1.2	nM	CHEMBL6012062
8.92	IC50	1.2	nM	CHEMBL5929812
8.92	IC50	1.2	nM	CHEMBL6046857
8.92	IC50	1.2	nM	CHEMBL5932076
8.92	IC50	1.21	nM	CHEMBL129123
8.89	IC50	1.3	nM	CHEMBL4293287
8.89	IC50	1.3	nM	CHEMBL5805040
8.89	IC50	1.3	nM	CHEMBL5838688
8.89	IC50	1.3	nM	CHEMBL5948297
8.89	IC50	1.3	nM	CHEMBL5886778
8.85	IC50	1.4	nM	CHEMBL4205154
8.85	IC50	1.4	nM	CHEMBL5840021
8.85	IC50	1.4	nM	CHEMBL6061078
8.85	IC50	1.4	nM	CHEMBL5996450
8.85	IC50	1.4	nM	CHEMBL5880837
8.85	IC50	1.4	nM	CHEMBL5743037
8.84	IC50	1.44	nM	CHEMBL6160755
8.82	IC50	1.5	nM	CHEMBL6046757
8.82	IC50	1.5	nM	CHEMBL5747138
8.82	IC50	1.5	nM	CHEMBL5991605
8.82	IC50	1.5	nM	CHEMBL5771148
8.82	IC50	1.5	nM	CHEMBL5767751
8.82	IC50	1.5	nM	CHEMBL5960722
8.82	IC50	1.52	nM	CHEMBL6144386
8.80	IC50	1.6	nM	CHEMBL4282034
8.80	IC50	1.585	nM	CHEMBL4876228

PubChem BioAssay actives

680 with measured affinity, of 1878 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-chloro-7,10-dioxa-13,17,18,21-tetrazatetracyclo[12.5.2.12,6.017,20]docosa-1(20),2(22),3,5,14(21),15,18-heptaene	1638761: Displacement of fluorescent tracer from N-terminus of human RIPK2 expressed in HEK293T cells after 2 hrs by NanoBRET target engagement assay	ic50	<0.0001	uM
(5S,8S,10aR)-3-[5-[4-[3-[6-tert-butylsulfonyl-4-[(4,5-dimethyl-1H-pyrazol-3-yl)amino]quinazolin-7-yl]oxypropyl]piperazin-1-yl]pyrazine-2-carbonyl]-5-[[(2S)-2-(methylamino)propanoyl]amino]-6-oxo-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide	1773563: Inhibition of full length His-tagged RIPK2 (unknown origin) expressed in baculovirus expression system using fluorescent labelled ATP competitive ligand by fluorescent polarization based binding assay	ic50	0.0001	uM
5-[4-[3-[6-tert-butylsulfonyl-4-[(4,5-dimethyl-1H-pyrazol-3-yl)amino]quinazolin-7-yl]oxypropyl]piperazin-1-yl]-N-[(3S,5S)-1-[(2R)-3,3-dimethyl-2-[[(2R)-2-(methylamino)propanoyl]amino]butanoyl]-5-[4-(4-fluorobenzoyl)-1,3-thiazol-2-yl]pyrrolidin-3-yl]pyrazine-2-carboxamide	1773563: Inhibition of full length His-tagged RIPK2 (unknown origin) expressed in baculovirus expression system using fluorescent labelled ATP competitive ligand by fluorescent polarization based binding assay	ic50	0.0002	uM
7-(4-aminocyclohexyl)-5-(2-fluoro-4-methylphenyl)pyrrolo[2,3-d]pyrimidin-4-amine	1880919: Binding affinity to human RIPK2 in HEK293 cells	kd	0.0003	uM
2-chloro-5-[(6,7-dimethoxyquinazolin-4-yl)amino]phenol;hydrochloride	2224282: Inhibition of human recombinant RIPK2 (1 to 317 residues) expressed in Sf21 insect cells using MBP as substrate preincubated for 10 mins followed by substrate addition and measured after 1 hr by ADP-Glo luminescence assay	ic50	0.0006	uM
7-(4-aminocyclohexyl)-5-(1,3-benzodioxol-5-yl)pyrrolo[2,3-d]pyrimidin-4-amine	1880875: Inhibition of human RIPK2 incubated for 120 mins in presence of [gamma33P]ATP by scintillation counting based radiometry assay	ic50	0.0008	uM
2-[4-(1,3-benzothiazol-5-ylamino)-6-tert-butylsulfonylquinazolin-7-yl]oxyethyl dihydrogen phosphate	1921722: Binding affinity to RIPK2 (unknown origin) assessed as dissociation constant by kinomescan assay	kd	0.0008	uM
4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol	1425155: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0009	uM
Ponatinib	1580373: Inhibition of recombinant human His-tagged RIPK2 (8 to 317 residues) incubated for 1 hr by ADP-Glo assay	ic50	0.0010	uM
N-(2,4-dichloro-5-methoxyphenyl)-6,7-dimethoxyquinazolin-4-amine	2224282: Inhibition of human recombinant RIPK2 (1 to 317 residues) expressed in Sf21 insect cells using MBP as substrate preincubated for 10 mins followed by substrate addition and measured after 1 hr by ADP-Glo luminescence assay	ic50	0.0012	uM
