MLKL

Summary

MLKL (mixed lineage kinase domain like pseudokinase, HGNC:26617) is a protein-coding gene on chromosome 16q23.1, encoding Mixed lineage kinase domain-like protein (Q8NB16). Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process.

This gene belongs to the protein kinase superfamily. The encoded protein contains a protein kinase-like domain; however, is thought to be inactive because it lacks several residues required for activity. This protein plays a critical role in tumor necrosis factor (TNF)-induced necroptosis, a programmed cell death process, via interaction with receptor-interacting protein 3 (RIP3), which is a key signaling molecule in necroptosis pathway. Inhibitor studies and knockdown of this gene inhibited TNF-induced necrosis. High levels of this protein and RIP3 are associated with inflammatory bowel disease in children. Alternatively spliced transcript variants have been described for this gene.

Source: NCBI Gene 197259 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 105 total
• Phenotypes (HPO): 1
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_152649

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26617
Approved symbol	MLKL
Name	mixed lineage kinase domain like pseudokinase
Location	16q23.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ34389
Ensembl gene	ENSG00000168404
Ensembl biotype	protein_coding
OMIM	615153
Entrez	197259

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000306247, ENST00000308807, ENST00000570846, ENST00000571303, ENST00000573267, ENST00000575686, ENST00000575695, ENST00000576529, ENST00000862152, ENST00000862153, ENST00000862154, ENST00000862155, ENST00000925881, ENST00000963639

RefSeq mRNA: 2 — MANE Select: NM_152649 NM_001142497, NM_152649

CCDS: CCDS32487, CCDS45528

Canonical transcript exons

ENST00000308807 — 11 exons

Exon	Start	End
ENSE00001176156	74678899	74678980
ENSE00001176162	74682651	74682786
ENSE00001204439	74675355	74675404
ENSE00001204441	74692342	74692416
ENSE00001204469	74685486	74685583
ENSE00001204481	74695298	74695759
ENSE00001274632	74691277	74691463
ENSE00001274653	74675613	74675764
ENSE00001515380	74700453	74700862
ENSE00002659957	74671855	74672538
ENSE00003553433	74674960	74675100

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 95.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.3517 / max 190.1758, expressed in 1344 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158119	3.2015	1004
158118	2.1171	595
158124	1.5981	676
158123	0.1560	76
158122	0.1398	53
158121	0.0835	39
158120	0.0557	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	95.99	gold quality
monocyte	CL:0000576	95.92	gold quality
leukocyte	CL:0000738	95.58	gold quality
blood	UBERON:0000178	94.41	gold quality
spleen	UBERON:0002106	93.97	gold quality
upper lobe of left lung	UBERON:0008952	91.36	gold quality
vermiform appendix	UBERON:0001154	91.25	gold quality
omental fat pad	UBERON:0010414	90.97	gold quality
peritoneum	UBERON:0002358	90.91	gold quality
left ventricle myocardium	UBERON:0006566	90.89	silver quality
upper lobe of lung	UBERON:0008948	90.84	gold quality
right lung	UBERON:0002167	90.68	gold quality
epithelial cell of pancreas	CL:0000083	90.55	gold quality
ileal mucosa	UBERON:0000331	90.37	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.36	gold quality
bone marrow	UBERON:0002371	89.80	gold quality
lower esophagus mucosa	UBERON:0035834	89.33	gold quality
bone marrow cell	CL:0002092	89.06	gold quality
trabecular bone tissue	UBERON:0002483	89.03	gold quality
caecum	UBERON:0001153	88.80	gold quality
parotid gland	UBERON:0001831	87.84	gold quality
esophagus mucosa	UBERON:0002469	87.82	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.69	gold quality
lymph node	UBERON:0000029	87.56	gold quality
subcutaneous adipose tissue	UBERON:0002190	87.41	gold quality
lung	UBERON:0002048	87.24	gold quality
sural nerve	UBERON:0015488	87.19	gold quality
gall bladder	UBERON:0002110	86.76	gold quality
mucosa of transverse colon	UBERON:0004991	86.71	gold quality
rectum	UBERON:0001052	86.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting MLKL, 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-4481	100.00	66.42	1669
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-6878-3P	99.24	64.23	920
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-1295B-5P	99.03	67.50	810
HSA-MIR-194-5P	99.01	69.65	1465
HSA-MIR-4712-3P	98.52	65.39	822
HSA-MIR-4709-5P	98.51	67.25	1335
HSA-MIR-4317	98.49	67.09	987
HSA-MIR-92A-1-5P	98.28	64.51	631
HSA-MIR-10226	98.25	66.50	811
HSA-MIR-1912-5P	97.94	67.98	832
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-6818-5P	97.50	67.10	1167
HSA-MIR-3201	97.16	65.42	1044
HSA-MIR-1587	96.95	64.03	932
HSA-MIR-4791	96.51	67.76	659

Literature-anchored findings (GeneRIF, showing 40)

