TLR8

Summary

TLR8 (toll like receptor 8, HGNC:15632) is a protein-coding gene on chromosome Xp22.2, encoding Toll-like receptor 8 (Q9NR97). Endosomal receptor that plays a key role in innate and adaptive immunity.

The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is predominantly expressed in lung and peripheral blood leukocytes, and lies in close proximity to another family member, TLR7, on chromosome X.

Source: NCBI Gene 51311 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 98 with autoinflammation, X-linked (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 139 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 24
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_138636

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15632
Approved symbol	TLR8
Name	toll like receptor 8
Location	Xp22.2
Locus type	gene with protein product
Status	Approved
Aliases	CD288, hTLR8
Ensembl gene	ENSG00000101916
Ensembl biotype	protein_coding
OMIM	300366
Entrez	51311

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000218032, ENST00000311912

RefSeq mRNA: 2 — MANE Select: NM_138636 NM_016610, NM_138636

CCDS: CCDS14152, CCDS14153

Canonical transcript exons

ENST00000218032 — 2 exons

Exon	Start	End
ENSE00001130430	12919044	12923169
ENSE00001907173	12906620	12906709

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 96.71.

FANTOM5 (CAGE): breadth broad, TPM avg 11.3357 / max 1505.7267, expressed in 343 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195534	10.3252	336
195535	1.0105	200

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	96.71	gold quality
mononuclear cell	CL:0000842	96.16	gold quality
leukocyte	CL:0000738	95.99	gold quality
blood	UBERON:0000178	92.92	gold quality
granulocyte	CL:0000094	89.43	gold quality
visceral pleura	UBERON:0002401	83.58	gold quality
trabecular bone tissue	UBERON:0002483	83.31	gold quality
bone marrow	UBERON:0002371	80.75	gold quality
spleen	UBERON:0002106	78.67	gold quality
vermiform appendix	UBERON:0001154	78.54	gold quality
pleura	UBERON:0000977	78.13	gold quality
parietal pleura	UBERON:0002400	77.20	gold quality
lower lobe of lung	UBERON:0008949	75.72	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.91	gold quality
caecum	UBERON:0001153	72.26	gold quality
lymph node	UBERON:0000029	72.17	gold quality
palpebral conjunctiva	UBERON:0001812	72.00	gold quality
germinal epithelium of ovary	UBERON:0001304	71.41	gold quality
right lung	UBERON:0002167	71.31	gold quality
bone marrow cell	CL:0002092	71.27	silver quality
gall bladder	UBERON:0002110	68.90	gold quality
upper lobe of lung	UBERON:0008948	67.25	gold quality
lung	UBERON:0002048	67.19	gold quality
upper lobe of left lung	UBERON:0008952	67.05	gold quality
smooth muscle tissue	UBERON:0001135	66.97	gold quality
amniotic fluid	UBERON:0000173	66.39	gold quality
skin of hip	UBERON:0001554	65.76	gold quality
mucosa of sigmoid colon	UBERON:0004993	65.72	silver quality
rectum	UBERON:0001052	65.00	gold quality
right coronary artery	UBERON:0001625	64.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.80

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AIRE, CEBPB, CEBPD, STAT1, TP53

miRNA regulators (miRDB)

51 targeting TLR8, 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-3662	99.99	73.82	5684
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-6513-5P	99.43	67.81	1071
HSA-MIR-7151-5P	99.37	67.82	613
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-5693	99.24	66.67	1106
HSA-MIR-5584-3P	99.23	68.79	1351
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-299-5P	98.56	71.14	1140
HSA-MIR-548AO-5P	98.55	69.57	1362
HSA-MIR-548AX	98.55	69.58	1362
HSA-MIR-4703-5P	98.53	70.13	1645

Literature-anchored findings (GeneRIF, showing 40)

• Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. (PMID:12032557)
• mediates species-specific recognition of GU-rich single-stranded RNA (ssRNA); data suggest that ssRNA represents a physiological ligand for TLR8 (PMID:14976262)
• CBV-induced inflammatory response is mediated through TLR8. (PMID:16008579)
• TLR8 acts as a host sensor for human parechovirus 1, and activates signalling that leads to the synthesis of pro-inflammatory molecules by the host. (PMID:16025564)
• a mechanism described linking Toll-like receptor (TLR) 8 signaling to the control of CD4+ regulatory T cell function; results suggest that TLR8 signaling could play a critical role in controlling immune responses to cancer and other diseases (PMID:16123302)
• TLR8-mediated MEKK3-dependent IKKgamma phosphorylation might play an important role in the activation of IKK complex, leading to IkappaBalpha phosphorylation (PMID:16737960)
• analysis of human toll-like receptor 8 extracellular domain features that are essential for pH-dependent signaling (PMID:16857668)
• TLR3 agonist poly(I:C) activated epithelial cells, primary endothelial cells, and two types of primary human smooth muscle cells (airway [ASMC] and vascular) directly, while the TLR7/8 agonist R848 required the presence of leukocytes to activate ASMC (PMID:16935934)
• These data lead us to suggest that ongoing viral activation of TLR7/8 could alter the adaptive immune response by modifying DC differentiation and by down-regulating DC responsiveness to a subsequent bacterial TLR4-mediated signal. (PMID:17023556)
• TLR8 inhibits TLR7 and TLR9, and TLR9 inhibits TLR7 but not vice versa in HEK293 cells transfected with TLRs in a pairwise combination. (PMID:17040905)
• analyzed the expression of Toll-like receptors 1 to 9 on myeloid dendritic cells generated from X-linked agammaglobulinemia patients and evaluated their response to activation by specific Toll-like receptor agonists (PMID:17090647)
• Both types of compounds induced IFN-gamma-inducible protein 10, but only the 7-deazaguanosine-containing compound that activated both TLR7 and TLR8 induced IFN-alpha in monkeys (PMID:17698957)
• Ciprofloxacin inhibits lipopolysaccharide-induced toll-like receptor-4 and 8 expression on human monocytes derived from adult and cord blood. (PMID:17724596)
• analysis of modification and regulation of TLR8 in HEK-293 cells stimulated with imidazoquinoline agonists (PMID:17868034)
• Btk as a key signaling molecule that interacts with and acts downstream of TLR8 and TLR9. (PMID:17932028)
• TLR7-9 recognize single-stranded RNA, nucleoside analogs and single-stranded CpG-DNA, respectively, and their activation initiates the immune response against viruses and bacteria [review] (PMID:18406377)
• These results delineate the complex effects of triggering TLR7/8 for an efficient antiviral defense. (PMID:18431484)
• This first report of a functional TLR8 variant associated with a different clinical course of an RNA viral disease may have implications for the individual risk assessment of RNA virus infections as well as for future HIV vaccine development. (PMID:18605904)
• replicated association was obtained for SNPs or haplotypes of TLR7 and TLR8, suggesting these genes as novel disease genes for asthma and related disorders. (PMID:18682521)
• Human epidermal keratinocytes constitutively express all TLR 1-10 mRNA, which may enable human keratinocytes to respond to a wide range of pathogenic micro-organisms. (PMID:18686608)
• four polymorphisms in the TLR8 gene on chromosome X showed evidence of association with TB susceptibility in males, including a non-synonymous polymorphism rs3764880 (Met1Val; P = 0.007, odds ratio (OR) = 1.8, 95% c.i. = 1.2-2.7) (PMID:18927625)
• TLR8 is an X-linked IBD susceptibility gene with both common predisposing and protecting haplotypes. (PMID:18942751)
• These results do not support an involvement of SNPs rs3764879 and rs3764880 of TLR8 in predisposition to coronary artery disease. (PMID:18985439)
• Expression of TLR-8, but not Tollip, is highly up-regulated in the colonic epithelium from patients with active IBD. (PMID:18985539)
• TLR8 may play a role in driving TNF production in rheumatoid arthritis (PMID:19017992)
• DCIR is an antigen presenting cell receptor that is endocytosed efficiently in a clathrin-dependent manner and negatively affects TLR8-mediated cytokine production. (PMID:19028959)
• the Jak/STAT signaling pathway was involved in CD40 expression and cytokine production in TLR7-stimulated DCs but negatively regulated CD83 expression and cytokine secretion in DCs activated through TLR8 (PMID:19164127)
• TLR3, TLR4, and TLR8 ligands induce synergistic multiple signaling pathways leading to cytokine mRNA expression and protein production in human monocyte-derived macrophages and dendritic cells (PMID:19164128)
• Synergy between TLR4 and TLR7/8 controls the sequential production of regulatory and proinflammatory cytokines interleukin (IL)-10, interferon (IFN)-gamma, and IL-17A by naive CD4-positive T cells. (PMID:19265114)
• The ligand-induced activation of TLR 8 leads to the accumulation of hypoxia-inducible factor 1 alpha (HIF-1alpha) protein in THP-1 human myeloid macrophages via redox- and reactive nitrogen species-dependent mechanisms. (PMID:19381167)
• exptressed on Fallopian tube and uterus (PMID:19406482)
• Activation of TLR8 by double-stranded RNA (poly-I:C) or single-stranded RNA induced IFN-alpha/beta expression. Such activation done prior to HSV-1 infection reduced the susceptibility of the neuronal cells to infection. (PMID:19437550)
• In monocytes, the response to RNA oligonucleotides was mediated by either TLR8 or RIG-I. TLR8 was responsible for IL-12 induction upon endosomal delivery of ssRNA oligonucleotides (PMID:19454678)
• TLR8-mediated neutrophilic responses are markedly potentiated by oxidative stress, and the potentiation is mediated by enhanced NF-kB activation. (PMID:19527497)
• Results show that TLR8 activation may be an important, novel pathway for targeted treatment of Th1-mediated diseases, such as Crohn’s disease. (PMID:19637197)
• Activation of endosomal TLRs 7, 8 and 4 leads to downregulation of degradative HIF-1 alpha prolyl hydroxylation. (PMID:19841637)
• Fanconi anemia, complementation group C suppresses TNF-alpha production in mononuclear phagocytes by suppressing TLR8 activity (PMID:19850743)
• When dendritic cells were triggered with the potent synergistic combination of TLR4 and TLR7/8 in conjunction with a TLR2 ligand, there was a clear shift to more Th2- and Th17-prone responses in the naive and memory T cell subpopulations (PMID:19915052)
• A five-amino-acid motif in the undefined region of the TLR8 ectodomain is required for species-specific ligand recognition. (PMID:20004021)
• Studies show substantial decreases in older compared with young individuals in cytokine production in response to TLR1/2, TLR6, TLR3, TLR5, and TLR8, TLR7 and TLR9 in DCs. (PMID:20100933)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tlr8	ENSMUSG00000040522
rattus_norvegicus	Tlr8	ENSRNOG00000045992