6-tert-butylsulfonyl-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-methoxyquinolin-4-amine	1422976: Inhibition of full length His/flag-tagged RIPK2 (unknown origin) expressed in baculovirus expression system using fluorescently labeled substrate incubated for 10 mins followed by substrate addition measured after 10 mins by fluorescence polarization assay	ic50	0.0013	uM
4-chloro-1-N-(6,7-dimethoxyquinazolin-4-yl)benzene-1,3-diamine	2224282: Inhibition of human recombinant RIPK2 (1 to 317 residues) expressed in Sf21 insect cells using MBP as substrate preincubated for 10 mins followed by substrate addition and measured after 1 hr by ADP-Glo luminescence assay	ic50	0.0014	uM
N-(2,4-dichloro-5-methoxyphenyl)-7-[2-(diethylamino)ethoxy]-6-methoxyquinazolin-4-amine	2224282: Inhibition of human recombinant RIPK2 (1 to 317 residues) expressed in Sf21 insect cells using MBP as substrate preincubated for 10 mins followed by substrate addition and measured after 1 hr by ADP-Glo luminescence assay	ic50	0.0015	uM
(2S)-N-[(1S)-1-[1-[5-[4-[3-[6-tert-butylsulfonyl-4-[(4,5-dimethyl-1H-pyrazol-3-yl)amino]quinazolin-7-yl]oxypropyl]piperazin-1-yl]pyrazine-2-carbonyl]piperidin-4-yl]-2-[(2S)-2-[4-(4-fluorobenzoyl)-1,3-thiazol-2-yl]pyrrolidin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide	1773548: Protac activity at IAP/RIPK2 in human whole blood assessed as inhibition of MDP-induced TNFalpha production by ELISA	ic50	0.0016	uM
7-(4-aminocyclohexyl)-5-(4-fluorophenyl)pyrrolo[2,3-d]pyrimidin-4-amine	1880875: Inhibition of human RIPK2 incubated for 120 mins in presence of [gamma33P]ATP by scintillation counting based radiometry assay	ic50	0.0016	uM
6-tert-butylsulfonyl-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-ethoxyquinolin-4-amine	1422976: Inhibition of full length His/flag-tagged RIPK2 (unknown origin) expressed in baculovirus expression system using fluorescently labeled substrate incubated for 10 mins followed by substrate addition measured after 10 mins by fluorescence polarization assay	ic50	0.0016	uM
5-[(6,7-dimethoxyquinazolin-4-yl)amino]-2-fluorophenol	2224282: Inhibition of human recombinant RIPK2 (1 to 317 residues) expressed in Sf21 insect cells using MBP as substrate preincubated for 10 mins followed by substrate addition and measured after 1 hr by ADP-Glo luminescence assay	ic50	0.0017	uM
N-[5-[2-amino-5-(4-piperazin-1-ylphenyl)-3-pyridinyl]-3-fluoro-2-methoxyphenyl]propane-1-sulfonamide	2224282: Inhibition of human recombinant RIPK2 (1 to 317 residues) expressed in Sf21 insect cells using MBP as substrate preincubated for 10 mins followed by substrate addition and measured after 1 hr by ADP-Glo luminescence assay	ic50	0.0019	uM
N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(oxan-4-yloxy)quinazolin-4-amine	1425155: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0020	uM
1-(2-methoxyethyl)-2-methyl-3-(pyrazin-2-ylmethyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide	2025420: Inhibition of human RIPK2	ic50	0.0020	uM
(2S,4S)-4-[[2-[2-[2-[2-[2-[4-(1,3-benzothiazol-5-ylamino)-6-tert-butylsulfonylquinolin-7-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-1-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-N-[(1R)-1-phenylpropyl]pyrrolidine-2-carboxamide	1773563: Inhibition of full length His-tagged RIPK2 (unknown origin) expressed in baculovirus expression system using fluorescent labelled ATP competitive ligand by fluorescent polarization based binding assay	ic50	0.0020	uM
(2S)-N-[(1S)-1-[1-[2-[4-[3-[6-tert-butylsulfonyl-4-[(4,5-dimethyl-1H-pyrazol-3-yl)amino]quinazolin-7-yl]oxypropyl]piperazin-1-yl]pyrimidine-5-carbonyl]piperidin-4-yl]-2-[(2S)-2-[4-(4-fluorobenzoyl)-1,3-thiazol-2-yl]pyrrolidin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide	1773548: Protac activity at IAP/RIPK2 in human whole blood assessed as inhibition of MDP-induced TNFalpha production by ELISA	ic50	0.0020	uM