• Findings implicate MLKL as a key mediator of necrosis signaling downstream of the kinase RIP3. (PMID:22265413)
• study suggests that MLKL is a key RIP3 downstream component of TNF-induced necrotic cell death (PMID:22421439)
• 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)
• Low expression of MLKL is associated with decreased OS in patients with resected PAC and decreased RFS and OS in the subset of patients with resected PAC who receive adjuvant chemotherapy. (PMID:23720157)
• Data suggest that nucleotide- (ATP-) binding residues of human MLKL have divergently evolved from mouse Mlkl and conventional protein kinases; studies include small-angle X-ray scattering, thermal shift of nucleotide binding, and sequence alignment. (PMID:24219132)
• This study reveals a crucial mechanism of MLKL-mediated TNF-induced necroptosis. (PMID:24316671)
• MLKL protein expression is significantly upregulated in children, diagnosed with inflammatory bowel disease. (PMID:24322838)
• Report role of MLKL/RIP3 pathway in necrotic membrane disruption. (PMID:24703947)
• Authors demonstrate that the full four-helical bundle domain (4HBD) in the N-terminal region of MLKL is required and sufficient to induce its oligomerization and trigger cell death. (PMID:24813885)
• MLKL binding to phosphatidylinositol phosphates is required for plasma membrane rupture (PMID:24813885)
• MLKL structure determined by nuclear magnetic resonance spectroscopy reveals how different structural elements of the MLKL N-terminal region contribute to MLKL function and membrane permeation. (PMID:25220470)
• in the absence of caspase-8 activity, 24(S)-Hydroxycholesterol induces a necroptosis-like cell death which is RIPK1-dependent but MLKL-independent. (PMID:25697054)
• High expression of RIP3 in keratinocytes from toxic epidermal necrolysis patients potentiates MLKL phosphorylation/activation and necrotic cell death. (PMID:25748555)
• a novel non-enzymatic function of AChE-R is to stimulate RIPK1/MLKL-dependent regulated necrosis (necroptosis). The latter complements a cholinergic system in the ovary, which determines life and death of ovarian cells. (PMID:25766324)
• MLKL upregulation in SPARC overexpressed cells treated with Ara-C, indicates necrosis as a possible cell death process for the SKM-1 cells under these stringent conditions (PMID:26165695)
• These data reveal a potential role for RIPK3 as a suppressor of MLKL activation and indicate that phosphorylation can fine-tune the ability of MLKL to induce necroptosis. (PMID:26283547)
• Modelling predicts that a C-terminal helix constrains the activity of MLKL1, but not MLKL2 (PMID:26704887)
• MLKL was a prognostic biomarker for cervical squamous cell carcinoma (PMID:26823841)
• Results show that upon activation, MLKL undergoes oligomerization mediated by the brace domain, being recruited to the plasma membrane through avidity of N-terminal helix bundle for phosphatidylinositol phosphate (PIP). (PMID:26853145)
• Necroptosis signaling is modulated by the kinase RIPK1 and requires the kinase RIPK3 and the pseudokinase MLKL. (Review) (PMID:26865533)
• coexpression of Hsp90 increases MLKL oligomerization and plasma membrane translocation and enhances MLKL-mediated necroptosis. Findings demonstrate that an efficient necrotic response requires a functional Hsp90. (PMID:26866270)
• Phosphorylated MLKL leads to a conformational change, exposure of the N-terminal domain, results in MLKL membrane localization, oligomerization and membrane permeabilization. (PMID:26868910)
• Results from interaction proteomics identified MLKL as a novel HSP90 client protein in HT-29 cells. (PMID:26933192)
• MLKL forms cation channels that are permeable preferentially to Mg(2+) rather than Ca(2+) in the presence of Na(+) and K(+). (PMID:27033670)
• In AML, MLKL expression is reduced in specific subsets. This is linked to its function in activating the ASC inflammasome. (PMID:27411587)
• Low expression of mixed lineage kinase domain-like protein was associated with decreased overall survival in all patient-group with resected colon cancer. (PMID:27432118)
• Downregulated expression of MLKL is associated with gastric caner. (PMID:27473085)
• results reveal a pathway for MLKL-dependent programmed necrosis that is executed in the absence of RIPK3 and potentially drives the pathogenesis of severe liver diseases. (PMID:27756058)
• MLKL octamer formation depends on alpha-helices 4 and 5. (PMID:27920255)
• this study shows that MLKL is an endogenous activator of the NLRP3 inflammasome, and that MLKL activation provides a mechanism for concurrent processing and release of IL-1beta independently of gasdermin-D (PMID:28130493)
• adhesion-induced eosinophil cytolysis takes place through RIPK3-MLKL-dependent necroptosis, which can be counterregulated by autophagy (PMID:28412393)
• Data suggest that necroptotic cells externalize phosphatidylserine (PS) after translocation of phosphorylated MLKL to cell membrane; necroptotic cells with exposed PS release extracellular vesicles containing MLKL; inhibition of MLKL after PS exposure can reverse process of necroptosis and restore cell viability. (PMID:28650960)
• this study shows that release of phosphorylated MLKL within extracellular vesicles serves as a mechanism for self-restricting the necroptotic activity of this protein (PMID:28666573)
• Thus, activation of MLKL determines cell lysis with release of proinflammatory mediators. We found that pMLKL, the activated form of MLKL, is significantly increased in intestinal epithelial cells expressing RIP3 as well as in bioptic inflamed ileal and colonic tissues from CD and UC patients. (PMID:28844856)
• Biological events and molecular signaling following MLKL activation during necroptosis have been reported. (PMID:28854080)
• these findings demonstrate that Trx1 is a critical regulator of necroptosis that suppresses cell death by maintaining MLKL in a reduced inactive state. (PMID:28878015)
• Data show that phosphatidylinositol transfer protein alpha (PITPalpha) is involved in the function of mixed lineage kinase domain-like protein (MLKL) in necroptosis. (PMID:29104146)
• Results demonstrate that MLKL concentrations measured after three days of ICU treatment in critically ill patients predict prognosis during intensive care unit treatment. These data not only suggest a previously unrecognized function of MLKL as a biomarker in critical illness and sepsis but also highlight the clinical relevance of MLKL in the pathophysiology of inflammatory and infectious diseases. (PMID:29606984)
• MLKL expression alters APP metabolism and loss-of-function mutation might contribute to late-onset ApoE varepsilon4-negative AD in the Hong Kong Chinese population. (PMID:29656768)
• Highly phosphorylated inositol phosphates are an additional, crucial requirement for MLKL death effector function acting directly on MLKL to execute necroptosis. (PMID:29883610)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Mlkl	ENSMUSG00000012519
rattus_norvegicus	Mlkl	ENSRNOG00000042353

