RIPK3

Summary

RIPK3 (receptor interacting serine/threonine kinase 3, HGNC:10021) is a protein-coding gene on chromosome 14q12, encoding Receptor-interacting serine/threonine-protein kinase 3 (Q9Y572). Serine/threonine-protein kinase that activates necroptosis and apoptosis, two parallel forms of cell death.

The product of this gene is a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases, and contains a C-terminal domain unique from other RIP family members. The encoded protein is predominantly localized to the cytoplasm, and can undergo nucleocytoplasmic shuttling dependent on novel nuclear localization and export signals. It is a component of the tumor necrosis factor (TNF) receptor-I signaling complex, and can induce apoptosis and weakly activate the NF-kappaB transcription factor.

Source: NCBI Gene 11035 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary predisposition to infections (Moderate, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 77 total
• Druggable target: yes — 41 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_006871

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10021
Approved symbol	RIPK3
Name	receptor interacting serine/threonine kinase 3
Location	14q12
Locus type	gene with protein product
Status	Approved
Aliases	RIP3
Ensembl gene	ENSG00000129465
Ensembl biotype	protein_coding
OMIM	605817
Entrez	11035

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000216274, ENST00000554338, ENST00000554569, ENST00000554756, ENST00000557253, ENST00000557624, ENST00000557662, ENST00000948368, ENST00000948369, ENST00000948370

RefSeq mRNA: 1 — MANE Select: NM_006871 NM_006871

CCDS: CCDS9628

Canonical transcript exons

ENST00000216274 — 10 exons

Exon	Start	End
ENSE00000654468	24338249	24338295
ENSE00000654469	24338422	24338567
ENSE00000654470	24339015	24339324
ENSE00001664322	24336025	24336395
ENSE00002523851	24339807	24339991
ENSE00003513092	24336885	24336945
ENSE00003515761	24337695	24337762
ENSE00003543814	24337873	24338040
ENSE00003626373	24337086	24337460
ENSE00003690870	24339457	24339597

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 94.58.

FANTOM5 (CAGE): breadth broad, TPM avg 1.8465 / max 41.2566, expressed in 560 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142597	1.8465	560

Top tissues by expression

136 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	94.58	gold quality
mucosa of transverse colon	UBERON:0004991	93.01	gold quality
blood	UBERON:0000178	92.70	gold quality
duodenum	UBERON:0002114	90.78	gold quality
spleen	UBERON:0002106	90.71	gold quality
rectum	UBERON:0001052	90.64	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.84	gold quality
small intestine	UBERON:0002108	89.19	gold quality
transverse colon	UBERON:0001157	89.13	gold quality
monocyte	CL:0000576	87.94	gold quality
vermiform appendix	UBERON:0001154	87.94	gold quality
leukocyte	CL:0000738	87.86	gold quality
right lobe of thyroid gland	UBERON:0001119	87.84	gold quality
lymph node	UBERON:0000029	87.55	gold quality
left lobe of thyroid gland	UBERON:0001120	87.08	gold quality
thyroid gland	UBERON:0002046	86.82	gold quality
gall bladder	UBERON:0002110	86.60	gold quality
esophagus mucosa	UBERON:0002469	86.55	gold quality
body of stomach	UBERON:0001161	86.53	gold quality
minor salivary gland	UBERON:0001830	86.01	gold quality
subcutaneous adipose tissue	UBERON:0002190	85.39	gold quality
saliva-secreting gland	UBERON:0001044	84.89	gold quality
adipose tissue	UBERON:0001013	84.55	gold quality
bone marrow	UBERON:0002371	84.52	gold quality
intestine	UBERON:0000160	84.47	gold quality
lower esophagus mucosa	UBERON:0035834	84.42	gold quality
stomach	UBERON:0000945	83.99	gold quality
omental fat pad	UBERON:0010414	83.86	gold quality
vagina	UBERON:0000996	83.56	gold quality
bone marrow cell	CL:0002092	83.41	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.84

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

6 targeting RIPK3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-1179	99.71	68.70	1040
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-5002-3P	95.75	67.04	542

Literature-anchored findings (GeneRIF, showing 40)