N-[3-(6-tert-butylsulfonyl-7-methoxyimidazo[1,2-a]pyridin-3-yl)-5-chlorophenyl]acetamide	1503886: Inhibition of full length RIPK2 (unknown origin) pretreated for 30 mins followed by ATP addition measured after 2 hrs by ADP-d2 tracer based fluorescence assay	ic50	0.0020	uM
(4S)-1-[(2S)-2-[[2-[2-[2-[2-[2-[4-(1,3-benzothiazol-5-ylamino)-6-tert-butylsulfonylquinolin-7-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	2137475: Protac activity at VHL/RIPK2 in human THP-1 cells assessed as RIPK2 degradation measured after 16 hrs by Western blot analysis	ic50	0.0020	uM
N-(6-propan-2-ylsulfonylquinolin-4-yl)-1,3-benzothiazol-5-amine	2138417: Inhibition of N-terminal polyHis-tagged human RIPK2 (8 to 310 residues) expressed in Sf9 cells using MBP as substrate preincubated for 15 mins followed by ATP addition measured after 90 mins by ADP-Glo assay	ic50	0.0020	uM
2-[4-(1,3-benzothiazol-5-ylamino)-6-tert-butylsulfonylquinazolin-7-yl]oxyethanol	1638761: Displacement of fluorescent tracer from N-terminus of human RIPK2 expressed in HEK293T cells after 2 hrs by NanoBRET target engagement assay	ic50	0.0020	uM
N-(6,7-dimethoxyquinazolin-4-yl)-1,3-benzothiazol-5-amine;hydrochloride	2224282: Inhibition of human recombinant RIPK2 (1 to 317 residues) expressed in Sf21 insect cells using MBP as substrate preincubated for 10 mins followed by substrate addition and measured after 1 hr by ADP-Glo luminescence assay	ic50	0.0021	uM
7-(4-aminocyclohexyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-4-amine	1880875: Inhibition of human RIPK2 incubated for 120 mins in presence of [gamma33P]ATP by scintillation counting based radiometry assay	ic50	0.0024	uM
2-[(2R,5R)-2-[[(2R)-4-[5-[4-[3-[6-tert-butylsulfonyl-4-[(4,5-dimethyl-1H-pyrazol-3-yl)amino]quinazolin-7-yl]oxypropyl]piperazine-1-carbonyl]pyrimidin-2-yl]-2-methylpiperazin-1-yl]methyl]-5-methylpiperazin-1-yl]-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]ethanone	1773548: Protac activity at IAP/RIPK2 in human whole blood assessed as inhibition of MDP-induced TNFalpha production by ELISA	ic50	0.0025	uM
6-tert-butylsulfonyl-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-ethylquinolin-4-amine	1422976: Inhibition of full length His/flag-tagged RIPK2 (unknown origin) expressed in baculovirus expression system using fluorescently labeled substrate incubated for 10 mins followed by substrate addition measured after 10 mins by fluorescence polarization assay	ic50	0.0025	uM
2-[6-tert-butylsulfonyl-4-[(4,5-dimethyl-1H-pyrazol-3-yl)amino]quinolin-7-yl]oxyethanol	1422976: Inhibition of full length His/flag-tagged RIPK2 (unknown origin) expressed in baculovirus expression system using fluorescently labeled substrate incubated for 10 mins followed by substrate addition measured after 10 mins by fluorescence polarization assay	ic50	0.0025	uM
6-tert-butylsulfonyl-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(2-methoxyethoxy)quinolin-4-amine	1422976: Inhibition of full length His/flag-tagged RIPK2 (unknown origin) expressed in baculovirus expression system using fluorescently labeled substrate incubated for 10 mins followed by substrate addition measured after 10 mins by fluorescence polarization assay	ic50	0.0025	uM
4-(6-tert-butylsulfonyl-7-ethoxyimidazo[1,2-a]pyridin-3-yl)-6-fluoropyridin-2-amine	1503886: Inhibition of full length RIPK2 (unknown origin) pretreated for 30 mins followed by ATP addition measured after 2 hrs by ADP-d2 tracer based fluorescence assay	ic50	0.0030	uM