Paralogs (22): IGFALS (ENSG00000099769), LRRC17 (ENSG00000128606), RXFP2 (ENSG00000133105), CD180 (ENSG00000134061), TLR4 (ENSG00000136869), TLR2 (ENSG00000137462), LRRC32 (ENSG00000137507), LRRC3 (ENSG00000160233), LRRC53 (ENSG00000162621), TLR3 (ENSG00000164342), VASN (ENSG00000168140), RXFP1 (ENSG00000171509), NRROS (ENSG00000174004), TLR10 (ENSG00000174123), TLR1 (ENSG00000174125), TLR6 (ENSG00000174130), LRRC3B (ENSG00000179796), TSKU (ENSG00000182704), TLR5 (ENSG00000187554), TLR7 (ENSG00000196664), LRIT2 (ENSG00000204033), LRRC3C (ENSG00000204913)

Protein

Protein identifiers

Toll-like receptor 8 — Q9NR97 (reviewed: Q9NR97)

All UniProt accessions (2): Q9NR97, A0AA49X8T4

UniProt curated annotations — full annotation on UniProt →

Function. Endosomal receptor that plays a key role in innate and adaptive immunity. Controls host immune response against pathogens through recognition of RNA degradation products specific to microorganisms that are initially processed by RNASET2. Recognizes GU-rich single-stranded RNA (GU-rich RNA) derived from SARS-CoV-2, SARS-CoV-1 and HIV-1 viruses. Upon binding to agonists, undergoes dimerization that brings TIR domains from the two molecules into direct contact, leading to the recruitment of TIR-containing downstream adapter MYD88 through homotypic interaction. In turn, the Myddosome signaling complex is formed involving IRAK4, IRAK1, TRAF6, TRAF3 leading to activation of downstream transcription factors NF-kappa-B and IRF7 to induce pro-inflammatory cytokines and interferons, respectively.

Subunit / interactions. Homodimer. Interacts with MYD88 via their respective TIR domains. Interacts with UNC93B1. Interacts with BTK. Interacts with SMPDL3B.

Subcellular location. Endosome membrane.

Tissue specificity. Expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells.

Post-translational modifications. Ubiquitinated by RNF216; leading to degradation by the proteasome. Proteolytic processing occurs in monocytes and monocyte-derived macrophages by both furin-like proprotein convertase and cathepsins. The cleavage is necessary for dimer formation and subsequent activation.

Disease relevance. Immunodeficiency 98 with autoinflammation, X-linked (IMD98) [MIM:301078] An X-linked disorder characterized by onset of recurrent infections associated with lymphoproliferation and autoinflammation in the first decade of life. Mostly males are affected; carrier females may have mild symptoms. Features include mouth ulcers, fever, poor early growth, hepatosplenomegaly, lymphadenopathy, polyarthritis, and non-infectious enteritis. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by RNAs having enough uridines.

Similarity. Belongs to the Toll-like receptor family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NR97-1	1	yes
Q9NR97-2	2

RefSeq proteins (2): NP_057694, NP_619542* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000157	TIR_dom	Domain
IPR000483	Cys-rich_flank_reg_C	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR035897	Toll_tir_struct_dom_sf	Homologous_superfamily

Pfam: PF01582, PF13855

UniProt features (163 total): strand 49, repeat 23, helix 21, glycosylation site 21, turn 13, mutagenesis site 11, disulfide bond 6, sequence variant 6, sequence conflict 5, topological domain 2, domain 2, signal peptide 1, chain 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

39 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9MHW	X-RAY DIFFRACTION	1.52
9MHY	X-RAY DIFFRACTION	1.66
3WN4	X-RAY DIFFRACTION	1.81
4R0A	X-RAY DIFFRACTION	1.9
3W3J	X-RAY DIFFRACTION	2
4QBZ	X-RAY DIFFRACTION	2
4R07	X-RAY DIFFRACTION	2
5AWD	X-RAY DIFFRACTION	2.05
3W3N	X-RAY DIFFRACTION	2.1
4QC0	X-RAY DIFFRACTION	2.1
4R6A	X-RAY DIFFRACTION	2.1
5AWB	X-RAY DIFFRACTION	2.1
9MHX	X-RAY DIFFRACTION	2.13
5AWA	X-RAY DIFFRACTION	2.2
3W3G	X-RAY DIFFRACTION	2.3
3W3K	X-RAY DIFFRACTION	2.3
5WYZ	X-RAY DIFFRACTION	2.3
3W3L	X-RAY DIFFRACTION	2.33
4R08	X-RAY DIFFRACTION	2.4
5AZ5	X-RAY DIFFRACTION	2.4
5WYX	X-RAY DIFFRACTION	2.4
6ZJZ	X-RAY DIFFRACTION	2.49
5AWC	X-RAY DIFFRACTION	2.5
6WML	X-RAY DIFFRACTION	2.5
5HDH	X-RAY DIFFRACTION	2.6
4R09	X-RAY DIFFRACTION	2.62
6V9U	X-RAY DIFFRACTION	2.65
3W3M	X-RAY DIFFRACTION	2.7
7RC9	X-RAY DIFFRACTION	2.76
8PFI	X-RAY DIFFRACTION	2.79

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NR97-F1	86.12	0.57

Functional residue map

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

Disulfide bonds (6): 36–49, 181–187, 257–270, 260–267, 479–509, 776–803

Glycosylation sites (21): 29, 42, 80, 88, 115, 160, 247, 285, 293, 358, 362, 395, 416, 443, 511, 546, 582, 590, 640, 680 …

Mutagenesis-validated functional residues (11):