Paralogs (23): MAP3K9 (ENSG00000006432), TESK2 (ENSG00000070759), MAP3K13 (ENSG00000073803), ARAF (ENSG00000078061), MAP3K20 (ENSG00000091436), RIPK2 (ENSG00000104312), LIMK1 (ENSG00000106683), TESK1 (ENSG00000107140), TNNI3K (ENSG00000116783), RIPK3 (ENSG00000129465), MAP3K10 (ENSG00000130758), RAF1 (ENSG00000132155), RIPK1 (ENSG00000137275), MAP3K12 (ENSG00000139625), KSR1 (ENSG00000141068), MAP3K21 (ENSG00000143674), BRAF (ENSG00000157764), ILK (ENSG00000166333), KSR2 (ENSG00000171435), MOS (ENSG00000172680), MAP3K11 (ENSG00000173327), LIMK2 (ENSG00000182541), LRRK2 (ENSG00000188906)

Protein

Protein identifiers

Mixed lineage kinase domain-like protein — Q8NB16 (reviewed: Q8NB16)

All UniProt accessions (5): Q8NB16, I3L2T9, I3L2U3, I3L4A6, I3L4Z5

UniProt curated annotations — full annotation on UniProt →

Function. Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process. Does not have protein kinase activity. Activated following phosphorylation by RIPK3, leading to homotrimerization, 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 activation by ZBP1, MLKL is phosphorylated by RIPK3 in the nucleus, triggering disruption of the nuclear envelope and leakage of cellular DNA into the cytosol.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. Binds to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which is essential for its necroptotic function.

Subunit / interactions. Homooligomer. Homotrimer; forms homotrimers on necroptosis induction. Upon TNF-induced necrosis, forms in complex with PGAM5, RIPK1 and RIPK3. Within this complex, may play a role in the proper targeting of RIPK1-RIPK3 to its downstream effector PGAM5. Interacts with RIPK3; the interaction is direct and promotes its phosphorylation and subsequent activation.

Subcellular location. Cytoplasm. Cell membrane. Nucleus.

Post-translational modifications. Phosphorylation by RIPK3 induces a conformational switch that is required for necroptosis. It also induces homotrimerization and localization to the plasma membrane.

Activity regulation. Activated via binding to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which mediates the release of an N-terminal auto-inhibitory region. Activation requires not only RIPK3-dependent phosphorylation but also binding to highly phosphorylated inositol phosphates. Inhibited by necrosulfonamide, a specific inhibitor of necroptosis that targets Cys-86.

Domain organisation. The protein kinase domain is catalytically inactive but contains an unusual pseudoactive site with an interaction between Lys-230 and Gln-356 residues. Upon phosphorylation by RIPK3, undergoes an active conformation. The coiled coil region 2 is responsible for homotrimerization.

Miscellaneous. Interaction with RIPK3 is species specific: human MLKL only interacts with human RIPK3 and not mouse RIPK3.

Similarity. Belongs to the protein kinase superfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NB16-1	1	yes
Q8NB16-2	2

RefSeq proteins (2): NP_001135969, NP_689862* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR036537	Adaptor_Cbl_N_dom_sf	Homologous_superfamily
IPR051681	Ser/Thr_Kinases-Pseudokinases	Family
IPR054000	MLKL_N	Domain
IPR059179	MLKL-like_MCAfunc	Domain

Pfam: PF07714, PF22215

UniProt features (70 total): helix 19, strand 14, mutagenesis site 11, sequence variant 9, modified residue 4, turn 3, splice variant 2, coiled-coil region 2, binding site 2, chain 1, domain 1, region of interest 1, site 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
6ZVO	X-RAY DIFFRACTION	1.37
6ZZ1	X-RAY DIFFRACTION	1.64
4MWI	X-RAY DIFFRACTION	1.7
4M67	X-RAY DIFFRACTION	1.9
5KO1	X-RAY DIFFRACTION	2.16
7MON	X-RAY DIFFRACTION	2.23
6O5Z	X-RAY DIFFRACTION	2.29
8SLZ	X-RAY DIFFRACTION	2.3
6LK6	X-RAY DIFFRACTION	2.41
7JXU	X-RAY DIFFRACTION	2.44
6LK5	X-RAY DIFFRACTION	2.5
6UX8	X-RAY DIFFRACTION	2.5
7JW7	X-RAY DIFFRACTION	2.63
6BWK	X-RAY DIFFRACTION	2.79
5KNJ	X-RAY DIFFRACTION	2.88
2MSV	SOLUTION NMR
6D74	SOLUTION NMR
6ZLE	SOLUTION NMR
6ZPR	SOLUTION NMR
7NM2	SOLUTION NMR
7NM4	SOLUTION NMR
7NM5	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NB16-F1	83.25	0.50

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): 86 (target of necrosulfonamide inhibitor)

Ligand- & substrate-binding residues (2): 209–217; 230

Post-translational modifications (4): 358, 360, 125, 357

Mutagenesis-validated functional residues (11):

Position	Phenotype
58	does not affect formation of homotrimers, while translocation to the plasma membrane on necroptosis induction is impaire
76	does not affect formation of homotrimers, while translocation to the plasma membrane on necroptosis induction is impaire
86	abolishes binding to necrosulfonamide inhibitor.
162	impairs formation of homotrimers and translocation to the plasma membrane on necroptosis induction; when associated with
165	impairs formation of homotrimers and translocation to the plasma membrane on necroptosis induction; when associated with
230	abolishes atp-binding.
331	impairs atp-binding.
351	binds atp with an enhanced affinity.
357–358	mimics phosphorylation state; acts as a dominant-negative mutant that impairs necroptosis.
357	no effect. abolishes ability to mediate necroptosis; when associated with a-358.
358	no effect. abolishes ability to mediate necroptosis; when associated with a-357.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-168276	NS1 Mediated Effects on Host Pathways
R-HSA-3295583	TRP channels
R-HSA-5213460	RIPK1-mediated regulated necrosis
R-HSA-5675482	Regulation of necroptotic cell death
R-HSA-9686347	Microbial modulation of RIPK1-mediated regulated necrosis
R-HSA-1643685	Disease
R-HSA-2672351	Stimuli-sensing channels
R-HSA-382551	Transport of small molecules
R-HSA-5218859	Regulated Necrosis
R-HSA-5357801	Programmed Cell Death
R-HSA-9645723	Diseases of programmed cell death
R-HSA-9693928	Defective RIPK1-mediated regulated necrosis
R-HSA-983712	Ion channel transport