• RIP3 acts a nucleocytoplasmic shuttling protein with nuclear export and import signals (PMID:15208320)
• Real-time PCR analysis reveals that the ratio of RIP3 gamma to RIP3 is significantly increased in colon and lung cancers relative to their matched normal tissues, indicating that RIP3 gamma might be a splice form associated with tumorigenesis. (PMID:15896315)
• Evidence is found for an association between overexpression of RIP3 and homocysteine-induced congenital cardiovascular malformations. (PMID:16429275)
• tRIP3 may function upstream of Fas (TNFRSF6)-associated via death domain to induce apoptosis in TNFR-1 signaling pathway (PMID:16844082)
• the nuclear factor-kappaB signaling pathway is inhibed by gamma-tocopherol through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis (PMID:17114179)
• analysis of human receptor-interacting protein 3 truncation expressed in Escherichia coli (PMID:18025550)
• NLS of RIPK3 exhibits several other roles besides apoptotic function. (PMID:18533105)
• The expression of RIP3 in different cell lines correlates with their responsiveness to necrosis induction. (PMID:19524512)
• Gene expression of RIPK3 and RNF216 in PBMC could identify those obese subjects, who will regain more weight after a successful initial weight loss. The mRNA levels of these genes could be nutrigenomic biomarkers for predicting obesity treatment outcome. (PMID:19690434)
• RIP1 and RIP3 have roles in TNF-induced necrosis (PMID:20354226)
• RIP3 is an essential inducer of TNF-induced programmed necrosis (PMID:21153365)
• FADD: an endogenous inhibitor of RIP3-driven regulated necrosis (PMID:21894190)
• study suggests that MLKL is a key RIP3 downstream component of TNF-induced necrotic cell death (PMID:22421439)
• Study shows that RIP1 and RIP3 form an amyloid structure through their RIP homotypic interaction motifs and that this heterodimeric amyloid structure is a functional signaling complex that mediates programmed necrosis. (PMID:22817896)
• procaspase-8 activity is essential for cell survival by inhibiting both apoptotic and nonapoptotic cell death dependent on receptor-interacting protein kinase 1 (RIP1) and RIP3 (PMID:23071110)
• the importance of the RIP3-MLKL interaction in the formation of functional necrosomes and suggest that translocation of necrosomes to mitochondria-associated membranes is essential for necroptosis signaling. (PMID:23612963)
• an alanine residue substitution for Ser(89) enhanced RIP1 kinase activity and TNF-induced programmed necrosis without affecting RIP1-RIP3 necrosome formation. (PMID:24059293)
• RIP3-mediated MLKL phosphorylation, though important for downstream signaling, is dispensable for stable complex formation between RIP3 and MLKL. (PMID:24095729)
• The protein levels of crucial modulators of necroptosis, RIP1 and RIP3, are increased by shikonin treatment in primary tumor tissues. (PMID:24314238)
• RIP3 protein expression is significantly increased in the inflamed tissue of inflammatory boowel disease pediatric patients. (PMID:24322838)
• targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. (PMID:24413151)
• Report role of MLKL/RIP3 pathway in necrotic membrane disruption. (PMID:24703947)
• The results of this study showed that cerebral ischemia activates transcriptional changes that lead to an increase in the endogenous RIP3 protein level. (PMID:24746856)
• RIP3-dependent necroptosis mediates non-alcoholic steatohepatitis-induced liver fibrosis via activation of JNK, MCP-1-mediated recruitment of monocytes, and an expansion of intrahepatic biliary/progenitor cells. (PMID:24963148)
• RIP3 silencing in leukemia cells results in suppression of the complex regulation of the apoptosis/necroptosis switch and NF-kappaB activity. (PMID:25144719)
• our results reveal a specific role for the RIP1-RIP3-DRP1 pathway in RNA virus-induced activation of the NLRP3 inflammasome (PMID:25326752)
• although JNK activation and RIP3 expression are induced by FS, neither contributes to the liver injury. (PMID:25423287)
• RIPK3 serves as a negative regulator of selective autophagy by regulating regulates p62-LC3 complex formation via the caspase-8-dependent cleavage of p62 (PMID:25450619)
• RIP3 holds both necroptosis and apoptosis in balance through a Ripoptosome-like platform. (PMID:25459880)
• Enhanced RIP3 signaling in aneurysmal tissues contributes to abdominal aortic aneursym progression by causing smooth muscle cell necroptosis, as well as stimulating vascular inflammation. (PMID:25563840)
• Data suggest that neoalbaconol-induced necroptosis include receptor interacting serine/threonine kinase 1-dependent expression of tumor necrosis factor alpha and receptor interacting serine/threonine kinase 3-dependent generation of reactive oxygen species. (PMID:25575821)
• Herpes simplex virus 1- and 2 ICP6 and ICP10 proteins prevent necroptosis in human cells by inhibiting the interaction between receptor-interacting protein kinase 1 (RIP1) and RIP3, a key step in tumor necrosis factor (TNF)-induced necroptosis. (PMID:25674983)
• High expression of RIP3 in keratinocytes from toxic epidermal necrolysis patients potentiates MLKL phosphorylation/activation and necrotic cell death. (PMID:25748555)
• Suppression of RIP3-dependent necroptosis by human cytomegalovirus (PMID:25778401)
• RIP3 activation following the induction of necroptosis requires the activity of an HSP90 and CDC37 cochaperone complex. (PMID:25852146)
• PolyIC stimulation of cervical cancer cells induced necroptotic cell death, which was strictly dependent on the expression of the receptor-interacting protein kinase RIPK3. (PMID:25888634)
• Data implicate the infiltrating macrophages as a source of damaging inflammasomes after photoreceptor detachment in a RIP3-dependent manner and suggest a novel therapeutic target for treatment of retinal diseases. (PMID:25906154)
• The RIP3 expression is reduced in tumors compared to normal tissue in 85% of breast cancer patients, suggesting that RIP3 deficiency is positively selected during tumor growth/development. (PMID:25952668)
• Additionally, later in infection, RIP3 is cleaved by the coxsackievirus B3-encoded cysteine protease 3C(pro), which serves to abrogate RIP3-mediated necrotic signaling and induce a nonnecrotic form of cell death. (PMID:26269957)
• RIPK3 expression may allow unmasking the necroptotic signalling machinery in melanoma and points to reactivation of this pathway as a treatment option for metastatic melanoma. (PMID:26355347)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ripk3	ENSDARG00000090965
mus_musculus	Ripk3	ENSMUSG00000022221
rattus_norvegicus	Ripk3	ENSRNOG00000020465

Paralogs (23): MAP3K9 (ENSG00000006432), TESK2 (ENSG00000070759), MAP3K13 (ENSG00000073803), ARAF (ENSG00000078061), MAP3K20 (ENSG00000091436), RIPK2 (ENSG00000104312), LIMK1 (ENSG00000106683), TESK1 (ENSG00000107140), TNNI3K (ENSG00000116783), 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 3 — Q9Y572 (reviewed: Q9Y572)

Alternative names: RIP-like protein kinase 3, Receptor-interacting protein 3

All UniProt accessions (2): Q9Y572, H0YJN5

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase that activates necroptosis and apoptosis, two parallel forms of cell death. Necroptosis, a programmed cell death process in response to death-inducing TNF family members, is triggered by RIPK3 following activation by ZBP1. Activated RIPK3 forms a necrosis-inducing complex and mediates phosphorylation of MLKL, promoting MLKL localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage. In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: following ZBP1 activation, which senses double-stranded Z-RNA structures, nuclear RIPK3 catalyzes phosphorylation and activation of MLKL, promoting disruption of the nuclear envelope and leakage of cellular DNA into the cytosol. Also regulates apoptosis: apoptosis depends on RIPK1, FADD and CASP8, and is independent of MLKL and RIPK3 kinase activity. Phosphorylates RIPK1: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. In some cell types, also able to restrict viral replication by promoting cell death-independent responses. In response to Zika virus infection in neurons, promotes a cell death-independent pathway that restricts viral replication: together with ZBP1, promotes a death-independent transcriptional program that modifies the cellular metabolism via up-regulation expression of the enzyme ACOD1/IRG1 and production of the metabolite itaconate. Itaconate inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes. RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production. (Microbial infection) In case of herpes simplex virus 1/HHV-1 infection, forms heteromeric amyloid structures with HHV-1 protein RIR1/ICP6 which may inhibit RIPK3-mediated necroptosis, thereby preventing host cell death pathway and allowing viral evasion.

Subunit / interactions. Interacts (via RIP homotypic interaction motif) with RIPK1 (via RIP homotypic interaction motif); this interaction induces RIPK1 phosphorylation and formation of a RIPK1-RIPK3 necrosis-inducing complex. Interacts with MLKL; the interaction is direct and triggers necroptosis. Interacts with ZBP1 (via RIP homotypic interaction motif); interaction with ZBP1 activates RIPK3, triggering necroptosis. Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer further interacts with PGAM5 and MLKL; the formation of this complex leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase activity. Binds TRAF2 and is recruited to the TNFR-1 signaling complex. Interacts with PYGL, GLUL and GLUD1; these interactions result in activation of these metabolic enzymes. Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Interacts with ARHGEF2. Interacts with PELI1 (via atypical FHA domain); the phosphorylated form at Thr-182 binds preferentially to PELI1. Interacts with BUB1B, TRAF2 and STUB1. Interacts with CASP6. Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis). (Microbial infection) Interacts (via RIP homotypic interaction motif/RHIM) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via RHIM); this interaction may induce heteromeric amyloid assemblies and prevent necroptosis activation. (Microbial infection) Interacts (via RIP homotypic interaction motif/RHIM) with herpes simplex virus 2/HHV-2 protein RIR1/ICP10 (via RHIM); this interaction prevents necroptosis activation.

Subcellular location. Cytoplasm. Cytosol. Nucleus.

Tissue specificity. Highly expressed in the pancreas. Detected at lower levels in heart, placenta, lung and kidney. Expression is significantly increased in colon and lung cancers.