Position	Phenotype
348	abolishes activation of nf-kappa-b.
348	abolishes responses to both ssrna and chemical ligands.
378	increases activation of nf-kappa-b.
405	abolishes activation of nf-kappa-b.
405	abolishes responses to both ssrna and chemical ligands.
452–455	monomeric and inactive.
520	strongly decreases activation of nf-kappa-b.
543	abolishes activation of nf-kappa-b.
543	abolishes responses to both ssrna and chemical ligands.
574	abolishes responses to both ssrna and chemical ligands.
574	strongly decreases activation of nf-kappa-b.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1679131	Trafficking and processing of endosomal TLR
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses

MSigDB gene sets: 301 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_8_PRODUCTION, GOCC_VACUOLAR_MEMBRANE, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOCC_CELL_SURFACE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_INTERLEUKIN_1_PRODUCTION, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY, GOBP_B_CELL_MEDIATED_IMMUNITY, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS

GO Biological Process (23): toll-like receptor signaling pathway (GO:0002224), inflammatory response (GO:0006954), canonical NF-kappaB signal transduction (GO:0007249), response to virus (GO:0009615), immunoglobulin mediated immune response (GO:0016064), positive regulation of interferon-alpha production (GO:0032727), positive regulation of interferon-beta production (GO:0032728), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-6 production (GO:0032755), positive regulation of interleukin-8 production (GO:0032757), toll-like receptor 8 signaling pathway (GO:0034158), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), innate immune response (GO:0045087), positive regulation of innate immune response (GO:0045089), defense response to virus (GO:0051607), cellular response to mechanical stimulus (GO:0071260), immune system process (GO:0002376), immune response (GO:0006955), signal transduction (GO:0007165), negative regulation of interleukin-12 production (GO:0032695), defense response to other organism (GO:0098542), endolysosomal toll-like receptor signaling pathway (GO:0140894)

GO Molecular Function (8): DNA binding (GO:0003677), RNA binding (GO:0003723), double-stranded RNA binding (GO:0003725), single-stranded RNA binding (GO:0003727), signaling receptor activity (GO:0038023), pattern recognition receptor activity (GO:0038187), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (10): Golgi membrane (GO:0000139), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), endosome membrane (GO:0010008), endolysosome membrane (GO:0036020), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Toll-like Receptor Cascades	2
SARS-CoV-2-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cytokine production	3
defense response	2
positive regulation of type I interferon production	2
nucleic acid binding	2
RNA binding	2
bounding membrane of organelle	2
plasma membrane	2
endomembrane system	2
cellular anatomical structure	2
pattern recognition receptor signaling pathway	1
intracellular signaling cassette	1
response to other organism	1
B cell mediated immunity	1
interferon-alpha production	1
regulation of interferon-alpha production	1
interferon-beta production	1
regulation of interferon-beta production	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
interleukin-8 production	1
regulation of interleukin-8 production	1
endolysosomal toll-like receptor signaling pathway	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
immune response	1
defense response to symbiont	1
positive regulation of response to biotic stimulus	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
innate immune response	1
regulation of innate immune response	1
positive regulation of immune response	1
response to virus	1
response to mechanical stimulus	1

Protein interactions and networks

STRING

3512 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLR8	MYD88	P78397	997
TLR8	TLR7	Q9NYK1	962
TLR8	IRAK4	Q9NWZ3	908
TLR8	TLR3	O15455	903
TLR8	IFNB1	P01574	833
TLR8	IRAK1	P51617	833
TLR8	TLR2	O60603	818
TLR8	IRF7	Q92985	815
TLR8	IL6	P05231	809
TLR8	IFNA13	P01562	804
TLR8	UNC93B1	Q9H1C4	801
TLR8	IFNL1	Q8IU54	796
TLR8	TIRAP	P58753	777
TLR8	RIGI	O95786	776
TLR8	IFIH1	Q9BYX4	755

IntAct

12 interactions, top by confidence:

A	B	Type	Score
TLR8	UNC93B1	psi-mi:“MI:0915”(physical association)	0.600
TLR8	UNC93B1	psi-mi:“MI:0403”(colocalization)	0.600
SIGLEC5	TLR8	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC6	TLR8	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC9	TLR8	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC10	TLR8	psi-mi:“MI:0915”(physical association)	0.400
TLR8	TLR8	psi-mi:“MI:0915”(physical association)	0.370
TLR8	ATP2A3	psi-mi:“MI:0914”(association)	0.350
INSR	BLTP3B	psi-mi:“MI:0914”(association)	0.350
INSR	UBXN8	psi-mi:“MI:0914”(association)	0.350

BioGRID (8): ATP2A3 (Affinity Capture-MS), UNC93B1 (Affinity Capture-MS), CNPY3 (Affinity Capture-MS), PIK3R1 (Affinity Capture-Western), DHX9 (Affinity Capture-MS), RNF216 (Affinity Capture-Western), TLR8 (Protein-RNA), TLR8 (Two-hybrid)

ESM2 similar proteins: A3KNN3, A6H789, A8WHP9, C3YZ59, D3ZTV3, O00206, O08680, O15455, O43155, O60602, O73875, P06213, P08953, P15127, P15208, P54755, P54756, P54757, P58682, P58727, Q0PV50, Q2V898, Q504C1, Q5R7M3, Q5RAC4, Q5TJ59, Q68Y56, Q6R5N8, Q7TNJ4, Q80ZD9, Q810C1, Q86SJ2, Q8BZT5, Q8SPE8, Q8SPE9, Q8SXT3, Q8VCH9, Q96PB8, Q96PX8, Q99MB1

Diamond homologs: B1H134, B1H234, D3ZTV3, F1NUK7, G5EFX6, G5EG78, O43155, O88280, P19879, P20774, P24014, P58874, P79119, P83286, Q5R6T0, Q5RAC4, Q5RBL2, Q62000, Q6PEZ8, Q6RKD8, Q70AK3, Q810C1, Q8BGT1, Q8BLU0, Q8MJF1, Q96PX8, Q9DE65, Q9NR97, Q9NZU0, Q9NZU1, Q9UBM4, Q9W6H0, B2LT61, B2LT62, B2LT64, B2LT65, B3Y613, B3Y614, B3Y615, B3Y618

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
imiquimod	“up-regulates activity”	TLR8	“chemical activation”
resiquimod	“up-regulates activity”	TLR8	“chemical activation”
TLR8	“up-regulates quantity”	TNF
RNF216	“down-regulates quantity by destabilization”	TLR8	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	67
Likely benign	9
Benign	9

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1172678	NM_138636.5(TLR8):c.1715G>A (p.Gly572Asp)	Pathogenic
1172679	NM_138636.5(TLR8):c.1482C>A (p.Phe494Leu)	Pathogenic
1339649	NM_138636.5(TLR8):c.1715G>T (p.Gly572Val)	Pathogenic
4277487	NM_138636.5(TLR8):c.396del (p.Glu133fs)	Likely pathogenic
4279980	NM_138636.5(TLR8):c.1481T>A (p.Phe494Tyr)	Likely pathogenic

SpliceAI

301 predictions. Top by Δscore:

Variant	Effect	Δscore
X:12906706:CATGG:C	donor_loss	0.9900
X:12906707:ATGG:A	donor_loss	0.9900
X:12906708:TGGTA:T	donor_loss	0.9900
X:12906709:GGTAA:G	donor_loss	0.9900
X:12906710:G:A	donor_loss	0.9900
X:12906710:G:GG	donor_gain	0.9900
X:12906711:TAAG:T	donor_loss	0.9900
X:12906708:TG:T	donor_gain	0.9800
X:12906709:GG:G	donor_gain	0.9800
X:12919038:CCTTA:C	acceptor_loss	0.9800
X:12919039:CTTA:C	acceptor_loss	0.9800
X:12919040:TTA:T	acceptor_loss	0.9800
X:12919043:G:GA	acceptor_loss	0.9800
X:12906705:ACATG:A	donor_gain	0.9700
X:12906706:CATG:C	donor_gain	0.9700
X:12919042:A:AG	acceptor_gain	0.9700
X:12919043:G:GG	acceptor_gain	0.9700
X:12919206:G:GT	donor_gain	0.9600
X:12906707:ATG:A	donor_gain	0.9500
X:12919043:GGAA:G	acceptor_gain	0.9500
X:12919042:AG:A	acceptor_gain	0.9300
X:12919043:GG:G	acceptor_gain	0.9300
X:12919043:GGA:G	acceptor_gain	0.9200
X:12919026:A:AG	acceptor_loss	0.8900
X:12919043:GGAAA:G	acceptor_gain	0.8900
X:12909419:A:AG	donor_gain	0.8800
X:12919031:T:TA	acceptor_gain	0.8300
X:12910321:CAGTG:C	acceptor_gain	0.8200
X:12910322:AGTGT:A	acceptor_gain	0.8000
X:12917872:G:GC	acceptor_gain	0.8000