MSigDB gene sets: 162 (showing top): WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_PROTEIN_TRIMERIZATION, FINETTI_BREAST_CANCER_KINOME_GREEN, GOBP_DEFENSE_RESPONSE_TO_VIRUS, GOBP_PROTEIN_HOMOOLIGOMERIZATION, SENESE_HDAC1_TARGETS_UP, GOBP_RESPONSE_TO_VIRUS, GOMF_PROTEIN_KINASE_ACTIVITY, GOMF_KINASE_ACTIVITY, GOMF_KINASE_BINDING, GOMF_PROTEIN_SERINE_THREONINE_KINASE_ACTIVITY, GOMF_ADENYL_NUCLEOTIDE_BINDING, GOMF_TRANSFERASE_ACTIVITY_TRANSFERRING_PHOSPHORUS_CONTAINING_GROUPS, MEISSNER_BRAIN_HCP_WITH_H3K4ME3_AND_H3K27ME3, MEISSNER_NPC_HCP_WITH_H3K4ME2

GO Biological Process (8): cell surface receptor signaling pathway (GO:0007166), defense response to virus (GO:0051607), protein homotrimerization (GO:0070207), necroptotic process (GO:0070266), necroptotic signaling pathway (GO:0097527), execution phase of necroptosis (GO:0097528), protein phosphorylation (GO:0006468), programmed cell death (GO:0012501)

GO Molecular Function (7): ATP binding (GO:0005524), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell junction (GO:0030054), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Influenza Infection	1
Stimuli-sensing channels	1
Regulated Necrosis	1
RIPK1-mediated regulated necrosis	1
Defective RIPK1-mediated regulated necrosis	1
Ion channel transport	1
Programmed Cell Death	1
Disease	1
Diseases of programmed cell death	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
signal transduction	3
necroptotic process	2
binding	2
defense response	1
response to virus	1
protein homooligomerization	1
protein trimerization	1
programmed necrotic cell death	1
cellular process	1
phosphorylation	1
protein modification process	1
cell death	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
kinase binding	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1991 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MLKL	RIPK3	Q9Y572	989
MLKL	RIPK1	Q13546	989
MLKL	FADD	Q13158	966
MLKL	CASP8	Q14790	960
MLKL	PGAM5	Q96HS1	909
MLKL	TRADD	Q15628	853
MLKL	PCSK1	P29120	850
MLKL	GSDMD	P57764	829
MLKL	CFLAR	O15519	787
MLKL	TNFRSF1A	P19438	716
MLKL	CASP3	P42574	706
MLKL	DIABLO	Q9NR28	703
MLKL	CASP1	P29466	685
MLKL	TRAF2	Q12933	680
MLKL	TNF	P01375	679

IntAct

32 interactions, top by confidence:

A	B	Type	Score
RIPK3	RIPK1	psi-mi:“MI:0915”(physical association)	0.970
RIPK3	RIPK1	psi-mi:“MI:0914”(association)	0.970
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RIPK3	MLKL	psi-mi:“MI:0915”(physical association)	0.640
MLKL	RIPK3	psi-mi:“MI:0915”(physical association)	0.640
RIPK3	MLKL	psi-mi:“MI:0914”(association)	0.640
	MLKL	psi-mi:“MI:0914”(association)	0.590
	MLKL	psi-mi:“MI:0915”(physical association)	0.590
	MLKL	psi-mi:“MI:0407”(direct interaction)	0.590
MLKL	CDK1	psi-mi:“MI:0915”(physical association)	0.370
NDUFB7	MLKL	psi-mi:“MI:0915”(physical association)	0.370
MLKL	ANAPC11	psi-mi:“MI:0915”(physical association)	0.370
MLKL	RAD18	psi-mi:“MI:0915”(physical association)	0.370
THOC3	MLKL	psi-mi:“MI:0915”(physical association)	0.370
MLKL	CASP8	psi-mi:“MI:0914”(association)	0.350
ZNF281	KIF21B	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
MLKL	IMPDH2	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
SNW1		psi-mi:“MI:0914”(association)	0.350
KCNK3	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (67): CASP8 (Affinity Capture-MS), GLG1 (Affinity Capture-MS), SRA1 (Affinity Capture-MS), PARP16 (Affinity Capture-MS), LRCH3 (Affinity Capture-MS), MLKL (Affinity Capture-MS), MLKL (Affinity Capture-MS), TRAF2 (Affinity Capture-Western), MLKL (Affinity Capture-Western), RIPK1 (Affinity Capture-Western), RIPK3 (Affinity Capture-Western), MLKL (Affinity Capture-MS), MLKL (Affinity Capture-MS), MLKL (Affinity Capture-MS), MLKL (Affinity Capture-Western)

ESM2 similar proteins: B6SJQ0, F1M649, F1MHT9, F1QWA8, F4I3M3, F4IS56, G5ECP4, O00238, O14727, O76074, O88879, P19525, P36895, P36898, Q008S8, Q05438, Q05652, Q0DR28, Q1RMT8, Q28156, Q2M405, Q2QXC6, Q2RA93, Q2TBM9, Q3EBY6, Q3UP24, Q5K651, Q5WA76, Q692V3, Q69Z37, Q6Q899, Q80YE7, Q84WJ0, Q8IVG5, Q8NB16, Q8R4K2, Q8RXE5, Q8W4L3, Q93Z30, Q96JX3

