TLR9

Summary

TLR9 (toll like receptor 9, HGNC:15633) is a protein-coding gene on chromosome 3p21.2, encoding Toll-like receptor 9 (Q9NR96). Key component of 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. Studies in mice and human indicate that this receptor mediates cellular response to unmethylated CpG dinucleotides in bacterial DNA to mount an innate immune response.

Source: NCBI Gene 54106 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 140 total — 1 likely-pathogenic
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_017442

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15633
Approved symbol	TLR9
Name	toll like receptor 9
Location	3p21.2
Locus type	gene with protein product
Status	Approved
Aliases	CD289
Ensembl gene	ENSG00000239732
Ensembl biotype	protein_coding
OMIM	605474
Entrez	54106

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000360658

RefSeq mRNA: 1 — MANE Select: NM_017442 NM_017442

CCDS: CCDS2848

Canonical transcript exons

ENST00000360658 — 2 exons

Exon	Start	End
ENSE00001415425	52225527	52225645
ENSE00001931961	52221080	52224312

Expression profiles

Bgee: expression breadth ubiquitous, 119 present calls, max score 76.24.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7463 / max 131.5319, expressed in 85 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42408	0.6697	82
42407	0.0766	41

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	76.24	gold quality
granulocyte	CL:0000094	69.54	gold quality
lymph node	UBERON:0000029	68.21	gold quality
bone marrow cell	CL:0002092	66.24	silver quality
spleen	UBERON:0002106	64.07	gold quality
bone marrow	UBERON:0002371	64.04	gold quality
monocyte	CL:0000576	63.82	gold quality
cerebellar hemisphere	UBERON:0002245	63.44	gold quality
cerebellum	UBERON:0002037	63.35	gold quality
cerebellar cortex	UBERON:0002129	63.24	gold quality
right hemisphere of cerebellum	UBERON:0014890	63.02	gold quality
leukocyte	CL:0000738	62.85	gold quality
gastrocnemius	UBERON:0001388	62.56	gold quality
muscle of leg	UBERON:0001383	61.58	gold quality
skeletal muscle tissue	UBERON:0001134	61.37	gold quality
hindlimb stylopod muscle	UBERON:0004252	60.13	gold quality
vermiform appendix	UBERON:0001154	59.70	gold quality
right coronary artery	UBERON:0001625	59.62	gold quality
descending thoracic aorta	UBERON:0002345	59.57	gold quality
right ovary	UBERON:0002118	59.08	gold quality
thoracic aorta	UBERON:0001515	57.25	gold quality
small intestine Peyer’s patch	UBERON:0003454	57.15	gold quality
ascending aorta	UBERON:0001496	57.14	gold quality
apex of heart	UBERON:0002098	56.93	gold quality
left ovary	UBERON:0002119	56.80	gold quality
muscle tissue	UBERON:0002385	56.53	gold quality
ovary	UBERON:0000992	56.39	gold quality
urinary bladder	UBERON:0001255	55.99	gold quality
endocervix	UBERON:0000458	55.85	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	55.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	13.44
E-MTAB-8498	yes	12.09
E-MTAB-9801	yes	8.19
E-ANND-3	no	1.27

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPA, CEBPB, CEBPD, CEBPE, CREB1, ELF1, ELK1, ESR1, ETS2, HDAC3, IRF3, IRF6, JUN, NFKB1, NFKB, PTMA, RELA, STAT3

miRNA regulators (miRDB)

8 targeting TLR9, 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-4692	100.00	67.32	2066
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-6742-5P	96.32	64.01	869

Literature-anchored findings (GeneRIF, showing 40)