AlphaMissense

6934 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:12920081:C:A	N347K	0.999
X:12920081:C:G	N347K	0.999
X:12920252:T:A	N404K	0.999
X:12920252:T:G	N404K	0.999
X:12920003:C:A	N321K	0.998
X:12920003:C:G	N321K	0.998
X:12921874:T:A	V945D	0.998
X:12920513:C:A	N491K	0.997
X:12920513:C:G	N491K	0.997
X:12921726:T:A	W896R	0.997
X:12921726:T:C	W896R	0.997
X:12921728:G:C	W896C	0.997
X:12921728:G:T	W896C	0.997
X:12922052:G:C	W1004C	0.997
X:12922052:G:T	W1004C	0.997
X:12919921:T:C	L294P	0.996
X:12920324:C:A	N428K	0.996
X:12920324:C:G	N428K	0.996
X:12920732:T:A	N564K	0.996
X:12920732:T:G	N564K	0.996
X:12921804:T:A	W922R	0.996
X:12921804:T:C	W922R	0.996
X:12922050:T:A	W1004R	0.996
X:12922050:T:C	W1004R	0.996
X:12919808:C:A	N256K	0.995
X:12919808:C:G	N256K	0.995
X:12919915:T:C	L292P	0.995
X:12920076:T:C	F346L	0.995
X:12920078:T:A	F346L	0.995
X:12920078:T:G	F346L	0.995

dbSNP variants (sampled 300 via entrez): RS1000037346 (X:12918335 G>A), RS1000317624 (X:12911866 T>G), RS1000650274 (X:12914161 T>C), RS1000732818 (X:12923631 C>T), RS1001395926 (X:12915743 A>C), RS1002042478 (X:12923110 T>C), RS1002290616 (X:12915784 A>G), RS1002494994 (X:12921714 T>C), RS1002531774 (X:12909208 T>G), RS1002671456 (X:12917295 T>A), RS1002706371 (X:12907817 G>A), RS1003077987 (X:12910716 T>C), RS1003213854 (X:12917747 T>C), RS1003634318 (X:12907970 G>A), RS1003686718 (X:12907517 G>A)

Disease associations

OMIM: gene MIM:300366 | disease phenotypes: MIM:301078, MIM:205700

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 98 with autoinflammation, X-linked	Strong	X-linked

Mondo (3): immunodeficiency 98 with autoinflammation, X-linked (MONDO:0024777), autoimmune hemolytic anemia (MONDO:0020108), osteoarthritis (MONDO:0005178)

Orphanet (2): TLR8-related inflammation-severe neutropenia-bone marrow failure-lymphoproliferation syndrome (Orphanet:675628), Autoimmune hemolytic anemia (Orphanet:98375)

HPO phenotypes

24 total (25 of 24 shown, HPO-id order):

HPO	Term
HP:0000403	Recurrent otitis media
HP:0001417	X-linked inheritance
HP:0001510	Growth delay
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001890	Autoimmune hemolytic anemia
HP:0002240	Hepatomegaly
HP:0002716	Lymphadenopathy
HP:0002719	Recurrent infections
HP:0003453	Antineutrophil antibody positivity
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0004315	Decreased circulating IgG concentration
HP:0005528	Bone marrow hypocellularity
HP:0009098	Chronic oral candidiasis
HP:0010976	Decreased total B cell count
HP:0011107	Recurrent aphthous stomatitis
HP:0011974	Myelofibrosis
HP:0012156	Hemophagocytosis
HP:0012234	Absence of circulating granulocytes
HP:0020102	Pneumocystis jirovecii pneumonia
HP:0025708	Early young adult onset
HP:0100651	Type I diabetes mellitus
HP:0002758	Osteoarthritis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST000612_1	Celiac disease	6.000000e-08

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000744	Anemia, Hemolytic, Autoimmune	C15.378.050.141.125; C20.111.175
D010003	Osteoarthritis	C05.550.114.606; C05.799.613

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3137288 (PROTEIN FAMILY), CHEMBL4106182 (PROTEIN FAMILY), CHEMBL5805 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 24,125 (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
CHEMBL2424780	VESATOLIMOD	2	1,766
CHEMBL3301618	MOTOLIMOD	2	1,928
CHEMBL383322	RESIQUIMOD	2	18,616
CHEMBL4297492	GSK-2245035	2	809
CHEMBL4594258	SELGANTOLIMOD	2	821
CHEMBL4650329	AFIMETORAN	2	49
CHEMBL4802159	ENPATORAN	2	110
CHEMBL5417170	MHV-370	2	26

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Toll-like receptor family

Most potent curated ligand interactions (7 total), top 7:

Ligand	Action	Affinity	Parameter
compound 15 [PMID: 35450354]	Antagonist	8.7	pIC50
motolimod	Agonist	7.0	pEC50
selgantolimod	Agonist	6.66	pEC50
CU-CPT8m	Inhibition	6.66	pKd
3M-002	Agonist	5.88	pEC50
compound 12p [Larson et al., 2017]	Agonist	5.3	pEC50
resiquimod	Agonist	5.21	pEC50

Binding affinities (BindingDB)

