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
• Druggable target: yes — 64 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003821

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: 6 — 3 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000220751, ENST00000517696, ENST00000518673, ENST00000522965, ENST00000893222, ENST00000929530

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.

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

285 total, 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

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

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
IL12B	Activation

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

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)

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): A0A0S2Z4Z8, E5RGK6, E7ERW9, O43353

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 recruimtent 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), 3 shown:

• 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 (120 total): mutagenesis site 38, modified residue 24, helix 19, 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)

33 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7OBS	X-RAY DIFFRACTION	1.8
9F3V	X-RAY DIFFRACTION	1.94
5NG0	X-RAY DIFFRACTION	2
8X2O	X-RAY DIFFRACTION	2.26
7OBT	X-RAY DIFFRACTION	2.3
6ES0	X-RAY DIFFRACTION	2.38
5AR2	X-RAY DIFFRACTION	2.44
5J7B	X-RAY DIFFRACTION	2.53
6HMX	X-RAY DIFFRACTION	2.53
6SZJ	X-RAY DIFFRACTION	2.53
5NG3	X-RAY DIFFRACTION	2.6
6RNA	X-RAY DIFFRACTION	2.62
5AR5	X-RAY DIFFRACTION	2.66
6UL8	X-RAY DIFFRACTION	2.68
5J79	X-RAY DIFFRACTION	2.69
6RN8	X-RAY DIFFRACTION	2.69
5AR4	X-RAY DIFFRACTION	2.7
5AR7	X-RAY DIFFRACTION	2.71
4C8B	X-RAY DIFFRACTION	2.75
5AR8	X-RAY DIFFRACTION	2.79
5NG2	X-RAY DIFFRACTION	2.8
5W5J	X-RAY DIFFRACTION	2.85
5W5O	X-RAY DIFFRACTION	2.89
6SZE	X-RAY DIFFRACTION	2.94
6S1F	X-RAY DIFFRACTION	3.11
8AZA	ELECTRON MICROSCOPY	3.15
5AR3	X-RAY DIFFRACTION	3.23
6FU5	X-RAY DIFFRACTION	3.26
6GFJ	X-RAY DIFFRACTION	3.3
6GGS	ELECTRON MICROSCOPY	3.94

Predicted structure (AlphaFold)

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

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): 146 (proton acceptor)

Ligand- & substrate-binding residues (2): 24–32; 47

Post-translational modifications (28): 149, 168, 174, 174, 176, 176, 178, 178, 180, 181, 181, 183, 189, 363, 363, 381, 393, 397, 423, 474 …

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

9 pathways

ID	Pathway
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-202424	Downstream TCR signaling
R-HSA-209543	p75NTR recruits signalling complexes
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation
R-HSA-450302	activated TAK1 mediates p38 MAPK activation
R-HSA-450321	JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-HSA-5689896	Ovarian tumor domain proteases
R-HSA-9020702	Interleukin-1 signaling
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses

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 (65): positive regulation of cytokine-mediated signaling pathway (GO:0001961), adaptive immune response (GO:0002250), positive regulation of T-helper 1 type immune response (GO:0002827), apoptotic process (GO:0006915), inflammatory response (GO:0006954), signal transduction (GO:0007165), canonical NF-kappaB signal transduction (GO:0007249), JNK cascade (GO:0007254), cytokine-mediated signaling pathway (GO:0019221), positive regulation of protein ubiquitination (GO:0031398), lipopolysaccharide-mediated signaling pathway (GO:0031663), positive regulation of chemokine production (GO:0032722), positive regulation of interferon-alpha production (GO:0032727), positive regulation of interferon-beta production (GO:0032728), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-2 production (GO:0032743), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), positive regulation of stress-activated MAPK cascade (GO:0032874), immature T cell proliferation in thymus (GO:0033080), positive regulation of immature T cell proliferation in thymus (GO:0033092), toll-like receptor 2 signaling pathway (GO:0034134), toll-like receptor 4 signaling pathway (GO:0034142), CD4-positive, alpha-beta T cell proliferation (GO:0035739), defense response to bacterium (GO:0042742), positive regulation of apoptotic process (GO:0043065), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), response to exogenous dsRNA (GO:0043330), innate immune response (GO:0045087), positive regulation of T-helper 1 cell differentiation (GO:0045627), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of JNK cascade (GO:0046330), positive regulation of peptidyl-tyrosine phosphorylation (GO:0050731), defense response to Gram-positive bacterium (GO:0050830), T cell receptor signaling pathway (GO:0050852), protein homooligomerization (GO:0051260), stress-activated MAPK cascade (GO:0051403), positive regulation of macrophage cytokine production (GO:0060907)