Post-translational modifications. (Microbial infection) Proteolytically cleaved by S.flexneri OspD3 within the RIP homotypic interaction motif (RHIM), leading to its degradation and inhibition of necroptosis. RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. Autophosphorylated following interaction with ZBP1. Phosphorylation of Ser-199 plays a role in the necroptotic function of RIPK3. Autophosphorylates at Ser-227 following activation by ZBP1: phosphorylation at these sites is a hallmark of necroptosis and is required for binding MLKL. Phosphorylation at Thr-182 is important for its kinase activity, interaction with PELI1 and PELI1-mediated ‘Lys-48’-linked polyubiquitination and for its ability to mediate TNF-induced necroptosis. Polyubiquitinated with ‘Lys-48’ and ‘Lys-63’-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B. Polyubiquitinated with ‘Lys-48’-linked chains by PELI1 leading to its subsequent proteasome-dependent degradation. Ubiquitinated by STUB1 leading to its subsequent proteasome-dependent degradation. Deubiquitinated by USP22.

Activity regulation. Activity is stimulated by ZBP1, which senses double-stranded Z-RNA structures. RIPK3-dependent necroptosis is inhibited by RIPK1: RIPK1 prevents the ZBP1-induced activation of RIPK3 via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis.

Domain organisation. The RIP homotypic interaction motif/RHIM mediates interaction with the RHIM motif of RIPK1. Both motifs form a hetero-amyloid serpentine fold, stabilized by hydrophobic packing and featuring an unusual Cys-Ser ladder of alternating Ser (from RIPK1) and Cys (from RIPK3). (Microbial infection) The RIP homotypic interaction motif/RHIM mediates interaction with the RHIM motif of the herpes simplex virus 1/HHV-1 protein RIR1/ICP6 to form heteromeric amyloid structures.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y572-1	1	yes
Q9Y572-2	2, Beta
Q9Y572-3	3, Gamma

RefSeq proteins (1): NP_006862* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR025735	RHIM	Binding_site
IPR051681	Ser/Thr_Kinases-Pseudokinases	Family

Pfam: PF00069, PF12721

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)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. 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
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO	0.057	1
S1 PEPTIDE	0.037	1
EEEEY	—	0

Catalyzed reactions (Rhea), 2 shown:

• 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 (74 total): helix 16, strand 14, mutagenesis site 11, modified residue 10, cross-link 4, sequence variant 3, sequence conflict 3, region of interest 2, splice variant 2, turn 2, binding site 2, chain 1, domain 1, short sequence motif 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
5ZCK	X-RAY DIFFRACTION	1.27
7MON	X-RAY DIFFRACTION	2.23
9LFU	X-RAY DIFFRACTION	2.93
7MX3	X-RAY DIFFRACTION	3.23
7DA4	ELECTRON MICROSCOPY	4.24
8Z94	ELECTRON MICROSCOPY	4.56
12KL	SOLID-STATE NMR
5V7Z	SOLID-STATE NMR
7DAC	SOLID-STATE NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y572-F1	67.80	0.42

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): 142 (proton acceptor)

Ligand- & substrate-binding residues (2): 27–35; 50

Post-translational modifications (14): 164, 182, 199, 227, 252, 299, 333, 389, 401, 42, 351, 363, 518, 2

Mutagenesis-validated functional residues (11):

Position	Phenotype
50	abolishes kinase activity. loss of pgam5- and mlkl-binding. no effect on ripk1-binding. loss of interaction with peli1 a
50	abolishes kinase activity.
142	abolishes kinase activity and ability to mediate necroptosis.
182	abolishes kinase activity. loss of interaction with peli1 and peli1-mediated ubiquitination. no loss of interaction with
182	no loss of interaction with peli1 and peli1-mediated ubiquitination. no loss of interaction with ripk1 and mlkl.
185	loss of interaction with peli1 and peli1-mediated ubiquitination.
227	abolishes ability to mediate necroptosis. partial loss of kinase activity. no loss of peli1-mediated degradation.
227	no loss of peli1-mediated degradation.
363	loss of peli1-mediated ubiquitination. no loss of interaction with peli1.
458–461	abolished cleavage by s.flexneri ospd3.
518	reduced necroptosis-associated ubiquitination and amplified necrosome formation and necroptotic cell death.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-168927	TICAM1, RIP1-mediated IKK complex recruitment
R-HSA-1810476	RIP-mediated NFkB activation via ZBP1
R-HSA-2562578	TRIF-mediated programmed cell death
R-HSA-3295583	TRP channels
R-HSA-5213460	RIPK1-mediated regulated necrosis
R-HSA-5675482	Regulation of necroptotic cell death
R-HSA-9013957	TLR3-mediated TICAM1-dependent programmed cell death
R-HSA-937041	IKK complex recruitment mediated by RIP1
R-HSA-9686347	Microbial modulation of RIPK1-mediated regulated necrosis
R-HSA-9692913	SARS-CoV-1-mediated effects on programmed cell death
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses

MSigDB gene sets: 289 (showing top): REACTOME_IKK_COMPLEX_RECRUITMENT_MEDIATED_BY_RIP1, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, REACTOME_INNATE_IMMUNE_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, MODULE_169, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_T_CELL_HOMEOSTASIS, GOBP_LYMPHOCYTE_HOMEOSTASIS, GOBP_LYMPH_NODE_DEVELOPMENT, GOBP_REGULATION_OF_LYMPHOCYTE_APOPTOTIC_PROCESS, GOBP_THYMUS_DEVELOPMENT, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY

GO Biological Process (37): regulation of T cell mediated cytotoxicity (GO:0001914), regulation of adaptive immune response (GO:0002819), signal transduction (GO:0007165), activation of protein kinase activity (GO:0032147), regulation of type II interferon production (GO:0032649), T cell differentiation in thymus (GO:0033077), protein modification process (GO:0036211), non-canonical NF-kappaB signal transduction (GO:0038061), regulation of apoptotic process (GO:0042981), T cell homeostasis (GO:0043029), regulation of activated T cell proliferation (GO:0046006), lymph node development (GO:0048535), spleen development (GO:0048536), thymus development (GO:0048538), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), defense response to virus (GO:0051607), positive regulation of necroptotic process (GO:0060545), regulation of activation-induced cell death of T cells (GO:0070235), necroptotic process (GO:0070266), cellular response to hydrogen peroxide (GO:0070301), reactive oxygen species metabolic process (GO:0072593), apoptotic signaling pathway (GO:0097190), programmed necrotic cell death (GO:0097300), necroptotic signaling pathway (GO:0097527), execution phase of necroptosis (GO:0097528), ripoptosome assembly involved in necroptotic process (GO:1901026), amyloid fibril formation (GO:1990000), positive regulation of reactive oxygen species metabolic process (GO:2000379), regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation (GO:2000452), positive regulation of intrinsic apoptotic signaling pathway (GO:2001244), protein phosphorylation (GO:0006468), apoptotic process (GO:0006915), positive regulation of metabolic process (GO:0009893), regulation of gene expression (GO:0010468), programmed cell death (GO:0012501), positive regulation of DNA-templated transcription (GO:0045893), regulation of reactive oxygen species metabolic process (GO:2000377)