1070 measured of 1148 human assays (1148 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-[4-[2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]pentane-1,5-diol	IC50	0.1 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-[4-[2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-1-pyrrolidin-1-ylethanone	IC50	0.2 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
8-chloro-7-methyl-6-(5-piperidin-4-yl-3-propan-2-yl-1H-indol-2-yl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.2 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
1-[4-[2-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-2-methylpropan-2-ol	IC50	0.2 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
8-methoxy-6-[5-[1-(2-methylsulfonylethyl)piperidin-4-yl]-3-propan-2-yl-1H-indol-2-yl]-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.2 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-[4-[2-(8-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-N-methylacetamide	IC50	0.2 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
3-[4-[2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]propan-1-ol	IC50	0.2 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-(dimethylamino)-1-[4-[3-propan-2-yl-2-[8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-1H-indol-5-yl]piperidin-1-yl]ethanone	IC50	0.2 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
1-[4-[2-(8-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-2-(dimethylamino)ethanone	IC50	0.2 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
1-[4-[2-(8-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-2-(methylamino)ethanone	IC50	0.2 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-[cyclopropyl(2-hydroxyethyl)amino]-1-[4-[2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]ethanone	IC50	0.2 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
1-[4-[2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-2-[methyl(propan-2-yl)amino]ethanone	IC50	0.2 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
1-(3,3-difluoroazetidin-1-yl)-2-[4-[2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]ethanone	IC50	0.2 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-[[3-[4-[2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-3-oxopropyl]amino]acetamide	IC50	0.2 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine dihydrochloride	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
6-[5-[1-(isocyanomethyl)piperidin-4-yl]-3-propan-2-yl-1H-indol-2-yl]-8-methyl-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-[4-[2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]acetamide	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
8-methyl-6-[5-[1-(2-methylpropyl)piperidin-4-yl]-3-propan-2-yl-1H-indol-2-yl]-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
8-methoxy-6-[5-[1-(oxan-4-yl)piperidin-4-yl]-3-propan-2-yl-1H-indol-2-yl]-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
8-ethyl-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
8-chloro-2,7-dimethyl-6-(5-piperidin-4-yl-3-propan-2-yl-1H-indol-2-yl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
8-cyclopropyl-6-(5-piperidin-4-yl-3-propan-2-yl-1H-indol-2-yl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-[4-[2-(8-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-N,N-dimethylacetamide	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
8-methyl-6-[5-[1-(oxolan-3-yl)piperidin-4-yl]-3-propan-2-yl-1H-indol-2-yl]-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
6-[5-[1-[(3-methyloxetan-3-yl)methyl]piperidin-4-yl]-3-propan-2-yl-1H-indol-2-yl]-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
8-methoxy-6-[5-[1-[(3-methyloxetan-3-yl)methyl]piperidin-4-yl]-3-propan-2-yl-1H-indol-2-yl]-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-(methylamino)-1-[4-[3-propan-2-yl-2-[8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-1H-indol-5-yl]piperidin-1-yl]ethanone	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-[ethyl(methyl)amino]-1-[4-[3-propan-2-yl-2-[8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-1H-indol-5-yl]piperidin-1-yl]ethanone	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-[4-[2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-N-[(3-methyloxetan-3-yl)methyl]acetamide	IC50	0.3 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-[4-[2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-N-methylacetamide	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
1-[4-[2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-2-methylpropan-2-ol	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
1-[4-[2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-2-(propylamino)ethanone	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
8-isopropyl-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
6-(5-piperidin-4-yl-3-propan-2-yl-1H-indol-2-yl)-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-[4-[2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]ethanesulfonamide	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
1-[[4-[2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]methyl]cyclopropane-1-diazonium	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
6-[5-[1-(2-hydroxy-2-methylpropyl)piperidin-4-yl]-3-propan-2-yl-1H-indol-2-yl]-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-[4-[2-(8-chloro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-N,N-dimethylacetamide	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-[4-[2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-2-(3-methyloxetan-3-yl)acetonitrile	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
6-[5-[1-(oxolan-3-yl)piperidin-4-yl]-3-propan-2-yl-1H-indol-2-yl]-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
6-[5-[1-(2,2-dimethyloxan-4-yl)piperidin-4-yl]-3-propan-2-yl-1H-indol-2-yl]-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
(3R)-3-[[4-[2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]methyl]morpholine	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
6-[5-[1-(3-isocyanocyclobutyl)piperidin-4-yl]-3-propan-2-yl-1H-indol-2-yl]-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
8-methoxy-6-[5-[1-(oxolan-3-yl)piperidin-4-yl]-3-propan-2-yl-1H-indol-2-yl]-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-[4-[2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-N-methylethanamine	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
[(2S,4R)-4-fluoropyrrolidin-2-yl]-[4-[2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]methanone	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
[4-[2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-(1-methylpyrrolidin-3-yl)methanone	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
1-[4-[2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-2-[(3S)-3-fluoropyrrolidin-1-yl]ethanone	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
2-[(3R)-3-hydroxypyrrolidin-1-yl]-1-[4-[2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]ethanone	IC50	0.4 nM	US-10071079: [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 43 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.30	IC50	0.05	nM	CHEMBL5078689
10.30	EC50	0.05	nM	CHEMBL5277999
10.10	IC50	0.08	nM	CHEMBL5091113
10.10	IC50	0.08	nM	CHEMBL5090067
10.10	EC50	0.08	nM	CHEMBL5291249
10.00	IC50	0.1	nM	CHEMBL5399590
9.96	EC50	0.11	nM	CHEMBL5273537
9.92	IC50	0.12	nM	CHEMBL5745669
9.92	IC50	0.12	nM	CHEMBL5823006
9.82	IC50	0.15	nM	CHEMBL5760762
9.82	IC50	0.15	nM	CHEMBL5866075
9.77	IC50	0.17	nM	CHEMBL5895437
9.77	IC50	0.17	nM	CHEMBL5858961
9.74	EC50	0.18	nM	CHEMBL5266091
9.70	IC50	0.2	nM	CHEMBL5079910
9.64	IC50	0.23	nM	CHEMBL5756221
9.64	IC50	0.23	nM	CHEMBL6007248
9.62	IC50	0.24	nM	CHEMBL5930393
9.60	IC50	0.25	nM	CHEMBL5810296
9.60	IC50	0.25	nM	CHEMBL5860103
9.60	IC50	0.25	nM	CHEMBL5743407
9.59	IC50	0.26	nM	CHEMBL5802863
9.59	IC50	0.26	nM	CHEMBL6061597
9.57	EC50	0.27	nM	CHEMBL5272936
9.57	IC50	0.27	nM	CHEMBL5933041
9.55	IC50	0.28	nM	CHEMBL5915678
9.55	IC50	0.28	nM	CHEMBL5791168
9.54	IC50	0.29	nM	CHEMBL6046514
9.52	IC50	0.3	nM	CHEMBL5757661
9.51	IC50	0.31	nM	CHEMBL5855476
9.49	IC50	0.32	nM	CHEMBL5921788
9.49	IC50	0.32	nM	CHEMBL5845046
9.49	IC50	0.32	nM	CHEMBL6024977
9.47	IC50	0.34	nM	CHEMBL5834601
9.47	IC50	0.34	nM	CHEMBL6005947
9.44	IC50	0.36	nM	CHEMBL6034571
9.43	IC50	0.37	nM	CHEMBL5853023
9.43	IC50	0.37	nM	CHEMBL5869357
9.43	IC50	0.37	nM	CHEMBL5986614
9.42	IC50	0.38	nM	CHEMBL6043776
9.41	IC50	0.39	nM	CHEMBL6040062
9.41	IC50	0.39	nM	CHEMBL5827127
9.41	IC50	0.39	nM	CHEMBL5781362