• TLR9 acts at the cell surface and engages an intracellular signaling pathway that includes MyD88, IRAK, and TRAF6 (PMID:11867692)
• Toll-like receptor 9 functions in the activation of RF expressing B-cells. (PMID:11976718)
• In naive B cells, the expression of TLR9 and TLR10 is rapidly induced following B-cell-receptor (BCR) triggering. In contrast, memory B cells express several TLRs at constitutively high levels. (PMID:12560217)
• All nine patients expressed all of the TLRs studied, whereas only five out of the nine patients had any granulomas positive for IL-4.The associations between TLRs 1, 5, and 9 were different in IL-4-negative compared with IL-4-positive patients. (PMID:12600829)
• normal and neoplastic human B lymphocytes express a distinct TLR repertoire including TLR9 and TLR10 and expression is increased upon engagement of the antigen receptor complex or TLR9 itself (PMID:12689944)
• Costimulation with TLR9 (or TLR2) and TLR4 induces synergistic release of Th1 cytokines, IFN-gamma and TNF-alpha, and additive HIV-LTR trans-activation and HIV replication, as measured by p24 antigen release from HIV-1 transgenic mouse spleen cells. (PMID:12734363)
• A synergistic role is played by the TLR9/CD40 system in the orchestration of CpG-ODN-induced responses in B lymphocytes. (PMID:12778475)
• peptidoglycan signaling through TLR2 and bacterial CpG DNA signaling through TLR9 are functionally equivalent at synergizing with IFN-gamma in regulating Tap-1 expression in macrophages (PMID:14694183)
• mechanism of cellular activation involving the recruitment of TLR9 from the ER to sites of CpG DNA uptake, where signal transduction is initiated (PMID:14716310)
• TLR signals that activate NF-kappaB are diverse among different TLRs, and TLR9 signaling uniquely depends on IRF-8 in DCs. (PMID:15153500)
• mechanism of TLR9 gene regulation (PMID:15294971)
• Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. (PMID:15307186)
• TLR9 expression may function as a proinflammatory activation marker during the transition from monocyte to dendritic cells. (PMID:15585868)
• Moreover, the TLR9 transfectant demonstrated its usefulness for evaluation of immunostimulation by bacterial DNA through the detection of T(H)-1, T(H)-2 type cytokine induction via TLR9 signaling. (PMID:15607737)
• The expression of functionally active TLR9 in human malignant tumors might affect treatment approaches using CpG-ODN and shows that malignant cells can be regarded as active players in tumor-immunology. (PMID:15631627)
• TLR9 gene polymorphisms were not significantly associated with the susceptibility to systemic lupus erythematosus in Korean patients. (PMID:15730519)
• The TLR9 was analyzed by ICS as it was reported to be expressed in an intracellular compartment. (PMID:15790341)
• a CpR dinucleotide is recognized by TLR9 and leads immune-cell activation and cytokine secretion in vitro and in vivo (PMID:15860583)
• Diminished expression and function of TLR9 is a likely consequence of chronic filarial antigen stimulation and could serve as a novel mechanism underlying the dysfunctional immune response in lymphatic filariasis (PMID:16002719)
• results demonstrated that TLR9 expression is correlated with immune activation and differs between individuals with non-activated or chronically immune activated background (PMID:16024265)
• Data indicate that the two TLR-9 promotor polymorphisms are not involved in atherogenesis. (PMID:16125159)
• TLR9 may have a critical role in the promotion of lupus through the induction of IFN-alpha by predendritic cells. (PMID:16230478)
• TLR9- and FcepsilonRI-mediated responses oppose one another in plasmacytoid dendritic cells by down-regulating receptor expression. (PMID:16237063)
• Activation of TLR-9 induces IL-8 secretion through peroxynitrite signaling in neutrophils. (PMID:16394009)
• Broad TLR9 activation defects in common variable immune deficiency prevent CpG-DNA-initiated innate immune responses; these defects may lead to impaired responses of plasmacytoid dendritic cells and loss of B cell function. (PMID:16424230)
• Bacterial DNA preparations from different species differ in their capacity to activate TLR-9, which is dependent on the individual [CG] content. Moreover, increased intracellular delivery results in a marked enhancement of immunostimulation. (PMID:16428738)
• significant increase of the combined carriership of the CD14 -260T and TLR9 -1237C alleles in the chronic relapsing pouchitis group suggests that these markers identify a subgroup of patients with a risk of developing chronic or refractory pouchitis (PMID:16437636)
• we here demonstrate that S. pneumoniae, H. influenzae, and N. meningitidis each activate several TLRs in species-specific patterns and show that infection with live pathogens may lead to activation of PRR not targeted by inactivated bacteria. (PMID:16731773)
• TLR4 and TLR9 polymorphisms increased the risk of low birth weight in infants; polymorphisms of TLR4 increased the risk of maternal anemia. (PMID:16779724)
• findings demonstrate that TLR-3 and TLR-9 mediate the activation of corneal cells by Herpes simplex virus 1, HSV-1 DNA and HSV-1-antibody complexes (PMID:16847112)
• Toll-like receptor 9 (TLR9) recognizes microbial DNA. We show here that TLR9 protein is expressed in human breast cancer cells and clinical breast cancer samples. (PMID:16849519)
• This establishes that the primary determinant of TLR9 signaling is not valency but endosomal location and demonstrates a strict compartmentalization of the biological response to TLR9 activation in plasmacytoid dendritic cells (PDCs). (PMID:16864658)
• Plays a role of in the recognition of M. bovis BCG by dendritic cells. (PMID:16920494)
• TLR2 and TLR9 cooperate in the control of parasite replication during Trypanosoma cruzi infection; TLR9 has a primary role in the MyD88-dependent induction of IL-12/IFN-gamma synthesis during infection with T. cruzi. (PMID:16951309)
• The results of this study suggest a model where modification of the cytoplasmic tail of TLR9 results in trafficking to early endosomes where it encounters CpG DNA. (PMID:16990271)
• reviews experience with two distinct therapeutic strategies: TLR9-based immunomodulation and TLR9-based vaccination (PMID:17000223)
• 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)
• In patients with active systemic lupus erythematosus, the proportion of peripheral blood memory B cells and plasma cells expressing TLR-9 is increased (PMID:17075805)
• HMGB1 suppresses PDC cytokine secretion and maturation in response to TLR9 agonists including the hypomethylated oligodeoxynucleotide CpG- and DNA-containing viruses (PMID:17142771)
• immune cells use several mechanisms to discriminate between stimulatory and nonstimulatory DNA; however, it appears that TLR9 itself binds rather indiscriminately to a broad range of DNAs (PMID:17145922)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tlr9	ENSMUSG00000045322
rattus_norvegicus	Tlr9	ENSRNOG00000048161