Diamond homologs: A0A8I5ZNK2, G5ECN5, G5EDF7, H2L099, O19004, O23304, O65924, O75011, O88506, O95747, P04627, P10398, P14056, P32801, P9WI62, P9WI63, Q3UUJ4, Q4R6X5, Q54Q69, Q551H4, Q55GV3, Q5E9J9, Q5PP29, Q5R495, Q5RBJ6, Q5XF79, Q5ZK47, Q69SP5, Q6P9R2, Q7RTN6, Q7TNZ6, Q7TYY6, Q863I2, Q8G4G1, Q8K4T3, Q8NB16, Q8RWW0, Q91604, Q9C0K7, Q9FRS6

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
MLKL	“up-regulates activity”	Necroptosis
MERTK	“up-regulates quantity by stabilization”	MLKL	phosphorylation
AXL	“up-regulates quantity by stabilization”	MLKL	phosphorylation
TYRO3	“up-regulates quantity by stabilization”	MLKL	phosphorylation
MLKL	“down-regulates quantity by destabilization”	CNR2	phosphorylation
RIPK3	“up-regulates activity”	MLKL	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	74
Likely benign	9
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

2135 predictions. Top by Δscore:

Variant	Effect	Δscore
16:74675003:AT:A	donor_gain	1.0000
16:74675004:T:C	donor_gain	1.0000
16:74685480:CCTTA:C	donor_loss	1.0000
16:74685481:CTTA:C	donor_loss	1.0000
16:74685482:TTACC:T	donor_loss	1.0000
16:74685483:TACC:T	donor_loss	1.0000
16:74685484:A:T	donor_loss	1.0000
16:74685485:C:CA	donor_loss	1.0000
16:74685579:CTATT:C	acceptor_gain	1.0000
16:74685580:TATT:T	acceptor_gain	1.0000
16:74685582:TT:T	acceptor_gain	1.0000
16:74685583:TC:T	acceptor_loss	1.0000
16:74685584:C:CC	acceptor_gain	1.0000
16:74685584:CTATA:C	acceptor_loss	1.0000
16:74685585:T:A	acceptor_loss	1.0000
16:74692417:C:CC	acceptor_gain	1.0000
16:74695292:G:C	donor_gain	1.0000
16:74695302:T:TA	donor_gain	1.0000
16:74695307:G:C	donor_gain	1.0000
16:74674933:CGCT:C	donor_gain	0.9900
16:74674939:TTAC:T	donor_gain	0.9900
16:74675003:A:AC	donor_gain	0.9900
16:74675323:CCA:C	donor_gain	0.9900
16:74682787:C:CC	acceptor_gain	0.9900
16:74685581:ATT:A	acceptor_gain	0.9900
16:74685586:A:C	acceptor_gain	0.9900
16:74685593:T:TC	acceptor_gain	0.9900
16:74691477:C:CT	acceptor_gain	0.9900
16:74691477:C:T	acceptor_gain	0.9900
16:74691478:G:T	acceptor_gain	0.9900

AlphaMissense

3097 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:74675359:A:C	F412L	0.969
16:74675359:A:T	F412L	0.969
16:74675361:A:G	F412L	0.969
16:74674995:C:G	R449P	0.968
16:74678935:G:C	S334R	0.957
16:74678935:G:T	S334R	0.957
16:74678937:T:G	S334R	0.957
16:74674999:A:G	C448R	0.956
16:74675399:C:T	G399E	0.954
16:74675384:T:A	E404V	0.953
16:74678899:C:A	K346N	0.952
16:74678899:C:G	K346N	0.952
16:74678927:A:G	F337S	0.951
16:74682667:C:G	A314P	0.951
16:74675383:T:A	E404D	0.949
16:74675383:T:G	E404D	0.949
16:74682666:G:T	A314D	0.949
16:74682726:A:G	L294P	0.942
16:74675399:C:A	G399V	0.940
16:74682661:C:G	G316R	0.940
16:74682762:A:T	V282D	0.940
16:74695464:G:C	F98L	0.938
16:74695464:G:T	F98L	0.938
16:74695466:A:G	F98L	0.938
16:74675388:A:G	W403R	0.937
16:74675388:A:T	W403R	0.937
16:74675384:T:G	E404A	0.936
16:74675400:C:G	G399R	0.935
16:74675400:C:T	G399R	0.935
16:74695657:C:G	R34P	0.935

dbSNP variants (sampled 300 via entrez): RS1000071839 (16:74677832 C>T), RS1000073029 (16:74680701 T>C), RS1000161054 (16:74675457 G>A), RS1000162895 (16:74695014 A>T), RS1000259744 (16:74685691 G>A), RS1000265146 (16:74700197 A>C), RS1000274232 (16:74680390 T>C,G), RS1000317655 (16:74689962 G>A), RS1000551514 (16:74693996 G>A,C), RS1000599521 (16:74699006 G>A,C), RS1000645341 (16:74688828 G>A,C), RS1000652191 (16:74702624 C>G,T), RS1000652809 (16:74693693 C>G,T), RS1000722440 (16:74694715 T>C), RS1000745502 (16:74680102 G>A)

Disease associations

OMIM: gene MIM:615153 | disease phenotypes: MIM:253260, MIM:266600, MIM:609628

GenCC curated gene-disease

Mondo (3): biotinidase deficiency (MONDO:0009665), inflammatory bowel disease (MONDO:0005265), chronic recurrent multifocal osteomyelitis (MONDO:0009813)