PubChem BioAssay actives

614 with measured affinity, of 2045 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
5-cyclopropyl-6-(2,6-dimethyl-4-pyridinyl)-N-[(3R,4R)-3-fluoropiperidin-4-yl]-1H-indazol-3-amine	1827791: Antagonist activity at human TLR8 expressed in human PBMC cells assessed as inhibition of ssRNA stimulated TNF level preincubated for 30 mins followed by stimulation and measured after 20 hrs by multiplate reader assay	ic50	0.0001	uM
5-cyclopropyl-6-(2,6-dimethyl-4-pyridinyl)-N-[(3S,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-amine	1827791: Antagonist activity at human TLR8 expressed in human PBMC cells assessed as inhibition of ssRNA stimulated TNF level preincubated for 30 mins followed by stimulation and measured after 20 hrs by multiplate reader assay	ic50	0.0001	uM
5-cyclopropyl-6-(3-fluoro-2-methyl-4-pyridinyl)-N-(1-methylpiperidin-4-yl)-1H-indazol-3-amine	1827791: Antagonist activity at human TLR8 expressed in human PBMC cells assessed as inhibition of ssRNA stimulated TNF level preincubated for 30 mins followed by stimulation and measured after 20 hrs by multiplate reader assay	ic50	0.0001	uM
3-methyl-4-propan-2-yl-2-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(3,5,6-triazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7-tetraen-8-yl)-6H-thieno[2,3-b]pyrrole	1956348: Antagonist activity at human TLR8 expressed in human PBMC cells preincubated for 1 hr followed by GS-986 stimulation measured after 6 hrs by electrochemiluminescence immunoassay	ec50	0.0001	uM
2-[(1S,4R,5R)-5-[3-methyl-5-(4-methyl-3,5,6-triazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7-tetraen-8-yl)-4-propan-2-yl-6H-thieno[2,3-b]pyrrol-2-yl]-2-azabicyclo[2.2.1]heptan-2-yl]acetamide	1956348: Antagonist activity at human TLR8 expressed in human PBMC cells preincubated for 1 hr followed by GS-986 stimulation measured after 6 hrs by electrochemiluminescence immunoassay	ec50	0.0001	uM
3-methyl-2-[(1S,4R,5R)-2-(2-methylsulfonylethyl)-2-azabicyclo[2.2.1]heptan-5-yl]-4-propan-2-yl-5-(3,5,6-triazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7-tetraen-8-yl)-6H-thieno[2,3-b]pyrrole	1956348: Antagonist activity at human TLR8 expressed in human PBMC cells preincubated for 1 hr followed by GS-986 stimulation measured after 6 hrs by electrochemiluminescence immunoassay	ec50	0.0001	uM
4-[4-(7-methoxyquinolin-4-yl)-2-methylphenoxy]butan-1-ol	1989278: Antagonist activity at human TLR8	ic50	0.0001	uM
5-cyclopropyl-6-(3-fluoro-2-methyl-4-pyridinyl)-N-[(3S,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-amine	1827791: Antagonist activity at human TLR8 expressed in human PBMC cells assessed as inhibition of ssRNA stimulated TNF level preincubated for 30 mins followed by stimulation and measured after 20 hrs by multiplate reader assay	ic50	0.0002	uM
2-[3-methyl-4-propan-2-yl-5-(3,5,6-triazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7-tetraen-8-yl)-6H-thieno[2,3-b]pyrrol-2-yl]-5-oxa-8-azaspiro[3.5]nonane	1956348: Antagonist activity at human TLR8 expressed in human PBMC cells preincubated for 1 hr followed by GS-986 stimulation measured after 6 hrs by electrochemiluminescence immunoassay	ec50	0.0002	uM
2-deuterio-5-[(2S,6R)-11-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-methyl-4,7,10-triazatricyclo[7.4.0.02,7]trideca-1(9),10,12-trien-4-yl]quinoline-8-carbonitrile	1777160: Inhibition of human TLR8 expressed in HEK293-Blue cells assessed as inhibition of R848-induced NF-kappaB/AP-1 activation measured after 20 hrs using quanti-blue as substrate by SEAP reporter gene based spectrophotometry assay	ic50	0.0003	uM
2-deuterio-5-[(2S,6R)-6-methyl-11-piperidin-4-yloxy-4,7,10-triazatricyclo[7.4.0.02,7]trideca-1(9),10,12-trien-4-yl]quinoline-8-carbonitrile	1777160: Inhibition of human TLR8 expressed in HEK293-Blue cells assessed as inhibition of R848-induced NF-kappaB/AP-1 activation measured after 20 hrs using quanti-blue as substrate by SEAP reporter gene based spectrophotometry assay	ic50	0.0003	uM
5-[(2S,6R)-11-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-methyl-4,7,10-triazatricyclo[7.4.0.02,7]trideca-1(9),10,12-trien-4-yl]-2-deuterioquinoline-8-carbonitrile	1777160: Inhibition of human TLR8 expressed in HEK293-Blue cells assessed as inhibition of R848-induced NF-kappaB/AP-1 activation measured after 20 hrs using quanti-blue as substrate by SEAP reporter gene based spectrophotometry assay	ic50	0.0003	uM
2-(6-azaspiro[3.4]octan-2-yl)-3-methyl-4-propan-2-yl-5-(3,5,6-triazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7-tetraen-8-yl)-6H-thieno[2,3-b]pyrrole	1956348: Antagonist activity at human TLR8 expressed in human PBMC cells preincubated for 1 hr followed by GS-986 stimulation measured after 6 hrs by electrochemiluminescence immunoassay	ec50	0.0003	uM
8-[2-[(3S,4S)-3-fluoropiperidin-4-yl]-7-(trifluoromethyl)indazol-5-yl]-2,3-dihydro-1H-indolizin-5-one	1661567: Antagonist activity at TLR8 in human whole blood assessed as inhibition of DOTAP-ssRNA40 induced TNFalpha production preincubated for 30 mins followed by ssRNA40 addition measured after 20 hrs by HTRF assay	ic50	0.0004	uM
2-deuterio-5-[(2S,6R)-11-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-methyl-4,7,10-triazatricyclo[7.4.0.02,7]trideca-1(9),10,12-trien-4-yl]quinoline-8-carbonitrile	1777160: Inhibition of human TLR8 expressed in HEK293-Blue cells assessed as inhibition of R848-induced NF-kappaB/AP-1 activation measured after 20 hrs using quanti-blue as substrate by SEAP reporter gene based spectrophotometry assay	ic50	0.0004	uM
4-(7-methoxyquinolin-4-yl)-2-methylphenol	1692752: Inhibition of TLR8 in HEK-Blue hTLR8 assessed as reduction in SEAP production incubated for 20 to 24 hrs by Quanti-Blue assay	ic50	0.0005	uM
4-(4-hydroxy-3-methylphenyl)quinolin-7-ol	1846683: Antagonist activity at R848 stimulated TRL8 overexpressed in HEK293 cells measured after 20 to 24 hrs by SEAP reporter assay	ic50	0.0007	uM
2-deuterio-5-[(2S,6R)-11-(2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-4,7,10-triazatricyclo[7.4.0.02,7]trideca-1(9),10,12-trien-4-yl]quinoline-8-carbonitrile	1777160: Inhibition of human TLR8 expressed in HEK293-Blue cells assessed as inhibition of R848-induced NF-kappaB/AP-1 activation measured after 20 hrs using quanti-blue as substrate by SEAP reporter gene based spectrophotometry assay	ic50	0.0007	uM
5-(4-hydroxy-3-methylphenyl)naphthalen-2-ol	1930976: Inhibition of human TLR8	ic50	0.0007	uM
2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3,4-dimethyl-6-piperidin-4-yl-9H-carbazole	1768801: Inhibition of human TLR8 in HEK-Blue hTLR8 cells assessed as reduction in R848-activated NF-KappaB by SEAP reporter assay	ic50	0.0008	uM
7-methoxy-4-(5-methyl-6-phenylmethoxy-3-pyridinyl)quinoline	1989278: Antagonist activity at human TLR8	ic50	0.0008	uM
2-(2,5-dimethyl-4-pyridinyl)-5-piperidin-4-yl-3-propan-2-yl-1H-indole	1880295: Antagonist activity at R848 stimulated human TRL8 overexpressed in HEK293 cells assessed as inhibition of NF kappa B/Ap-1 activation preincubated with compound for 30 mins followed by R848 stimulation measured after 22 hrs by SEAP reporter assay	ic50	0.0010	uM
4-(7-chloroquinolin-4-yl)-2-methylphenol	1989278: Antagonist activity at human TLR8	ic50	0.0010	uM
5-[(4R,9aR)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile	1684821: Inhibition of human TLR8 expressed in HEK-Blue cells assessed as inhibition of R848-induced NF-kappaB and AP-1 activation measured after 20 hrs by quanti-blue based SEAP reporter gene assay	ic50	0.0010	uM
4-[[3-methyl-5-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2-pyridinyl]oxymethyl]bicyclo[2.2.2]octan-1-amine	1721817: Antagonist activity at TLR8 in human THP-1 cells assessed as inhibition of resiquimod-induced TNFalpha production	ic50	0.0010	uM
4-[[3-methyl-5-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2-pyridinyl]oxymethyl]bicyclo[2.2.2]octan-1-ol	1721817: Antagonist activity at TLR8 in human THP-1 cells assessed as inhibition of resiquimod-induced TNFalpha production	ic50	0.0010	uM
3-[6-[(4-amino-1-bicyclo[2.2.2]octanyl)methoxy]-5-methyl-3-pyridinyl]-1-methylpyrazolo[3,4-d]pyrimidin-6-amine	1721817: Antagonist activity at TLR8 in human THP-1 cells assessed as inhibition of resiquimod-induced TNFalpha production	ic50	0.0010	uM
8-[2-[(3R,4R)-3-fluoropiperidin-4-yl]-7-(trifluoromethyl)indazol-5-yl]-2,3-dihydro-1H-indolizin-5-one	1661555: Antagonist activity at TLR8 in human PBMC assessed as inhibition of DOTAP-ssRNA40 induced TNFalpha production preincubated for 30 mins followed by ssRNA40 addition measured after 20 hrs by HTRF assay	ic50	0.0011	uM