GO Molecular Function (12): transcription coactivator activity (GO:0003713), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), protein serine kinase activity (GO:0106310), protein serine/threonine kinase binding (GO:0120283), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), protein-containing complex (GO:0032991), ripoptosome (GO:0097342)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Toll Like Receptor 3 (TLR3) Cascade	2
TRIF (TICAM1)-mediated TLR4 signaling	2
SARS-CoV-1-host interactions	2
ZBP1(DAI) mediated induction of type I IFNs	1
Stimuli-sensing channels	1
Regulated Necrosis	1
RIPK1-mediated regulated necrosis	1
Defective RIPK1-mediated regulated necrosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
hematopoietic or lymphoid organ development	3
protein kinase activity	2
binding	2
cellular anatomical structure	2
regulation of leukocyte mediated cytotoxicity	1
T cell mediated cytotoxicity	1
regulation of T cell mediated immunity	1
adaptive immune response	1
regulation of immune response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
positive regulation of protein kinase activity	1
regulation of cytokine production	1
type II interferon production	1
T cell differentiation	1
protein metabolic process	1
macromolecule modification	1
intracellular signaling cassette	1
apoptotic process	1
regulation of programmed cell death	1
lymphocyte homeostasis	1
regulation of T cell proliferation	1
activated T cell proliferation	1
gland development	1
defense response	1
response to virus	1
regulation of necroptotic process	1
positive regulation of programmed necrotic cell death	1
necroptotic process	1
regulation of immune system process	1
activation-induced cell death of T cells	1
regulation of T cell apoptotic process	1
programmed necrotic cell death	1
cellular response to reactive oxygen species	1
response to hydrogen peroxide	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1

Protein interactions and networks

STRING

2931 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RIPK3	CASP8	Q14790	998
RIPK3	FADD	Q13158	996
RIPK3	TRADD	Q15628	996
RIPK3	RIPK1	Q13546	989
RIPK3	MLKL	Q8NB16	989
RIPK3	CFLAR	O15519	987
RIPK3	ZBP1	Q9H171	957
RIPK3	TLR3	O15455	926
RIPK3	CASP1	P29466	907
RIPK3	TNFRSF1A	P19438	891
RIPK3	PCSK1	P29120	884
RIPK3	CASP6	P55212	860
RIPK3	GSDMD	P57764	811
RIPK3	IFNB1	P01574	787
RIPK3	TNF	P01375	760

IntAct

152 interactions, top by confidence:

A	B	Type	Score
CASP8	FADD	psi-mi:“MI:0915”(physical association)	0.980
RIPK1	RIPK3	psi-mi:“MI:0914”(association)	0.970
RIPK3	RIPK1	psi-mi:“MI:0915”(physical association)	0.970
RIPK1	RIPK3	psi-mi:“MI:0915”(physical association)	0.970
RIPK1	RIPK3	psi-mi:“MI:0217”(phosphorylation reaction)	0.970
RIPK3	RIPK1	psi-mi:“MI:0914”(association)	0.970
RIPK3	RIPK1	psi-mi:“MI:0407”(direct interaction)	0.970
RIPK1	RIPK3	psi-mi:“MI:0407”(direct interaction)	0.970
CASP8	RIPK1	psi-mi:“MI:0914”(association)	0.960
FADD	RIPK1	psi-mi:“MI:0914”(association)	0.930

BioGRID (122): EPHA4 (Affinity Capture-MS), AMY1C (Affinity Capture-MS), ZG16B (Affinity Capture-MS), PTPRK (Affinity Capture-MS), RIPK3 (Reconstituted Complex), DAXX (Reconstituted Complex), DAXX (Affinity Capture-Western), DAXX (Biochemical Activity), RIPK3 (Biochemical Activity), RIPK1 (Affinity Capture-Western), RIPK1 (Affinity Capture-Western), RIPK1 (Affinity Capture-Western), FADD (Affinity Capture-Western), RIPK3 (Biochemical Activity), RIPK3 (Affinity Capture-Western)

ESM2 similar proteins: A0JPN4, A4PES0, A4QNA8, D2HHP1, D4A7V9, E1BTE1, E2RSS3, O02776, O57473, O88622, O88866, P0C1S8, P47810, P47817, P54350, P57058, Q08D35, Q1LX29, Q1LX51, Q20443, Q2KIP2, Q63185, Q63802, Q66JT0, Q68UT7, Q6DFE0, Q6IRU7, Q6NVF4, Q6P1H6, Q6P1W0, Q6Z829, Q86W56, Q8AYG3, Q8AYK6, Q8BGE5, Q8BMI4, Q8C0Q4, Q8CFA1, Q8L4H0, Q8NG66

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

20 interactions.

A	Effect	B	Mechanism
RIPK3	up-regulates	PYGL	binding
RIPK3	up-regulates	GLUD1	binding
ponatinib	“down-regulates activity”	RIPK3	“chemical inhibition”
BIRC2	“up-regulates activity”	RIPK3	polyubiquitination
BIRC3	“up-regulates activity”	RIPK3	polyubiquitination
RIPK1	“up-regulates activity”	RIPK3	phosphorylation
RIPK3	“down-regulates activity”	TRIM28	phosphorylation
MAP3K7	“up-regulates activity”	RIPK3	phosphorylation
RIPK3	“up-regulates activity”	RIPK1	phosphorylation
RIPK3	“up-regulates activity”	MLKL	phosphorylation
ZBP1	“up-regulates activity”	RIPK3	binding
RIPK3	“up-regulates activity”	DLD	phosphorylation
RIPK3	“up-regulates activity”	PDH	phosphorylation
RIPK3	“up-regulates activity”	OGDC	phosphorylation
RIPK3	“up-regulates activity”	RIPK3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 99 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
Regulation of necroptotic cell death	10	54.2×	7e-13
RHOBTB2 GTPase cycle	8	47.0×	5e-10
RIPK1-mediated regulated necrosis	8	45.1×	6e-10
Regulated Necrosis	5	44.1×	2e-06
RHO GTPases activate PAKs	6	40.3×	3e-07
TICAM1, RIP1-mediated IKK complex recruitment	5	37.1×	5e-06
Formation of tubulin folding intermediates by CCT/TriC	7	36.5×	6e-08
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	7	35.2×	7e-08

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of necroptotic process	5	53.3×	8e-06
actin filament-based movement	5	43.1×	2e-05
protein refolding	6	40.3×	4e-06
positive regulation of telomere maintenance via telomerase	5	39.4×	2e-05
canonical NF-kappaB signal transduction	5	19.7×	3e-04
substantia nigra development	5	19.7×	3e-04
response to unfolded protein	5	16.2×	6e-04
cellular response to type II interferon	7	15.7×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	11
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1470 predictions. Top by Δscore:

Variant	Effect	Δscore
14:24337758:GCATT:G	acceptor_gain	1.0000
14:24337759:CATT:C	acceptor_gain	1.0000
14:24337759:CATTC:C	acceptor_gain	1.0000
14:24337760:ATT:A	acceptor_gain	1.0000
14:24337761:TT:T	acceptor_gain	1.0000
14:24337761:TTC:T	acceptor_loss	1.0000
14:24337762:TCT:T	acceptor_loss	1.0000
14:24337763:C:CC	acceptor_gain	1.0000
14:24337764:T:G	acceptor_loss	1.0000
14:24337868:CTCA:C	donor_loss	1.0000
14:24337869:TCACC:T	donor_loss	1.0000
14:24337870:CACC:C	donor_loss	1.0000
14:24337871:A:AC	donor_gain	1.0000
14:24337871:A:T	donor_loss	1.0000
14:24337871:AC:A	donor_gain	1.0000
14:24337872:C:A	donor_loss	1.0000
14:24337872:C:CC	donor_gain	1.0000
14:24337872:CC:C	donor_gain	1.0000
14:24337890:T:TA	donor_gain	1.0000
14:24337901:A:AC	donor_gain	1.0000
14:24337902:C:CC	donor_gain	1.0000
14:24338038:GCA:G	acceptor_gain	1.0000
14:24338039:CAC:C	acceptor_gain	1.0000
14:24338041:C:CC	acceptor_gain	1.0000
14:24338046:G:GC	acceptor_gain	1.0000
14:24337080:TCTCA:T	donor_loss	0.9900
14:24337081:CTCAC:C	donor_loss	0.9900
14:24337082:TCA:T	donor_loss	0.9900
14:24337083:CA:C	donor_loss	0.9900
14:24337085:C:CT	donor_loss	0.9900

AlphaMissense

3370 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:24339468:C:A	K50N	0.995
14:24339468:C:G	K50N	0.995
14:24339522:G:C	F32L	0.994
14:24339522:G:T	F32L	0.994
14:24339524:A:G	F32L	0.994
14:24338559:A:C	D160E	0.993
14:24338559:A:T	D160E	0.993
14:24339472:A:T	V49D	0.992
14:24339060:G:C	D142E	0.990
14:24339060:G:T	D142E	0.990
14:24337886:T:A	R273S	0.988
14:24337886:T:G	R273S	0.988
14:24338291:C:A	G208W	0.986
14:24339061:T:G	D142A	0.985
14:24339470:T:C	K50E	0.985
14:24339061:T:A	D142V	0.984
14:24339064:C:G	R141P	0.984
14:24338560:T:A	D160V	0.983
14:24338561:C:G	D160H	0.983
14:24339470:T:G	K50Q	0.983
14:24339043:A:T	V148D	0.981
14:24339469:T:G	K50T	0.979
14:24339475:G:T	A48E	0.978
14:24338541:A:C	F166L	0.977
14:24338541:A:T	F166L	0.977
14:24338543:A:G	F166L	0.977
14:24338560:T:G	D160A	0.977
14:24337887:C:G	R273T	0.976
14:24338556:A:C	F161L	0.976
14:24338556:A:T	F161L	0.976

dbSNP variants (sampled 300 via entrez): RS1000226345 (14:24338724 G>A,T), RS1000305647 (14:24336474 G>A), RS1000568844 (14:24337345 G>C), RS1000676766 (14:24337673 G>A), RS1001129793 (14:24336745 C>T), RS1001294847 (14:24337267 C>T), RS1001798390 (14:24340301 C>T), RS1003238832 (14:24335866 C>T), RS1003910342 (14:24338637 G>A,T), RS1005154754 (14:24338826 G>A), RS1005349262 (14:24339462 T>C), RS1005755079 (14:24335597 G>A,C), RS1005818550 (14:24341857 A>T), RS1006155702 (14:24340387 C>T), RS1007380 (14:24340468 C>A)

Disease associations

OMIM: gene MIM:605817 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary predisposition to infections	Moderate	Autosomal recessive

Mondo (1): (MONDO:0015979)

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006979_1041	Heel bone mineral density	4.000000e-15
GCST007094_10	Diastolic blood pressure	3.000000e-09
GCST90002383_253	Hematocrit	2.000000e-09
GCST90002384_332	Hemoglobin	5.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0006336	diastolic blood pressure
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1795199 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

41 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 378,089 (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
CHEMBL1229517	VEMURAFENIB	4	15,704
CHEMBL1289494	TIVOZANIB	4	4,455
CHEMBL1289601	LENVATINIB	4	8,784
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
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL3301612	ENCORAFENIB	4	4,624
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL3348923	TOVORAFENIB	4	834
CHEMBL3989868	TUCATINIB	4	3,159
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL939	GEFITINIB	4	117,814
CHEMBL1091644	LINSITINIB	3	1,446
CHEMBL217092	SARACATINIB	3
CHEMBL3186534	RIVOCERANIB	3
CHEMBL31965	CANERTINIB	3
CHEMBL3544983	TESEVATINIB	3
CHEMBL3545154	POZIOTINIB	3
CHEMBL572881	MOTESANIB	3
CHEMBL1230165	SILMITASERTIB	2
CHEMBL1230609	FORETINIB	2
CHEMBL1738757	REBASTINIB	2
CHEMBL2029988	CEP-32496	2

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 (8 total), top 8:

Ligand	Action	Affinity	Parameter
ponatinib	Inhibition	8.8	pKi
RIPK3 inhibitor 18	Inhibition	8.04	pIC50
SZM594	Inhibition	7.11	pKd
RIPK3 inhibitor 42	Inhibition	7.09	pKd
TAK-632	Inhibition	6.98	pKd
WJH-C19	Inhibition	6.0	pIC50
SZM679	Inhibition	5.3	pKd
RIPK1 inhibitor 22b	Inhibition	5.14	pKd

Binding affinities (BindingDB)