Orphanet (3): Biotinidase deficiency (Orphanet:79241), Rare inflammatory bowel disease (Orphanet:104012), Chronic nonbacterial osteomyelitis/Chronic recurrent multifocal osteomyelitis (Orphanet:324964)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0002754	Osteomyelitis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002023_2	Testicular germ cell tumor	5.000000e-12
GCST012489_11	Heel bone mineral density x serum urate levels interaction	4.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D028921	Biotinidase Deficiency	C16.320.565.100.620.100; C16.320.565.202.720.100; C18.452.648.100.620.100; C18.452.648.202.720.100
D015212	Inflammatory Bowel Diseases	C06.405.205.731; C06.405.469.432
C535456	Chronic recurrent multifocal osteomyelitis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1938217 (SINGLE PROTEIN), CHEMBL5465220 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 14,403 (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
CHEMBL601719	CRIZOTINIB	4	14,403

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — TKL-unique family

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 56 [PMID: 36136378]	Inhibition	7.09	pEC50
MLKL compound 1	Inhibition	7.0	pIC50

Binding affinities (BindingDB)

59 measured of 153 human assays (153 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[4-(4-amino-1-methylpyrazolo[4,3-c]pyridin-3-yl)-2-[(4-fluorophenyl)methoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-(3,6-dihydro-2H-pyran-4-yl)-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-2,2,2-trifluoroethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-1-propan-2-yl-7-(1,2,3,6-tetrahydropyridin-5-yl)pyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-(3-amino-1H-pyrazolo[4,3-c]pyridin-4-yl)-2-[(4-fluorophenyl)methoxy]phenyl]-2,2,2-trifluoroethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-(3-amino-6-phenyl-2H-pyrazolo[3,4-b]pyridin-4-yl)-2-[(4-fluorophenyl)methoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-1-methyl-7-[1-(oxan-4-yl)pyrazol-4-yl]pyrazolo[4,5-c]pyridin-3-yl]-2-[(1R)-1-(4-fluorophenyl)-2-methoxyethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-1-methyl-7-[1-(oxan-4-yl)pyrazol-4-yl]pyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)-2-methoxyethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-(3,3-difluorocyclopentyl)pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-(oxan-4-yl)pyrazol-4-yl]-1H-pyrazolo[4,5-c]pyridin-3-yl]-2-[(3-chlorophenyl)methoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-(4-amino-1-methyl-7-morpholin-4-ylpyrazolo[4,5-c]pyridin-3-yl)-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-(4-(4-amino-1-methyl- 7-(1-(1-methyl-2- (trifluoromethyl)piperidin- 4-yl)-1H-pyrazol-4- yl)-1H-pyrazolo[4,3- c]pyridin-3-yl)-2-((S)-1- (4-fluorophenyl)eth- oxy)phenyl)-1,1- difluoromethane- sulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4S)-1-[(2S)-2-[[2-[2-[2-[4-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]pyrazol-1-yl]ethoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-1-[(2S)-2-[7-[4-[4-amino-3-[4-(ethylsulfonylamino)phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]pyrazol-1-yl]heptanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-1-[(2S)-2-[[2-[2-[2-[4-[4-amino-3-[4-(ethylsulfonylamino)phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]pyrazol-1-yl]ethoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-N-[[2-[7-[4-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]pyrazol-1-yl]heptoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[(2R)-2-[(1-fluorocyclopropanecarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[7-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyheptyl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-1-[(2S)-2-[7-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]hept-6-ynoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-1-[(2S)-2-[[4-[2-[4-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]pyrazol-1-yl]ethoxy]benzoyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-1-[(2S)-2-[[3-[2-[4-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]pyrazol-1-yl]ethoxy]benzoyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-N-[[2-[7-[4-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]pyrazol-1-yl]heptoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[(2S)-2-[(1-fluorocyclopropanecarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-1-[(2S)-2-[6-[4-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]phenoxy]hexanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[3-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]piperidin-4-yl]propanoyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-N-[[2-[8-[4-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]pyrazol-1-yl]octoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[(2S)-2-[(1-fluorocyclopropanecarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-1-[(2S)-2-[[2-[2-[4-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]phenoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-1-[(2S)-2-[6-[[5-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]-2-pyridinyl]oxy]hexanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]azetidine-3-carbonyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-1-[(2S)-2-[9-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-fluorophenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]non-8-ynoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[2-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]pyrrolidin-3-yl]acetyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]pyrrolidine-3-carbonyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]cyclobutanecarbonyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-1-[(2S)-2-[[2-[4-[4-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]pyrazol-1-yl]butoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-N-[[2-[6-[4-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]pyrazol-1-yl]hexoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[(2S)-2-[(1-fluorocyclopropanecarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]cyclohexanecarbonyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
4-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}butyl 4-{4-amino-3-[4-(difluoromethanesulfonamido)-3-[(1 S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl}benzoate	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
(2S,4R)-N-[[2-[5-[4-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]pyrazol-1-yl]pentoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[(2S)-2-[(1-fluorocyclopropanecarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[7-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]-7-azaspiro[3.5]nonane-2-carbonyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]morpholine-2-carbonyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[2-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]piperidin-3-yl]acetyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]-2-azaspiro[3.3]heptane-6-carbonyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[3-[1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl]piperidin-4-yl]propanoyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[4-[[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]methyl]benzoyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[[3-[[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]methyl]phenyl]methyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]piperidin-4-yl]methyl 4-[4-[4-amino-3-[4-(difluoromethylsulfonylamino)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methylpyrazolo[4,5-c]pyridin-7-yl]pyrazol-1-yl]piperidine-1-carboxylate	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[4-[3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]cyclobutanecarbonyl]-4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]-1-fluorocyclobutanecarbonyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[[4-[[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]methyl]phenyl]methyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]cyclohexanecarbonyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[4-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]piperidine-1-carbonyl]cyclohexyl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[(1S,2S)-2-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]piperidin-4-yl]cyclopropanecarbonyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS
N-[4-[4-amino-7-[1-[1-[(1S,2R)-2-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]piperidin-4-yl]cyclopropanecarbonyl]piperidin-4-yl]pyrazol-4-yl]-1-methylpyrazolo[4,5-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide	KD	275 nM	US-20250115598: BIFUNCTIONAL ARYLSULPHONAMIDE COMPOUNDS