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 (8): 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), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
MAP kinase activation	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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cytokine production	5
protein kinase activity	3
cellular anatomical structure	3
cell surface receptor signaling pathway	2
positive regulation of type I interferon production	2
protein binding	2
protein domain specific binding	2
cytoplasm	2
regulation of cytokine-mediated signaling pathway	1
positive regulation of signal transduction	1
cytokine-mediated signaling pathway	1
positive regulation of response to cytokine stimulus	1
immune response	1
positive regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
regulation of T-helper 1 type immune response	1
T-helper 1 type immune response	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
defense response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular signaling cassette	1
MAPK cascade	1
cellular response to cytokine stimulus	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
cellular response to lipopolysaccharide	1
chemokine production	1
regulation of chemokine production	1
interferon-alpha production	1
regulation of interferon-alpha production	1
interferon-beta production	1
regulation of interferon-beta production	1
type II interferon production	1
regulation of type II interferon production	1

Protein interactions and networks

STRING

2761 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RIPK2	NOD2	Q9HC29	999
RIPK2	NOD1	Q9Y239	999
RIPK2	CARD6	Q9BX69	955
RIPK2	TRAF3	Q13114	928
RIPK2	XIAP	P98170	911
RIPK2	IKBKG	Q9Y6K9	863
RIPK2	NLRP3	Q96P20	848
RIPK2	TRAF6	Q9Y4K3	825
RIPK2	CASP1	P29466	774
RIPK2	TAB2	Q9NYJ8	761
RIPK2	NLRC4	Q9NPP4	752
RIPK2	CCDC122	Q5T0U0	749
RIPK2	TAB3	Q8N5C8	738
RIPK2	NLRP1	Q9C000	736
RIPK2	ATG16L1	Q676U5	727

IntAct

141 interactions, top by confidence:

A	B	Type	Score
RIPK2	XIAP	psi-mi:“MI:0915”(physical association)	0.950
XIAP	RIPK2	psi-mi:“MI:0915”(physical association)	0.950
XIAP	RIPK2	psi-mi:“MI:0914”(association)	0.950
NOD2	RIPK2	psi-mi:“MI:0915”(physical association)	0.870
RIPK2	NOD2	psi-mi:“MI:0915”(physical association)	0.870
RIPK2	NOD2	psi-mi:“MI:2364”(proximity)	0.870

BioGRID (195): RIPK2 (Two-hybrid), RIPK2 (Two-hybrid), RIPK2 (Affinity Capture-RNA), RIPK2 (Affinity Capture-RNA), RIPK2 (Affinity Capture-RNA), RIPK2 (Reconstituted Complex), RIPK2 (Two-hybrid), RIPK2 (Affinity Capture-Western), RIPK2 (Proximity Label-MS), RIPK2 (Affinity Capture-Western), RIPK2 (Co-localization), IRF4 (Affinity Capture-Western), RIPK2 (Affinity Capture-Western), RIPK2 (Biochemical Activity), KCTD12 (Affinity Capture-MS)

ESM2 similar proteins: A2RT67, A2RUS2, A4IJ06, B0CM32, B0KW86, E1B8U2, G3X9X1, O15519, O35732, O43353, O94955, O95267, O95456, P29594, P42575, P55215, P58801, Q0P5F2, Q14790, Q1RMU2, Q2TBA3, Q568M3, Q5E9Y6, Q5RD56, Q5RDY3, Q5RED8, Q66H62, Q69ZK0, Q6NTL4, Q6ZWE6, Q70Z35, Q80TQ2, Q86TP1, Q8BM47, Q8C0Q9, Q8CHT1, Q8IV45, Q8IY47, Q8K2I9, Q8N5V2

Diamond homologs: A2VDU3, C0LGF4, C0LGI2, C0LGL9, C0LGP2, C0LGT5, C0LGU1, C0LGX3, D7UPN3, F4JTP5, O22558, O43318, O43353, O80963, O81069, P0C8E4, P18161, P47735, P57078, P58801, Q05609, Q0PW40, Q0WNY5, Q13546, Q2MHE4, Q3SZJ2, Q54H45, Q54H46, Q54I36, Q54IP4, Q54M77, Q54N73, Q54QQ1, Q54RB7, Q54RR9, Q54TA1, Q54TM7, Q54XX5, Q54Y55, Q55GU0