130 measured of 180 human assays (180 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-Fluoro-2-((4-oxo-2-(pyridin-4-yl)-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzonitrile	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
5-fluoro-2-[[3-(4-fluorophenyl)-2-(3-methoxy-4-pyridinyl)-4-oxo-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]benzonitrile	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
5-fluoro-2-[[3-(4-fluorophenyl)-2-(2-methyl-4-pyridinyl)-4-oxo-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]benzonitrile	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
4-[[3-(4-fluorophenyl)-4-oxo-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]benzonitrile	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
3-(4-fluorophenyl)-1-phenyl-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
3-(4-fluorophenyl)-2-pyridin-4-yl-1-[[4-(trifluoromethyl)phenyl]methyl]-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
2-fluoro-4-[[3-(4-fluorophenyl)-4-oxo-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]benzonitrile	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
3-(4-fluorophenyl)-1-[(4-methylphenyl)methyl]-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
1-[(4-cyclopropylphenyl)methyl]-3-(4-fluorophenyl)-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
6-[[3-(4-fluorophenyl)-4-oxo-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]pyridine-3-carbonitrile	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
3-(4-fluorophenyl)-1-pentyl-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
3-(4-fluorophenyl)-1-(2-methylpropyl)-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
3-(4-fluorophenyl)-1-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
3-(4-fluorophenyl)-1-[[2-methoxy-4-(trifluoromethyl)phenyl]methyl]-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
3-(4-fluorophenyl)-1-(3-hydroxypropyl)-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
3-(4-fluorophenyl)-1-(2-oxo-2-pyrrolidin-1-ylethyl)-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
3-(4-fluorophenyl)-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
3-(4-fluorophenyl)-1-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
N-[4-[3-(4-fluorophenyl)-1-(oxan-4-ylmethyl)-4-oxo-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-2-yl]-2-pyridinyl]cyclopropanecarboxamide	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
ethyl N-[4-[3-(4-fluorophenyl)-1-(oxan-4-ylmethyl)-4-oxo-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-2-yl]-2-pyridinyl]carbamate	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
N-[4-[1-[(3-cyano-4-fluorophenyl)methyl]-3-(4-fluorophenyl)-4-oxo-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-2-yl]-2-pyridinyl]acetamide	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
5-fluoro-2-[[4-oxo-2-pyridin-4-yl-3-[3-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]benzonitrile	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
5-fluoro-2-[[3-(3-fluoro-5-methoxyphenyl)-4-oxo-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]benzonitrile	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
5-fluoro-2-[[3-(1-methylindol-5-yl)-4-oxo-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]benzonitrile	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
5-fluoro-2-[(4-oxo-3-pyridin-3-yl-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl)methyl]benzonitrile	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
5-fluoro-2-[[3-(4-methoxyphenyl)-4-oxo-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]benzonitrile	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
2-[[3-(2,3-dichlorophenyl)-4-oxo-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]-5-fluorobenzonitrile	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
2-[[3-(3-cyanophenyl)-4-oxo-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]-5-fluorobenzonitrile	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
5-fluoro-2-[[4-oxo-3-[(E)-2-phenylethenyl]-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]benzonitrile	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
3-(4-fluorophenyl)-1-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-[2-(2-hydroxyethylamino)-4-pyridinyl]-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
N-[4-[3-(4-fluorophenyl)-1-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-4-oxo-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-2-yl]-2-pyridinyl]propanamide	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
N-[4-[3-(4-fluorophenyl)-1-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-4-oxo-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-2-yl]-2-pyridinyl]-2-methoxyacetamide	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
tert-butyl N-[4-[1-[(2-cyano-4-fluorophenyl)methyl]-3-(4-fluorophenyl)-4-oxo-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-2-yl]-2-pyridinyl]carbamate	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
tert-butyl N-[3-[1-[(4-chloro-2-fluorophenyl)methyl]-4-oxo-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-3-yl]phenyl]carbamate	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
tert-butyl N-[3-[1-[(2,5-dimethylpyrazol-3-yl)methyl]-4-oxo-2-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-3-yl]phenyl]carbamate	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
1-[(2,5-dimethylpyrazol-3-yl)methyl]-3-(4-fluorophenyl)-2-(3-fluoro-4-pyridinyl)-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	65 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
5-Fluoro-2-((3-(4-fluorophenyl)-2-(3-methyl-1H-pyrazol-4-yl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzonitrile	IC50	7550 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
N-(4-(3-(4-Fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)pyridin-2-yl)acetamide	IC50	7550 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
3-([1,1′-Biphenyl]-3-yl)-2-(pyridin-4-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one	IC50	7550 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
2-(2-Chloropyridin-4-yl)-1-(2-fluoro-4-(trifluoromethyl)benzyl)-3-(4-fluorophenyl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one	IC50	7550 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
N-(4-(1-(2-Fluoro-4-(trifluoromethyl)benzyl)-3-(4-fluorophenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)pyridin-2-yl)isobutyramide	IC50	7550 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
3-(4-fluorophenyl)-1-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-[2-(methylamino)-4-pyridinyl]-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-4-one	IC50	7550 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
2-((2-(2-Chloropyridin-4-yl)-4-oxo-3-(pyridin-3-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)-5-fluorobenzonitrile	IC50	7550 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
2-(2-Aminopyridin-4-yl)-1-(2-fluoro-4-(trifluoromethyl)benzyl)-3-(4-fluorophenyl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one	IC50	7550 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
5-fluoro-2-[[3-(4-fluorophenyl)-4-oxo-2-[2-(trifluoromethyl)-4-pyridinyl]-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]benzonitrile	IC50	7550 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
5-fluoro-2-[[3-(4-fluorophenyl)-4-oxo-2-pyrimidin-5-yl-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]benzonitrile	IC50	7550 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
5-fluoro-2-[[3-(4-fluorophenyl)-2-(2-fluoro-4-pyridinyl)-4-oxo-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]benzonitrile	IC50	7550 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
5-fluoro-2-[[3-(4-fluorophenyl)-2-(1H-indol-5-yl)-4-oxo-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]benzonitrile	IC50	7550 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
N-[3-[1-[(2-cyano-4-fluorophenyl)methyl]-3-(4-fluorophenyl)-4-oxo-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-2-yl]phenyl]acetamide	IC50	7550 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors
2-[[2-(2-chloro-4-pyridinyl)-3-(4-fluorophenyl)-4-oxo-6,7-dihydro-5H-pyrrolo[3,2-c]pyridin-1-yl]methyl]-5-fluorobenzonitrile	IC50	7550 nM	US-10301306: Substituted dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones as RIPK3 inhibitors

ChEMBL bioactivities

338 potent at pChembl≥5 of 339 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.52	IC50	0.3	nM	CHEMBL4470115
9.52	IC50	0.3	nM	CHEMBL4439913
9.05	IC50	0.9	nM	CHEMBL4439913
9.00	IC50	1	nM	CHEMBL4779280
8.89	IC50	1.3	nM	CHEMBL4779280
8.87	Kd	1.35	nM	CHEMBL5407694
8.80	IC50	1.6	nM	PONATINIB
8.74	IC50	1.8	nM	CHEMBL4779280
8.70	IC50	2	nM	DABRAFENIB
8.54	IC50	2.9	nM	CHEMBL4455682
8.52	Kd	3	nM	CHEMBL400402
8.19	IC50	6.5	nM	CHEMBL4441118
8.14	Kd	7.2	nM	CHEMBL4861646
8.10	IC50	8	nM	CHEMBL4476485
8.07	IC50	8.6	nM	CHEMBL4441118
8.00	IC50	10	nM	CHEMBL4779280
7.96	Kd	11	nM	GALUNISERTIB
7.85	IC50	14	nM	CHEMBL5629959
7.80	IC50	16	nM	CHEMBL3823499
7.80	IC50	16	nM	CHEMBL4552106
7.75	IC50	18	nM	CHEMBL6161247
7.73	IC50	18.6	nM	REBASTINIB
7.73	Kd	18.7	nM	CHEMBL6161247
7.72	IC50	18.9	nM	CHEMBL1214141
7.70	IC50	20	nM	CHEMBL5632140
7.68	EC50	20.8	nM	CHEMBL4091441
7.64	Kd	23	nM	PONATINIB
7.48	Kd	33	nM	CHEMBL4444744
7.37	Kd	43	nM	CHEMBL5267954
7.30	IC50	50	nM	CHEMBL4438939
7.28	Kd	53	nM	CHEMBL4548552
7.26	Kd	55	nM	CHEMBL4464579
7.19	IC50	65	nM	CHEMBL5792737
7.19	IC50	65	nM	CHEMBL5843208
7.19	IC50	65	nM	CHEMBL5799635
7.19	IC50	65	nM	CHEMBL5798411
7.19	IC50	65	nM	CHEMBL6006513
7.19	IC50	65	nM	CHEMBL6026147
7.19	IC50	65	nM	CHEMBL5908356
7.19	IC50	65	nM	CHEMBL5785851
7.19	IC50	65	nM	CHEMBL5819773
7.19	IC50	65	nM	CHEMBL5747589
7.19	IC50	65	nM	CHEMBL5847818
7.19	IC50	65	nM	CHEMBL5972371
7.19	IC50	65	nM	CHEMBL5931678
7.19	IC50	65	nM	CHEMBL5892428
7.19	IC50	65	nM	CHEMBL6052801
7.19	IC50	65	nM	CHEMBL5964036
7.19	IC50	65	nM	CHEMBL5846294
7.19	IC50	65	nM	CHEMBL5832516