ChEMBL bioactivities

18 potent at pChembl≥5 of 27 total, top 11 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.15	Kd	0.7	nM	CHEMBL5421128
6.82	Kd	150	nM	CHEMBL5396374
6.66	Kd	217	nM	CRIZOTINIB
6.64	Kd	230	nM	CHEMBL4440337
6.28	Kd	530	nM	GW806742X
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
5.75	Kd	1800	nM	CHEMBL189354
5.62	EC50	2400	nM	CHEMBL5408513
5.03	Kd	9300	nM	GW806742X

PubChem BioAssay actives

15 with measured affinity, of 228 total; 7 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
5-[4-(difluoromethylsulfonylamino)phenyl]-3-(3-methoxyanilino)-1H-pyrazole-4-carboxamide	1975948: Binding affinity to MLKL (unknown origin)	kd	0.0007	uM
3-anilino-5-[4-(propan-2-ylsulfonylamino)phenyl]-1H-pyrazole-4-carboxamide	1975948: Binding affinity to MLKL (unknown origin)	kd	0.1500	uM
Crizotinib	1580397: Binding affinity to human MLKL by kinome scan based method	kd	0.2170	uM
[(1R)-2-(4-fluoroanilino)-2-oxo-1-phenylethyl] 3-aminopyrazine-2-carboxylate	1580397: Binding affinity to human MLKL by kinome scan based method	kd	0.2300	uM
1-[4-[methyl-[2-(3-sulfamoylanilino)pyrimidin-4-yl]amino]phenyl]-3-[4-(trifluoromethoxy)phenyl]urea	1896651: Binding affinity to full length human MLKL pseudokinase domain by Kinomescan method	kd	0.5300	uM
1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-[methyl-[2-(3-sulfamoylanilino)pyrimidin-4-yl]amino]phenyl]urea	1896651: Binding affinity to full length human MLKL pseudokinase domain by Kinomescan method	kd	1.8000	uM
5-[4-(difluoromethylsulfonylamino)phenyl]-3-[3-[8-[3-[3-(2,4-dioxo-1,3-diazinan-1-yl)-4-methoxybenzoyl]-3,9-diazaspiro[5.5]undecan-9-yl]-8-oxooctoxy]anilino]-1H-pyrazole-4-carboxamide	1975952: PROTAC activity at CRBN/MLKL in human HT-29 cells assessed as degraded protein level in cell lysates incubated for 24 hrs measured by capillary immunoassay relative to vehicle treated control	ec50	2.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	5
Valproic Acid	decreases expression, affects cotreatment, increases expression	5
Cyclosporine	affects cotreatment, increases expression	5
bisphenol A	increases reaction, affects cotreatment, decreases expression, decreases reaction, increases expression	3
necrostatin-1	increases expression, increases phosphorylation, increases reaction, decreases reaction	3
Acetaminophen	affects cotreatment, decreases expression	3
Acetylcysteine	decreases reaction, increases expression, increases phosphorylation, increases reaction	3
Benzo(a)pyrene	increases methylation, increases mutagenesis, decreases methylation, increases expression	3
Cadmium	affects binding, increases abundance, increases reaction, affects cotreatment, decreases reaction (+3 more)	3
Cadmium Chloride	decreases reaction, decreases expression, affects binding, increases abundance, increases reaction (+2 more)	3
Particulate Matter	decreases reaction, increases abundance, increases phosphorylation, affects cotreatment, decreases expression	3
GSK872	decreases reaction, increases phosphorylation, affects cotreatment, affects reaction, increases expression	2
sodium arsenite	decreases expression, increases expression	2
entinostat	increases expression, affects cotreatment	2
Atazanavir Sulfate	affects cotreatment, increases expression	2
Arsenic Trioxide	decreases expression, increases phosphorylation	2
Chenodeoxycholic Acid	affects cotreatment, increases expression, decreases expression	2
Deoxycholic Acid	affects cotreatment, increases expression, decreases expression	2
Glycochenodeoxycholic Acid	affects cotreatment, increases expression, decreases expression	2
Glycocholic Acid	affects cotreatment, increases expression, decreases expression	2
Glycodeoxycholic Acid	affects cotreatment, increases expression, decreases expression	2
Nickel	increases expression	2
tetrachlorobenzoquinone	decreases reaction, increases expression, affects localization, increases phosphorylation	1
SC-66 compound	affects cotreatment, increases abundance, increases phosphorylation	1
CBLC137	increases expression	1
OTX015	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
AKT activator SC79	decreases reaction, increases abundance, increases phosphorylation	1
mivebresib	decreases expression	1
NMS-873	decreases reaction, increases abundance, increases phosphorylation	1

ChEMBL screening assays

112 unique, capped per target: 112 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1943611	Binding	Inhibition of human MLKL in HL-60 cells lysate assessed as reduction of labeling of acyl-phosphate ATP probe at 100 nM	6-Position optimization of tricyclic 4-quinolone-based inhibitors of glycogen synthase kinase-3β: discovery of nitrile derivatives with picomolar potency. — Bioorg Med Chem Lett