SIGNOR signaling

21 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”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 81 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	35.5×	6e-06
Gap junction trafficking	5	35.5×	6e-06
TNFR1-induced NF-kappa-B signaling pathway	7	35.1×	1e-07
TNFR1-induced proapoptotic signaling	5	32.8×	8e-06
Regulation of necroptotic cell death	5	32.8×	8e-06
RHO GTPases activate IQGAPs	6	31.0×	2e-06
Attenuation phase	5	30.4×	1e-05
NOD1/2 Signaling Pathway	6	28.4×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein refolding	5	41.1×	5e-05
positive regulation of type I interferon production	5	27.7×	2e-04
canonical NF-kappaB signal transduction	5	24.1×	3e-04
tumor necrosis factor-mediated signaling pathway	5	21.7×	4e-04
response to unfolded protein	5	19.8×	5e-04
cellular response to type II interferon	5	13.7×	2e-03
obsolete positive regulation of NF-kappaB transcription factor activity	5	13.5×	2e-03
regulation of inflammatory response	6	13.3×	5e-04

Disease & clinical

Clinical variants and AI predictions

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

1363 predictions. Top by Δscore:

Variant	Effect	Δscore
8:89758234:GTA:G	donor_loss	1.0000
8:89758235:T:A	donor_loss	1.0000
8:89762827:A:AG	acceptor_gain	1.0000
8:89762828:G:GG	acceptor_gain	1.0000
8:89762828:GT:G	acceptor_gain	1.0000
8:89762983:GTAA:G	donor_loss	1.0000
8:89762984:T:A	donor_loss	1.0000
8:89765327:A:AG	acceptor_gain	1.0000
8:89765329:A:AG	acceptor_gain	1.0000
8:89765330:T:G	acceptor_gain	1.0000
8:89765331:A:AG	acceptor_gain	1.0000
8:89765333:A:AG	acceptor_gain	1.0000
8:89765333:ATAT:A	acceptor_gain	1.0000
8:89765334:T:G	acceptor_gain	1.0000
8:89765335:A:AG	acceptor_gain	1.0000
8:89765335:AT:A	acceptor_gain	1.0000
8:89765336:T:TA	acceptor_gain	1.0000
8:89765336:TGAA:T	acceptor_loss	1.0000
8:89765337:GAAGA:G	acceptor_loss	1.0000
8:89765339:A:AG	acceptor_gain	1.0000
8:89765339:AGA:A	acceptor_loss	1.0000
8:89765340:G:GC	acceptor_gain	1.0000
8:89765340:GA:G	acceptor_gain	1.0000
8:89765340:GAA:G	acceptor_gain	1.0000
8:89765340:GAAA:G	acceptor_gain	1.0000
8:89765492:T:G	donor_gain	1.0000
8:89765493:TAAGG:T	donor_loss	1.0000
8:89765494:AAG:A	donor_gain	1.0000
8:89765494:AAGG:A	donor_loss	1.0000
8:89765495:AGGT:A	donor_loss	1.0000

AlphaMissense

3555 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:89758201:G:C	K47N	1.000
8:89758201:G:T	K47N	1.000
8:89762903:G:A	G83E	1.000
8:89762936:T:A	V94D	1.000
8:89765417:T:C	L135P	1.000
8:89765443:C:G	H144D	1.000
8:89765450:A:C	D146A	1.000
8:89765450:A:G	D146G	1.000
8:89765450:A:T	D146V	1.000
8:89765451:C:A	D146E	1.000
8:89765451:C:G	D146E	1.000
8:89765453:T:C	L147S	1.000
8:89765466:T:A	N151K	1.000
8:89765466:T:G	N151K	1.000
8:89769778:G:C	D164H	1.000
8:89769779:A:C	D164A	1.000
8:89769779:A:T	D164V	1.000
8:89769780:T:A	D164E	1.000
8:89769780:T:G	D164E	1.000
8:89769781:T:C	F165L	1.000
8:89769783:T:A	F165L	1.000
8:89769783:T:G	F165L	1.000
8:89772814:G:C	R280T	1.000
8:89772815:A:C	R280S	1.000
8:89772815:A:T	R280S	1.000
8:89758164:C:A	A35D	0.999
8:89758194:C:A	A45D	0.999
8:89758199:A:C	K47Q	0.999
8:89758199:A:G	K47E	0.999
8:89762854:G:C	A67P	0.999