PubChem BioAssay actives

165 with measured affinity, of 610 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
tert-butyl 2-[4-[5-(methylcarbamoyl)benzimidazol-1-yl]phenyl]acetate	1625395: Inhibition of human recombinant RIP3 (2 to 328 residues) expressed in baculovirus by ADP-glo assay	ic50	0.0003	uM
N-[4-[[2-amino-3-[2-(5-amino-2-pyridinyl)ethynyl]-4-pyridinyl]oxy]-3-fluorophenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide	1547490: Displacement of fluorescein labeled probe from full length human GST-tagged RIPK3 expressed in Sf9 cells incubated for 60 mins by HTRF assay	ic50	0.0003	uM
N-(6-propan-2-ylsulfonylquinolin-4-yl)-1,3-benzothiazol-5-amine	1987001: Inhibition of recombinant human RIPK3 (2-328) residues expressed in baculovirus by ADP-glo assay	ic50	0.0013	uM
N-(1,3-benzothiazol-5-yl)-3-cyclopropyl-1,1-dioxothieno[2,3-g]quinolin-8-amine;hydrochloride	1987002: Binding affinity to human RIPK3 assessed as dissociation constant	kd	0.0014	uM
Ponatinib	1580374: Inhibition of recombinant GST-tagged RIPK3 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 4 hrs by ADP-Glo assay	ic50	0.0016	uM
Dabrafenib	1580391: Inhibition of human RIPK3 using MBP as substrate by [gamma33-ATP] based radiometric assay	ic50	0.0020	uM
N-[4-[[2-(cyclopropanecarbonylamino)-4-pyridinyl]oxy]-3-fluorophenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide	1547493: Displacement of fluorescein labeled ATP probe from full length His/GST-tagged RIPK3 (unknown origin) incubated for 60 mins by HTRF assay	ic50	0.0029	uM
4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol	1425156: 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	0.0030	uM
3-(1,3-benzothiazol-5-yl)-7-(2,5-dimethylpyrazol-3-yl)thieno[3,2-c]pyridin-4-amine	1987001: Inhibition of recombinant human RIPK3 (2-328) residues expressed in baculovirus by ADP-glo assay	ic50	0.0065	uM
N-(1,3-benzothiazol-5-yl)-1’,1’-dioxospiro[1,3-dioxolane-2,3’-2H-thieno[2,3-g]quinoline]-8’-amine	1758199: Binding affinity to human wild type RIPK3 (M1/Q307) expressed in bacterial expression system by Kinomescan method	kd	0.0072	uM
N-[4-[[2-(cyclopropanecarbonylamino)-4-pyridinyl]oxy]-3-methylphenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide	1547493: Displacement of fluorescein labeled ATP probe from full length His/GST-tagged RIPK3 (unknown origin) incubated for 60 mins by HTRF assay	ic50	0.0080	uM
4-[2-(6-methyl-2-pyridinyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline-6-carboxamide	1425156: 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	0.0110	uM
N-(6-ethenylpyrido[3,4-d]pyrimidin-4-yl)-1,3-benzothiazol-5-amine	2136767: Inhibition of human recombinant RIPK3 using MBP as substrate preincubated for 15 mins followed by substrate addition and measured after 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0140	uM
N-[4-[(2-amino-3-prop-1-ynyl-4-pyridinyl)oxy]-3-fluorophenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide	1547493: Displacement of fluorescein labeled ATP probe from full length His/GST-tagged RIPK3 (unknown origin) incubated for 60 mins by HTRF assay	ic50	0.0160	uM
6-tert-butylsulfonyl-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine	1309973: Inhibition of RIPK3 (unknown origin) 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	0.0160	uM
4-[4-[(3-tert-butyl-1-quinolin-6-ylpyrazol-5-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	2067422: Inhibition of recombinant RIPK3 (unknown origin) by ADP-Glo assay	ic50	0.0186	uM
N-[4-methyl-3-[1-methyl-7-[(6-methyl-3-pyridinyl)amino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]phenyl]-3-(trifluoromethyl)benzamide	2067424: Inhibition of RIPK3 (unknown origin)	ic50	0.0189	uM
N-[6-[(E)-2-(4-chlorophenyl)ethenyl]pyrido[3,4-d]pyrimidin-4-yl]-1,3-benzothiazol-5-amine	2136767: Inhibition of human recombinant RIPK3 using MBP as substrate preincubated for 15 mins followed by substrate addition and measured after 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0200	uM
4-(4-methylphenoxy)-7-(1-piperidin-4-ylpyrazol-4-yl)quinoline	1987019: Inhibition of human RIPK3 using MBP as substrate by [gamma33-ATP] based radiometric assay	ec50	0.0208	uM
N-[6-[4-fluoro-3-[[2-(3-methylphenyl)acetyl]amino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.0330	uM
N-(1,3-benzothiazol-5-yl)-8-ethoxy-6,6-dioxothieno[2,3-g]quinazolin-4-amine	1921744: Binding affinity to RIPK3 (unknown origin) assessed as dissociation constant by kinomescan assay	kd	0.0430	uM
1-(4-fluorophenyl)-2-oxo-N-(4-pyridin-4-yloxynaphthalen-1-yl)pyridine-3-carboxamide	1547493: Displacement of fluorescein labeled ATP probe from full length His/GST-tagged RIPK3 (unknown origin) incubated for 60 mins by HTRF assay	ic50	0.0500	uM
N-[6-[3-[(3-acetylphenyl)carbamoylamino]-4-fluorophenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.0530	uM
N-[6-[4-fluoro-3-[[2-(3-methoxyphenyl)acetyl]amino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.0550	uM
N-[6-[4-fluoro-3-[(3-methoxyphenyl)carbamoylamino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.0690	uM
N-[6-[3-[[2-(3,4-dimethylphenyl)acetyl]amino]-4-fluorophenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.0720	uM
ethyl 3-[[5-[[2-(cyclopropanecarbonylamino)-1,3-benzothiazol-6-yl]oxy]-2-fluorophenyl]carbamoylamino]benzoate	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.0720	uM
4-methyl-3-[(7-pyridin-2-ylquinolin-4-yl)amino]phenol	1987022: Inhibition of RIPK3 (unknown origin) expressed in NIH3T3 cells assessed as inhibition of dimerizer-induced pMLKL level by Western blot analysis	ec50	0.0736	uM
7-(4-aminocyclohexyl)-5-(2-fluoro-4-methylphenyl)pyrrolo[2,3-d]pyrimidin-4-amine	1880920: Binding affinity to human RIPK3 in human Jurkat cells	kd	0.0745	uM
6-[(E)-2-(4-chlorophenyl)ethenyl]-N-(6-methyl-3-pyridinyl)pyrido[3,4-d]pyrimidin-4-amine	2136767: Inhibition of human recombinant RIPK3 using MBP as substrate preincubated for 15 mins followed by substrate addition and measured after 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0760	uM
N-[6-[4-fluoro-3-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.0770	uM
N-[6-fluoro-5-[4-fluoro-3-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1848493: Binding affinity to recombinant human wild type partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system by KINOMEscan TM assay	kd	0.0770	uM
N-[6-[3-[[2-(3-bromophenyl)acetyl]amino]-4-fluorophenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1896650: Binding affinity to RIPK3 (unknown origin) by Kinomescan method	kd	0.0800	uM