[6-(3-fluoro-2-methyl-4-pyridinyl)-5-methoxy-1H-indazol-3-yl]-(4-methylpiperazin-1-yl)methanone	1827791: Antagonist activity at human TLR8 expressed in human PBMC cells assessed as inhibition of ssRNA stimulated TNF level preincubated for 30 mins followed by stimulation and measured after 20 hrs by multiplate reader assay	ic50	0.0012	uM
6-(3-fluoro-2-methyl-4-pyridinyl)-5-methoxy-N-(1-methylpiperidin-4-yl)-1H-indazol-3-amine	1827791: Antagonist activity at human TLR8 expressed in human PBMC cells assessed as inhibition of ssRNA stimulated TNF level preincubated for 30 mins followed by stimulation and measured after 20 hrs by multiplate reader assay	ic50	0.0012	uM
2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-methyl-6-piperidin-4-yl-9H-carbazole	1768801: Inhibition of human TLR8 in HEK-Blue hTLR8 cells assessed as reduction in R848-activated NF-KappaB by SEAP reporter assay	ic50	0.0014	uM
6-(3-fluoro-2-methyl-4-pyridinyl)-5-methyl-N-(1-methylpiperidin-4-yl)-1H-indazol-3-amine	1827791: Antagonist activity at human TLR8 expressed in human PBMC cells assessed as inhibition of ssRNA stimulated TNF level preincubated for 30 mins followed by stimulation and measured after 20 hrs by multiplate reader assay	ic50	0.0015	uM
5-[(2R)-11-(4-amino-4-methylpiperidin-1-yl)-4,7,10-triazatricyclo[7.4.0.02,7]trideca-1(9),10,12-trien-4-yl]quinoline-8-carbonitrile	1777160: Inhibition of human TLR8 expressed in HEK293-Blue cells assessed as inhibition of R848-induced NF-kappaB/AP-1 activation measured after 20 hrs using quanti-blue as substrate by SEAP reporter gene based spectrophotometry assay	ic50	0.0019	uM
5-[(4R,9aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile	1684821: Inhibition of human TLR8 expressed in HEK-Blue cells assessed as inhibition of R848-induced NF-kappaB and AP-1 activation measured after 20 hrs by quanti-blue based SEAP reporter gene assay	ic50	0.0020	uM
4-[[5-(1,6-dimethylpyrazolo[3,4-b]pyridin-4-yl)-3-methyl-2-pyridinyl]oxymethyl]bicyclo[2.2.2]octan-1-amine	1721817: Antagonist activity at TLR8 in human THP-1 cells assessed as inhibition of resiquimod-induced TNFalpha production	ic50	0.0020	uM
5-methoxy-6-pyridin-4-yl-1H-indole	1827773: Antagonist activity at human TLR8 expressed in Drosophila S2 by TR-FRET assay	ic50	0.0020	uM
[6-(2,6-dimethyl-4-pyridinyl)-5-methoxy-1H-indazol-3-yl]-(4-methylpiperazin-1-yl)methanone	1827791: Antagonist activity at human TLR8 expressed in human PBMC cells assessed as inhibition of ssRNA stimulated TNF level preincubated for 30 mins followed by stimulation and measured after 20 hrs by multiplate reader assay	ic50	0.0025	uM
6-fluoro-2-(2-methyl-4-pyridinyl)-5-piperidin-4-yl-3-propan-2-yl-1H-indole	1880295: Antagonist activity at R848 stimulated human TRL8 overexpressed in HEK293 cells assessed as inhibition of NF kappa B/Ap-1 activation preincubated with compound for 30 mins followed by R848 stimulation measured after 22 hrs by SEAP reporter assay	ic50	0.0027	uM
8-[2-piperidin-4-yl-7-(trifluoromethyl)indazol-5-yl]-2,3-dihydro-1H-indolizin-5-one	1661555: Antagonist activity at TLR8 in human PBMC assessed as inhibition of DOTAP-ssRNA40 induced TNFalpha production preincubated for 30 mins followed by ssRNA40 addition measured after 20 hrs by HTRF assay	ic50	0.0027	uM
3-ethyl-4,6-difluoro-2-(2-methyl-4-pyridinyl)-5-piperidin-4-yl-1H-indole	1880295: Antagonist activity at R848 stimulated human TRL8 overexpressed in HEK293 cells assessed as inhibition of NF kappa B/Ap-1 activation preincubated with compound for 30 mins followed by R848 stimulation measured after 22 hrs by SEAP reporter assay	ic50	0.0028	uM
3-[4-[(4-amino-1-bicyclo[2.2.2]octanyl)methoxy]-3-fluorophenyl]-1-methylpyrazolo[3,4-d]pyrimidin-6-amine	1721817: Antagonist activity at TLR8 in human THP-1 cells assessed as inhibition of resiquimod-induced TNFalpha production	ic50	0.0030	uM
2-(2,6-dimethyl-4-pyridinyl)-4-fluoro-5-piperidin-4-yl-3-propan-2-yl-1H-indole	1880295: Antagonist activity at R848 stimulated human TRL8 overexpressed in HEK293 cells assessed as inhibition of NF kappa B/Ap-1 activation preincubated with compound for 30 mins followed by R848 stimulation measured after 22 hrs by SEAP reporter assay	ic50	0.0030	uM
5-[(4R,10bS)-8-(3a-methoxy-1,2,3,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]quinoline-8-carbonitrile	1846686: Antagonist activity at R848 stimulated TRL8 in HEK-Blue hTLR8 cells assessed as inhibition of NF kappa B/Ap-1 activation measured after 20 hrs by SEAP reporter assay	ic50	0.0030	uM
5-[(2S,6R)-2-[[8-(2,6-dimethyl-4-pyridinyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]methyl]-6-methylmorpholin-4-yl]quinoline-8-carbonitrile	1846686: Antagonist activity at R848 stimulated TRL8 in HEK-Blue hTLR8 cells assessed as inhibition of NF kappa B/Ap-1 activation measured after 20 hrs by SEAP reporter assay	ic50	0.0030	uM
5-[(4R,9aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile	1684821: Inhibition of human TLR8 expressed in HEK-Blue cells assessed as inhibition of R848-induced NF-kappaB and AP-1 activation measured after 20 hrs by quanti-blue based SEAP reporter gene assay	ic50	0.0030	uM
2-(2,6-dimethyl-4-pyridinyl)-5-piperidin-4-yl-3-propan-2-yl-1H-indole	1880295: Antagonist activity at R848 stimulated human TRL8 overexpressed in HEK293 cells assessed as inhibition of NF kappa B/Ap-1 activation preincubated with compound for 30 mins followed by R848 stimulation measured after 22 hrs by SEAP reporter assay	ic50	0.0032	uM
2-(2-fluoro-6-methyl-4-pyridinyl)-5-piperidin-4-yl-3-propan-2-yl-1H-indole	1880295: Antagonist activity at R848 stimulated human TRL8 overexpressed in HEK293 cells assessed as inhibition of NF kappa B/Ap-1 activation preincubated with compound for 30 mins followed by R848 stimulation measured after 22 hrs by SEAP reporter assay	ic50	0.0038	uM
2-(2-methyl-4-pyridinyl)-5-piperidin-4-yl-3-propan-2-yl-1H-indole	1880295: Antagonist activity at R848 stimulated human TRL8 overexpressed in HEK293 cells assessed as inhibition of NF kappa B/Ap-1 activation preincubated with compound for 30 mins followed by R848 stimulation measured after 22 hrs by SEAP reporter assay	ic50	0.0039	uM
5-[(4R,9aR)-8-[5-(6-amino-2-azaspiro[3.3]heptan-2-yl)-3-methyl-2-pyridinyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-2-deuterioquinoline-8-carbonitrile	1684821: Inhibition of human TLR8 expressed in HEK-Blue cells assessed as inhibition of R848-induced NF-kappaB and AP-1 activation measured after 20 hrs by quanti-blue based SEAP reporter gene assay	ic50	0.0040	uM
5-[(4R,9aS)-8-[2-[6-[(3R,4S)-3-amino-4-fluoropyrrolidin-1-yl]-3-pyridinyl]ethyl]-4-methyl-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile	1684821: Inhibition of human TLR8 expressed in HEK-Blue cells assessed as inhibition of R848-induced NF-kappaB and AP-1 activation measured after 20 hrs by quanti-blue based SEAP reporter gene assay	ic50	0.0040	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Nickel	decreases expression, increases expression	3
resiquimod	decreases reaction, increases activity, affects binding	2
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
quinoline	increases phosphorylation, increases activity	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
bafilomycin A1	decreases reaction, increases activity	1
lipopolysaccharide, E. coli O26-B6	increases expression	1
N-(4-(4-amino-2-ethyl-1H-imidazo(4,5c)quinolin-1-yl)butyl)methanesulfonamide	increases activity	1
gardiquimod	increases expression, decreases reaction	1
CL097 compound	affects binding, increases activity	1
nabiximols	decreases expression	1
Arsenic Trioxide	increases expression	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Air Pollutants	increases abundance, affects expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	decreases expression	1
Chloroquine	decreases activity	1
Diazinon	increases methylation	1
Estradiol	affects cotreatment, increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression, affects response to substance, increases expression	1
Malathion	increases expression	1
Metformin	affects cotreatment, increases expression	1
Oligoribonucleotides	increases activity, decreases reaction, increases secretion	1
Ozone	affects expression, increases abundance	1
Tretinoin	increases expression	1
Aflatoxin B1	decreases methylation	1
Paclitaxel	affects cotreatment, increases expression	1
Antirheumatic Agents	decreases expression	1
beta-Naphthoflavone	increases expression	1