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1X9	Abcam HeLa MLKL KO	Cancer cell line	Female
CVCL_D7V6	Ubigene A-549 MLKL KO	Cancer cell line	Male
CVCL_D8QP	Ubigene HCT 116 MLKL KO	Cancer cell line	Male
CVCL_E0I6	Ubigene HeLa MLKL KO	Cancer cell line	Female
CVCL_F1U7	HyCyte THP-1 KO-hMLKL	Cancer cell line	Male
CVCL_SY54	HAP1 MLKL (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00167882	PHASE4	COMPLETED	The Influence of 5-Aminosalicylates on Thiopurine Metabolite Levels
NCT00205062	PHASE4	TERMINATED	Positron Emission Tomography (PET)-Computed Tomography (CT) in Inflammatory Bowel Disease (IBD)
NCT00567593	PHASE4	COMPLETED	Gene Regulation by Thiazolidinediones
NCT00746395	PHASE4	COMPLETED	Randomized, Placebo-controlled Trial of Lubiprostone as a Preparation for Capsule Endoscopy
NCT01034358	PHASE4	COMPLETED	Immune Response to the Human Papillomavirus Vaccine in Young Women With Inflammatory Bowel Disease
NCT01056913	PHASE4	COMPLETED	NITI CAR27 (ColonRing) Compression Anastomosis in Colorectal Surgery
NCT01067547	PHASE4	COMPLETED	A Trial of Iron Replacement in Patients With Iron Deficiency.
NCT01341808	PHASE4	COMPLETED	Immunogenicity of Hepatitis A Vaccine in Inflammatory Bowel Disease (IBD) Patients
NCT01908283	PHASE4	COMPLETED	Induction of Immunity Against Streptococcus Pneumoniae in Adults With Inflammatory Bowel Disease
NCT01934088	PHASE4	COMPLETED	Satisfaction With Nurse Administered Propofol Sedation vs. Midazolam With Fentanyl Sedation for Endoscopy
NCT02162862	PHASE4	COMPLETED	Treating Disrupted Sleep in Individuals With Inflammatory Bowel Disease
NCT02248337	PHASE4	COMPLETED	Low Volume Colon Preparation for IBD
NCT02281799	PHASE4	WITHDRAWN	Thiopurine Induced Pancreatitis in IBD Patients
NCT02392286	PHASE4	TERMINATED	Corticosteroid Dosage for Crohn’s Disease Flare
NCT02437591	PHASE4	COMPLETED	Study to Evaluate the Pharmacokinetics of Fidaxomicin in Inflammatory Bowel Disease (IBD) Subjects With Clostridium Difficile Infection (CDI)
NCT02453776	PHASE4	COMPLETED	Precision Dosing of Infliximab Versus Conventional Dosing of Infliximab
NCT02461758	PHASE4	COMPLETED	Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory Bowel Disease Patients
NCT02566889	PHASE4	TERMINATED	An Efficacy and Safety Study of Infliximab Dose Escalation in Pediatric Participants With Inflammatory Bowel Disease
NCT02774057	PHASE4	UNKNOWN	Trial of Captafer® vs. Oral Iron Sulfate in the Treatment of Iron Deficiency Anemia in Patients With IBD
NCT02806206	PHASE4	UNKNOWN	Prucalopride Prior to Small Bowel Capsule Endoscopy
NCT02946203	PHASE4	COMPLETED	Comparison of VoLumen and Breeza Oral Contrast Agents in Pediatric Patients
NCT02994836	PHASE4	COMPLETED	GIS-SUSANTI-TNF-2015 (Anti-TNF Discontinuation )
NCT03220841	PHASE4	UNKNOWN	Stricture Definition and Treatment (STRIDENT) Drug Therapy Study
NCT03351972	PHASE4	COMPLETED	Differences in Preparation for Small Bowel Capsule Endoscopy
NCT03466983	PHASE4	COMPLETED	A Trial Comparing the Incidence of Hypophosphatemia in Relation to Treatment With Iron Isomaltoside and Ferric Carboxymaltose in Subjects With Iron Deficiency Anaemia Due to Inflammatory Bowel Disease
NCT03591770	PHASE4	TERMINATED	Shingrix Vaccine in Patients With Moderate to Severe Ulcerative Colitis on Tofacitinib
NCT03629379	PHASE4	COMPLETED	Response to Ustekinumab for Anti-tnf Induced Psoriasiform Skin Lesions
NCT03723447	PHASE4	COMPLETED	Intraoperative TAP Block With Bupivacaine/Dexamethasone Against Liposomal Bupivacaine (Exparel®)
NCT03798691	PHASE4	COMPLETED	Immunogenicity of Herpes Zoster Subunit Vaccine in Inflammatory Bowel Disease Patients Treated With Vedolizumab
NCT03860012	PHASE4	UNKNOWN	Folic Acid in Pediatric Inflammatory Bowel Disease
NCT03885713	PHASE4	COMPLETED	Identification of Predictive Biomarkers for Response to Biologic Therapies and Tofacitinib in Inflammatory Bowel Disease
NCT03917303	PHASE4	RECRUITING	Control Crohn Safe Trial
NCT04045782	PHASE4	COMPLETED	Evaluation of the Safety and Effectiveness of Switching From Humira® to Imraldi® in Flanders
NCT04304950	PHASE4	COMPLETED	Chronotherapy in Inflammatory Bowel Disease
NCT04626947	PHASE4	TERMINATED	Prevention of Recurrent Clostridium Difficile Infection (CDI) in Patients With Inflammatory Bowel Disease (IBD).
NCT04646187	PHASE4	ENROLLING_BY_INVITATION	De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease
NCT04835506	PHASE4	ACTIVE_NOT_RECRUITING	Proactive Infliximab Optimization Using a Pharmacokinetic Dashboard Versus Standard of Care in Patients With Inflammatory Bowel Disease: The OPTIMIZE Trial
NCT04982172	PHASE4	COMPLETED	Model-informed Dose De-escalation of Infliximab in Patients With Inflammatory Bowel Diseases
NCT05180175	PHASE4	COMPLETED	The Nordic IBD Treatment Strategy Trial
NCT05280405	PHASE4	UNKNOWN	Early Proactive Therapeutic Drug Monitoring of Infliximab in Children: EPIC Study