N-[6-[3-[(3-bromophenyl)carbamoylamino]-4-fluorophenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.0810	uM
N-[6-[3-[[2-(1,3-benzodioxol-5-yl)acetyl]amino]-4-fluorophenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.0810	uM
Ibrutinib	1425156: 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	0.0850	uM
N-[4-[[2-(cyclopropanecarbonylamino)-4-pyridinyl]oxy]-3,5-dimethylphenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide	1547493: Displacement of fluorescein labeled ATP probe from full length His/GST-tagged RIPK3 (unknown origin) incubated for 60 mins by HTRF assay	ic50	0.0880	uM
4-N-[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]-6-N-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]quinazoline-4,6-diamine	1425156: 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	0.0880	uM
N-[7-cyano-6-[4-fluoro-3-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1987019: Inhibition of human RIPK3 using MBP as substrate by [gamma33-ATP] based radiometric assay	ic50	0.0900	uM
5-[(7-chloro-1H-indol-3-yl)methyl]-3-[4-[3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylphenyl]butyl]imidazolidine-2,4-dione	2067434: Inhibition of human recombinant RIPK3 incubated for 1 hr by ADP-Glo kinase assay	ic50	0.0900	uM
N-[4-[[2-(cyclopropanecarbonylamino)-4-pyridinyl]oxy]-2,3-dimethylphenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide	1547493: Displacement of fluorescein labeled ATP probe from full length His/GST-tagged RIPK3 (unknown origin) incubated for 60 mins by HTRF assay	ic50	0.0910	uM
N-[6-[4-fluoro-3-[(3-methylphenyl)carbamoylamino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.0930	uM
N-[6-[4-fluoro-3-[[2-[2-fluoro-3-(trifluoromethyl)phenyl]acetyl]amino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.0990	uM
N-[6-[4-fluoro-3-[[2-(3-nitrophenyl)acetyl]amino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.1100	uM
[5-[4-(1,3-benzothiazol-5-ylamino)-6-thiophen-2-ylquinazolin-7-yl]furan-2-yl]methanol	2138418: Inhibition of N-terminal polyHis-tagged human RIPK3 (1 to 307 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	0.1170	uM
N-[6-[4-fluoro-3-[[2-[3-(trifluoromethoxy)phenyl]acetyl]amino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.1200	uM
N-[6-[3-[[2-(3-cyanophenyl)acetyl]amino]-4-fluorophenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.1200	uM
N-[6-fluoro-5-[4-fluoro-3-[[2-[3-(trifluoromethoxy)phenyl]acetyl]amino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1848493: Binding affinity to recombinant human wild type partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system by KINOMEscan TM assay	kd	0.1200	uM
[3-[4-(1,3-benzothiazol-5-ylamino)-6-(3-methylthiophen-2-yl)quinazolin-7-yl]phenyl]methanol	2138418: Inhibition of N-terminal polyHis-tagged human RIPK3 (1 to 307 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	0.1220	uM
N-[6-[4-fluoro-3-[[2-[4-fluoro-3-(trifluoromethyl)phenyl]acetyl]amino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide	1607636: Binding affinity to wild-type human partial length RIPK3 (M1 to Q307 residues) expressed in bacterial expression system after 1 hr by quantitative PCR based KINOMEscan assay	kd	0.1300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
necrostatin-1	affects binding, affects cotreatment, affects reaction, decreases reaction, increases expression (+2 more)	5
bisphenol A	affects cotreatment, increases methylation, decreases reaction, increases expression, increases reaction	3
Ethanol	affects binding, increases reaction, increases expression, decreases reaction, affects reaction (+2 more)	3
Cadmium	affects cotreatment, increases phosphorylation, decreases reaction, affects binding, increases abundance (+2 more)	3
GSK872	decreases reaction, increases expression, affects cotreatment	2
benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone	affects cotreatment, increases expression, increases phosphorylation, affects binding, increases reaction	2
SM 164	affects cotreatment, increases expression, increases phosphorylation	2
Acetaminophen	increases expression	2
Acetylcysteine	increases expression, increases reaction, decreases reaction	2
Arsenic	affects methylation, increases methylation	2
Cadmium Chloride	increases expression, decreases reaction, affects binding, increases abundance, increases reaction	2
tetrachlorobenzoquinone	increases expression	1
GSK-J4	decreases expression	1
CBLC137	increases expression, increases phosphorylation	1
NMS-873	decreases reaction, increases abundance, increases expression	1
apabetalone	affects cotreatment, increases phosphorylation	1
ABBV-744	affects cotreatment, increases phosphorylation	1
dihydrotanshinone I	increases phosphorylation, decreases reaction	1
3-monochloropropane-1, 2 diol ester	increases expression, decreases reaction	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
acacetin	increases expression	1
palmitoyl glycerol	decreases expression	1
pyranoprofen	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
pterostilbene	decreases reaction, increases expression, affects binding, increases reaction, decreases activity (+1 more)	1
CA 074 methyl ester	decreases reaction, increases expression	1

ChEMBL screening assays

141 unique, capped per target: 138 binding, 2 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1221007	Binding	Inhibition of human RIP3 autophosphorylation expressed in HEK293T cells	Identification of RIP1 kinase as a specific cellular target of necrostatins. — Nat Chem Biol
CHEMBL4814495	ADMET	Inhibition of recombinant human RIPK3 expressed in baculovirus infected Sf9 cells using MBP as substrate in presence of ATP measured after 30 mins by ADP-Glo assay	In vitro identification of imidazo[1,2-a]pyrazine-based antileishmanial agents and evaluation of L. major casein kinase 1 inhibition. — Eur J Med Chem
CHEMBL5209922	Functional	Affinity Phenotypic Cellular interaction (Cell Titer-Glo Luminescent Cell Viability Assay (Promega; inhibition of TNF-induced necroptosis in Human HT-29 cells)) EUB0000632a RIPK3	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomics Library wave 3

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_D9QL	Ubigene HEK293 RIPK3 KO	Transformed cell line	Female
CVCL_E2JD	HAP1 RIPK3 (-) 2	Cancer cell line	Male
CVCL_E2JE	HAP1 RIPK3 (-) 3	Cancer cell line	Male
CVCL_XS27	HAP1 RIPK3 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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