dbSNP variants (sampled 300 via entrez): RS1000021635 (8:89772543 G>C), RS1000058498 (8:89763085 A>G), RS1000071789 (8:89777936 A>G), RS1000074293 (8:89772216 A>T), RS1000212765 (8:89767391 T>A), RS1000366155 (8:89764986 A>G), RS1000453154 (8:89781341 C>T), RS1000468543 (8:89758042 G>A,C), RS1000611672 (8:89791008 A>G), RS1000649465 (8:89774263 G>A), RS1000746386 (8:89774550 A>G), RS1000772473 (8:89759276 G>A), RS1000804882 (8:89759650 T>C), RS1000869928 (8:89779566 C>A,T), RS1001223138 (8:89781239 G>A)

Disease associations

OMIM: gene MIM:603455 | disease phenotypes: MIM:609888

GenCC curated gene-disease

Mondo (1): leprosy, susceptibility to, 1 (MONDO:0012358)

Orphanet (1): Leprosy (Orphanet:548)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000546_5	Leprosy	1.000000e-12
GCST000546_6	Leprosy	1.000000e-16
GCST000579_54	Cognitive performance	3.000000e-06
GCST001729_17	Crohn’s disease	1.000000e-08
GCST002772_19	Leprosy	2.000000e-35
GCST002772_6	Leprosy	1.000000e-21
GCST003073_5	Cerebral amyloid deposition (PET imaging)	7.000000e-07
GCST004009_11	Leprosy	5.000000e-08

EFO canonical traits (2, from GWAS)

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

64 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 395,244 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL1229517	VEMURAFENIB	4	15,704
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289494	TIVOZANIB	4	4,455
CHEMBL1289601	LENVATINIB	4	8,784
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1873475	IBRUTINIB	4	7,994
CHEMBL1946170	REGORAFENIB	4	12,678
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL2105717	CABOZANTINIB	4	11,177
CHEMBL2110732	DACOMITINIB ANHYDROUS	4	6,578
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301612	ENCORAFENIB	4	4,624
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL5416410	DASATINIB	4	655
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL554	LAPATINIB	4
CHEMBL576982	QUIZARTINIB	4
CHEMBL601719	CRIZOTINIB	4
CHEMBL939	GEFITINIB	4
CHEMBL1091644	LINSITINIB	3
CHEMBL2087361	ICOTINIB	3
CHEMBL2105728	CRENOLANIB	3
CHEMBL217092	SARACATINIB	3
CHEMBL31965	CANERTINIB	3
CHEMBL3544983	TESEVATINIB	3

PharmGKB: 1 entry (VIP=true, CPIC=false)

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)