ChEMBL screening assays

395 unique, capped per target: 378 binding, 16 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1248011	Binding	Inhibition of TLR7/TLR8-mediated IFN-gamma production in 3M-011-stimulated human PBMC at 100 uM after 20 hrs by ELISA	Chloroquine modulates HIV-1-induced plasmacytoid dendritic cell alpha interferon: implication for T-cell activation. — Antimicrob Agents Chemother
CHEMBL1023609	Functional	Agonist activity at human TLR8 expressed in HEK293XL cells assessed as NF-kappaB activation after 18 hrs	Synthetic oligoribonucleotides containing arabinonucleotides act as agonists of TLR7 and 8. — Bioorg Med Chem Lett
CHEMBL4187730	ADMET	Agonist activity at human TLR8 expressed in HEK293 cells assessed as induction of receptor activation incubated for 6 hrs by NF-kappaB-luciferase reporter gene assay	Discovery of selective 2,4-diaminoquinazoline toll-like receptor 7 (TLR 7) agonists. — Bioorg Med Chem Lett

Cellosaurus cell lines

11 cell lines: 7 transformed cell line, 3 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A8BW	THP1-Dual KO-TLR8	Cancer cell line	Male
CVCL_D7A4	Leeporter HEK293 TLR8/NF-kB luciferase	Transformed cell line	Female
CVCL_E2LX	HAP1 TLR8 (-)	Cancer cell line	Male
CVCL_E6V2	Genomeditech HEK-293 H_TLR8	Transformed cell line	Female
CVCL_E6V3	Genomeditech HEK-293 H_TLR8 Reporter	Transformed cell line	Female
CVCL_E8FC	THP1-Dual hTLR8	Cancer cell line	Male
CVCL_IM85	HEK-Blue hTLR8	Transformed cell line	Female
CVCL_RQ77	HEK 293/TLR8/NF-kB Luciferase Reporter	Transformed cell line	Female
CVCL_WR15	KSCBi005-A-5	Induced pluripotent stem cell	Male
CVCL_Y411	293XL/hTLR8-HA	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03918265	PHASE4	UNKNOWN	Tacrolimus Treatment for Refractory Autoimmune Cytopenia
NCT00130468	PHASE4	COMPLETED	TREAD-20: Trial of Hyalgan Three Injection-Regimen for the Treatment of Knee Pain Due to Osteoarthritis
NCT00138892	PHASE4	UNKNOWN	A Randomized Controlled Trial of Long Versus Short Wait For Primary Total Hip and Knee Arthroplasty
NCT00140972	PHASE4	COMPLETED	A Study to Assess Etoricoxib Versus Diclofenac in Chinese Patients With Osteoarthritis of the Knee or Hip (0663-080)(COMPLETED)
NCT00141102	PHASE4	COMPLETED	Study Of Celecoxib Or Diclofenac And Omeprazole For Gastrointestinal (GI) Safety In High GI Risk Patients With Arthritis
NCT00208364	PHASE4	TERMINATED	A Two Centre Study to Assess the Long-term Performance of the Pinnacle™ Cup With a Metal-on-Metal Bearing in Primary Total Hip Replacement
NCT00208377	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the DePuy ASR™ System in Primary Hip Resurfacing Surgery
NCT00208390	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the Summit™ Hip in Primary Total Hip Replacement
NCT00208403	PHASE4	TERMINATED	A Randomised Single Centre Study to Compare the Long-term Performance of Acryloc™ and Palacos® R Bone Cements in Primary Total Hip Replacement
NCT00208416	PHASE4	TERMINATED	A Randomised Multi-centre Study to Compare the Short-term Outcomes of Minimally Invasive and Conventional Surgery in Primary Total Hip Replacement
NCT00208429	PHASE4	WITHDRAWN	A Multi-centre Study to Assess the Long-term Performance of the Pinnacle™ Cup With a Polyethylene-on-metal Bearing in Primary Total Hip Replacement
NCT00208442	PHASE4	COMPLETED	A Randomised Single Centre Study to Compare the Long-term Wear Characteristics of Marathon™ and Enduron™ Polyethylene Cup Liners in Primary Total Hip Replacement
NCT00208455	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the DePuy PROXIMA™ Hip in Primary Total Hip Replacement
NCT00236366	PHASE4	COMPLETED	A Study of the Effect on Pain Control of Treatment With Fentanyl, Administered Through the Skin, Compared With Placebo in Patients With Osteoarthritis
NCT00251069	PHASE4	COMPLETED	Glucosamine Sulphate and Increased Level of Blood Cholesterol
NCT00253851	PHASE4	COMPLETED	Does Thinning the Blood During Surgery Prevent Blood Clots Following Total Knee Replacement Surgery
NCT00267176	PHASE4	COMPLETED	Safety and Efficacy of Lumiracoxib in Patients With Osteoarthritis and With Controlled Hypertension
NCT00270322	PHASE4	TERMINATED	Pain Treatment After Total Knee Replacement - Continuous Epidural Versus Intravenous Patient Controlled Analgesia With Morphine
NCT00279838	PHASE4	COMPLETED	Computer Assisted Total Knee Replacement
NCT00294801	PHASE4	UNKNOWN	Effect of Flex-a-New on Osteoarthritis of the Knee
NCT00324038	PHASE4	COMPLETED	Buprenorphine in the Treatment of Osteoarthritis (OA) in the Elderly
NCT00346788	PHASE4	COMPLETED	The Subvastus Approach in Total Knee Arthroplasty
NCT00359151	PHASE4	TERMINATED	Celebrex Total Knee Arthroplasty Study
NCT00373685	PHASE4	COMPLETED	GI-Reasons- A Trial Of GI Safety Of Celecoxib Compared With Non-Selective Nonsteroidal Antiinflammatory Drugs (NSAIDS)
NCT00393393	PHASE4	UNKNOWN	Effectiveness Study of Hylan G-F 20 to Preserve Cartilage in Osteoarthritis of the Knee
NCT00399178	PHASE4	COMPLETED	A Randomised Open Controlled Parallel Group Study Comparing Norspan and Tramadol
NCT00426647	PHASE4	COMPLETED	Norspan® Patches Versus Tramadol in Subjects With Chronic, Moderate to Severe Osteoarthritis Pain in the Hip Knee and/or Lumbar Spine
NCT00431509	PHASE4	UNKNOWN	Trial Comparing Navigated and Conventional Implantation Techniques in Knee Replacement Surgery
NCT00440661	PHASE4	COMPLETED	Exploration of the Synovial Fluid Inflammation Mediators Under Diacerhein in Knee Osteoarthritis
NCT00443092	PHASE4	COMPLETED	Efficacy of Proprietary Cherry Juice Blend in Osteoarthritis of the Knee
NCT00447759	PHASE4	COMPLETED	The Standard Care Versus Celecoxib Outcome Trial
NCT00484718	PHASE4	TERMINATED	Measuring Gait And Self-Reported Pain In Patients With Osteoarthritis Of The Knee Using Placebo/Oxycodone/Celecoxib.
NCT00524160	PHASE4	COMPLETED	A Study of the Effect on Pain Control of Treatment With Fentanyl, Administered Through the Skin, in Patients With Rheumatoid Arthritis or Osteoarthritis
NCT00542139	PHASE4	COMPLETED	Evaluation of Diprospan Injection to the Knee on Rehabilitation of Patients After TKR of the Contralateral Knee
NCT00546598	PHASE4	TERMINATED	Post-approval Study of the DURALOC® Option Ceramic-on-Ceramic Hip Prosthesis System
NCT00565500	PHASE4	COMPLETED	Celecoxib, Ibuprofen and the Antiplatelet Effect of Aspirin
NCT00598234	PHASE4	COMPLETED	Perioperative Pain Control With Celecoxib (Celebrex) in Total Knee Arthroplasty
NCT00609557	PHASE4	COMPLETED	A Single-Blind Placebo Run-in Study of Duloxetine for Activity-Limiting Osteoarthritis Pain
NCT00611676	PHASE4	COMPLETED	A Single-Blind Placebo Run-In Study of Venlafaxine for Activity-Limiting Osteoarthritis Pain
NCT00620828	PHASE4	COMPLETED	The Role of Intra-Operative Intracapsular Blocks in Post-Operative Pain Management Following Total Knee Arthroplasty