4-(7-ethoxy-6-propan-2-ylsulfonylimidazo[1,2-a]pyridin-3-yl)-6-fluoropyridin-2-amine	1503886: Inhibition of full length RIPK2 (unknown origin) pretreated for 30 mins followed by ATP addition measured after 2 hrs by ADP-d2 tracer based fluorescence assay	ic50	0.0030	uM
7-[4-(benzylamino)cyclohexyl]-5-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-amine	1880875: Inhibition of human RIPK2 incubated for 120 mins in presence of [gamma33P]ATP by scintillation counting based radiometry assay	ic50	0.0030	uM
[5-[4-(1,3-benzothiazol-5-ylamino)-6-thiophen-2-ylquinazolin-7-yl]furan-2-yl]methanol	2138417: Inhibition of N-terminal polyHis-tagged human RIPK2 (8 to 310 residues) expressed in Sf9 cells using MBP as substrate preincubated for 15 mins followed by ATP addition measured after 90 mins by ADP-Glo assay	ic50	0.0030	uM
N-[7-chloro-6-(1-methylimidazol-2-yl)quinazolin-4-yl]-1,3-benzothiazol-5-amine	2138417: Inhibition of N-terminal polyHis-tagged human RIPK2 (8 to 310 residues) expressed in Sf9 cells using MBP as substrate preincubated for 15 mins followed by ATP addition measured after 90 mins by ADP-Glo assay	ic50	0.0030	uM
[3-[4-(1,3-benzothiazol-5-ylamino)thieno[2,3-d]pyrimidin-6-yl]phenyl]methanol	2118988: Inhibition of N-terminal poly his-tagged recombinant RIPK2 (8 to 310 residues) (unknown origin) expressed in Sf9 cells preincubated for 15 mins followed by ATP addition and measured after 90 mins mins by by ADP-Glo reagent based luminescence assay	ic50	0.0030	uM
4-methyl-3-[(6-methylsulfonylquinolin-4-yl)amino]phenol	1309961: Competitive inhibition of full length FLAG-His-tagged RIP2K (unknown origin) expressed in baculovirus expression system preincubated for 10 mins followed by addition of fluorescent-labeled 2-Methyl-5-(2-propen-l-yloxy)aniline measured after 10 mins by fluorescence polarization assay	ic50	0.0030	uM
(2S)-N-[(1S)-1-[1-[2-[4-[3-[6-tert-butylsulfonyl-4-[(4,5-dimethyl-1H-pyrazol-3-yl)amino]quinazolin-7-yl]oxypropyl]piperidin-1-yl]pyrimidine-5-carbonyl]piperidin-4-yl]-2-[(2S)-2-[4-(4-fluorobenzoyl)-1,3-thiazol-2-yl]pyrrolidin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide	1773548: Protac activity at IAP/RIPK2 in human whole blood assessed as inhibition of MDP-induced TNFalpha production by ELISA	ic50	0.0032	uM
5-[4-[3-[6-tert-butylsulfonyl-4-[(4,5-dimethyl-1H-pyrazol-3-yl)amino]quinazolin-7-yl]oxypropyl]piperazin-1-yl]-N-[(3S,5S)-5-[(2,6-difluorophenyl)carbamoyl]-1-[(2S)-3,3-dimethyl-2-[[(2R)-2-(methylamino)propanoyl]amino]butanoyl]pyrrolidin-3-yl]pyrazine-2-carboxamide	1773548: Protac activity at IAP/RIPK2 in human whole blood assessed as inhibition of MDP-induced TNFalpha production by ELISA	ic50	0.0032	uM
N-(1,3-benzothiazol-5-yl)-8-cyclopropyl-6,6-dioxothieno[2,3-g]quinazolin-4-amine	1921722: Binding affinity to RIPK2 (unknown origin) assessed as dissociation constant by kinomescan assay	kd	0.0033	uM
N-[4-[4-amino-5-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]-3,4,5-trimethoxybenzamide	1880875: Inhibition of human RIPK2 incubated for 120 mins in presence of [gamma33P]ATP by scintillation counting based radiometry assay	ic50	0.0039	uM
7-(4-aminocyclohexyl)-5-(4-amino-3-fluorophenyl)pyrrolo[2,3-d]pyrimidin-4-amine	1880875: Inhibition of human RIPK2 incubated for 120 mins in presence of [gamma33P]ATP by scintillation counting based radiometry assay	ic50	0.0040	uM
N-[7-chloro-6-(1-methylpyrazol-4-yl)quinazolin-4-yl]-1,3-benzothiazol-5-amine	2138417: Inhibition of N-terminal polyHis-tagged human RIPK2 (8 to 310 residues) expressed in Sf9 cells using MBP as substrate preincubated for 15 mins followed by ATP addition measured after 90 mins by ADP-Glo assay	ic50	0.0040	uM