440 measured of 633 human assays (828 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
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
BDBM303369	IC50	0.81 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
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-10138241: 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-10138241: 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-10138241: 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-10138241: 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-10138241: 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-10138241: 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-10138241: 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-10138241: 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-10138241: Substituted benzamides as RIPK2 inhibitors
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-10138241: Substituted benzamides as RIPK2 inhibitors
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-10138241: 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-10138241: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-2-fluoro-4-methyl-5-[1-[6-[(3S)-1-methylpyrrolidin-3-yl]imidazo[1,2-a]pyridin-3-yl]pyrazol-4-yl]benzamide	IC50	1.6 nM	US-10138241: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-4-methyl-3-[1-[5-[[1-(oxan-4-ylmethyl)piperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]benzamide	IC50	1.7 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-cyclopropyl-5-[1-[5-[[(4S)-3,3-difluoro-1-methylpiperidin-4-yl]amino]-3-pyridinyl]pyrazol-4-yl]-2-fluoro-4-methylbenzamide	IC50	1.7 nM	US-10138222: Substituted benzamides as RIPK2 inhibitors
N-Cyclopropyl-2-fluoro-4-methyl-5-{1-[6-(1-oxetan-3-yl-piperidin-4-yl)-imidazo[1,2-a]pyridin-3-yl]-1H-pyrazol-4-yl}-benzamide	IC50	1.7 nM	US-10138241: Substituted benzamides as RIPK2 inhibitors
Staurosporine	KD	1.7 nM
3-(6-(tert- butylsulfonyl)-7- methoxyimidazo[1,2- a]pyridin-3-yl)-2,5- difluoroaniline	IC50	1.75 nM	US-20250346593: IMIDAZO(1,2-1)PYRIDINE DERIVATIVES AS RIPK2 INHIBITORS
5-(6-(tert- butylsulfonyl)-7- methoxyimidazo[1,2- a]pyridin-3-yl)-2- (difluoromethoxy)-3- fluoroaniline	IC50	1.75 nM	US-20250346593: IMIDAZO(1,2-1)PYRIDINE DERIVATIVES AS RIPK2 INHIBITORS
4-(6-(tert- butylsulfonyl)-7- methoxyimidazo[1,2- a]pyridin-3-yl)-3,6- difluoro-2- methylaniline	IC50	1.75 nM	US-20250346593: IMIDAZO(1,2-1)PYRIDINE DERIVATIVES AS RIPK2 INHIBITORS
5-(5-(tert- butylsulfonyl)-6- ethoxypyrazolo[1,5- a]pyridin-3-yl)-3- chloro-6-fluoropyridin- 2-amine	IC50	1.75 nM	US-20250346593: IMIDAZO(1,2-1)PYRIDINE DERIVATIVES AS RIPK2 INHIBITORS
N-{2-methoxy-5-[7- methoxy-6-(2- methylpropane-2- sulfonyl)imidazo[1,2- a]pyridin-3- yl]phenyl}propane-1- sulfonamide	IC50	1.75 nM	US-20250346593: IMIDAZO(1,2-1)PYRIDINE DERIVATIVES AS RIPK2 INHIBITORS
N-(5-(5-(tert- butylsulfonyl)pyrazolo [1,5-a]pyridin-3-yl)-2,3- dimethoxyphenyl) propane-1-sulfonamide	IC50	1.75 nM	US-20250346593: IMIDAZO(1,2-1)PYRIDINE DERIVATIVES AS RIPK2 INHIBITORS
N-(5-(5-(tert- butylsulfonyl)-6- methoxypyrazolo[1,5- a]pyridin-3-yl)-2,3- dimethoxyphenyl) methanesulfonamide	IC50	1.75 nM	US-20250346593: IMIDAZO(1,2-1)PYRIDINE DERIVATIVES AS RIPK2 INHIBITORS
N-(4-(6-(tert- butylsulfonyl)-7- methoxyimidazo[1,2- a]pyridin-3-yl)-6- (difluoromethoxy) pyridin-2-yl)propane-1- sulfonamide	IC50	1.75 nM	US-20250346593: IMIDAZO(1,2-1)PYRIDINE DERIVATIVES 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

632 with measured affinity, of 1809 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
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
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
(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
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
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
N-(1,3-benzothiazol-5-yl)-6-(1-methylpyrazol-4-yl)thieno[2,3-d]pyrimidin-4-amine	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	0.0040	uM
N-(1,3-benzothiazol-5-yl)-6-(3-methylimidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine	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	0.0040	uM
N-(6-tert-butylsulfonyl-7-methoxyquinazolin-4-yl)-1,3-benzothiazol-5-amine	1569497: Inhibition of fluorescent-labelled ligand binding to human RIP2K preincubated for 10 mins followed by fluorescent-labelled ligand addition and measured after 10 mins by fluorescence polarization assay	ic50	0.0040	uM
7-(4-aminocyclohexyl)-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	0.0042	uM
Vandetanib	435935: Binding constant for RIPK2 kinase domain	kd	0.0046	uM
6-(2,6-dichlorophenyl)-2-[4-[2-(diethylamino)ethoxy]anilino]-8-(2-methylpropyl)pyrido[2,3-d]pyrimidin-7-one	1756906: Inhibition of recombinant RIPK2 (unknown origin) using RS repeat peptide as substrate preincubated for 5 mins followed by substrate and ATP addition and further incubated for 2 hrs by ADP-Glo reagent based assay	ic50	0.0050	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	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	0.0050	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
sodium arsenite	increases expression, decreases expression, affects reaction	2
Doxorubicin	decreases expression, affects response to substance	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	affects cotreatment, decreases expression	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	increases expression, affects response to substance	1
beta-methylcholine	affects expression	1
cordycepin	decreases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
usnic acid	increases 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)

0 trials via MONDO — disease-level, not drug-specific.