N-(6-thiophen-2-ylquinazolin-4-yl)-1,3-benzothiazol-5-amine	2138417: Inhibition of N-terminal polyHis-tagged human RIPK2 (8 to 310 residues) expressed in Sf9 cells using MBP as substrate preincubated for 15 mins followed by ATP addition measured after 90 mins by ADP-Glo assay	ic50	0.0040	uM
N-[6-(2-methyl-1,3-thiazol-5-yl)quinazolin-4-yl]-1,3-benzothiazol-5-amine	2138417: Inhibition of N-terminal polyHis-tagged human RIPK2 (8 to 310 residues) expressed in Sf9 cells using MBP as substrate preincubated for 15 mins followed by ATP addition measured after 90 mins by ADP-Glo assay	ic50	0.0040	uM
N-[6-(1-methylpyrazol-4-yl)quinazolin-4-yl]-1,3-benzothiazol-5-amine	2138417: Inhibition of N-terminal polyHis-tagged human RIPK2 (8 to 310 residues) expressed in Sf9 cells using MBP as substrate preincubated for 15 mins followed by ATP addition measured after 90 mins by ADP-Glo assay	ic50	0.0040	uM
N-[6-(3-methylimidazol-4-yl)quinazolin-4-yl]-1,3-benzothiazol-5-amine	2138417: Inhibition of N-terminal polyHis-tagged human RIPK2 (8 to 310 residues) expressed in Sf9 cells using MBP as substrate preincubated for 15 mins followed by ATP addition measured after 90 mins by ADP-Glo assay	ic50	0.0040	uM
[3-[4-(1,3-benzothiazol-5-ylamino)-6-(3-methylthiophen-2-yl)quinazolin-7-yl]phenyl]methanol	2138417: Inhibition of N-terminal polyHis-tagged human RIPK2 (8 to 310 residues) expressed in Sf9 cells using MBP as substrate preincubated for 15 mins followed by ATP addition measured after 90 mins by ADP-Glo assay	ic50	0.0040	uM

CTD chemical–gene interactions

87 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
sodium arsenite	decreases expression, affects reaction, increases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Doxorubicin	affects response to substance, decreases expression	2
Estradiol	affects expression, decreases reaction, increases expression	2
Valproic Acid	decreases methylation, increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	decreases phosphorylation	1
immune checkpoint inhibitor BMS-1	decreases expression, affects cotreatment	1
dicrotophos	decreases expression	1
tungsten carbide	affects cotreatment, decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
propylparaben	increases expression	1
pirinixic acid	decreases reaction, increases expression	1
VX-agent	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
nickel chloride	increases expression	1
zinc chromate	increases abundance, increases expression	1
chloroquine diphosphate	decreases expression	1
ochratoxin A	decreases acetylation, decreases expression	1
nickel sulfate	increases expression	1
coumarin	decreases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
beta-methylcholine	affects expression	1
cordycepin	decreases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1

ChEMBL screening assays

455 unique, capped per target: 452 binding, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4026936	Binding	Proteolysis targeting chimera activity in human THP1 cells assessed as induction of VHL-mediated delivery of RIPK2 for protein degradation by proteasome by measuring drug level causing 50% cellular protein depletion incubated for 16 hrs by	Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones? — *J Med Chem*
CHEMBL4344881	ADMET	Displacement of fluorescein labeled probe from full length human GST-tagged RIPK2 expressed in Sf9 cells incubated for 60 mins by HTRF assay	Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage. — *ACS Med Chem Lett*

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2DU	Abcam HeLa RIPK2 KO	Cancer cell line	Female
CVCL_D9QK	Ubigene HEK293 RIPK2 KO	Transformed cell line	Female
CVCL_TJ12	HAP1 RIPK2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for RIPK2 across ~30M SureChEMBL compounds — explore on Sugi Predict.