Paralogs (25): SLITRK3 (ENSG00000121871), LRFN3 (ENSG00000126243), LRFN1 (ENSG00000128011), SLIT2 (ENSG00000145147), LRFN2 (ENSG00000156564), LRRC38 (ENSG00000162494), SLITRK5 (ENSG00000165300), LRFN5 (ENSG00000165379), LRTM2 (ENSG00000166159), LINGO1 (ENSG00000169783), LRRN2 (ENSG00000170382), LRRN3 (ENSG00000173114), LRFN4 (ENSG00000173621), LINGO2 (ENSG00000174482), LRRN1 (ENSG00000175928), SLITRK1 (ENSG00000178235), GP5 (ENSG00000178732), SLITRK4 (ENSG00000179542), LRRC55 (ENSG00000183908), SLIT3 (ENSG00000184347), SLITRK6 (ENSG00000184564), SLITRK2 (ENSG00000185985), LRRC70 (ENSG00000186105), SLIT1 (ENSG00000187122), TPBGL (ENSG00000261594)

Protein

Protein identifiers

Toll-like receptor 9 — Q9NR96 (reviewed: Q9NR96)

All UniProt accessions (1): Q9NR96

UniProt curated annotations — full annotation on UniProt →

Function. Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Also acts via ADCY7, leading to cyclic di-AMP (c-di-AMP) synthesis and activation of the NLRP3 inflammasome. Plays a role in defense against systemic mouse cytomegalovirus infection. Controls lymphocyte response to Helicobacter infection. Upon CpG stimulation, induces B-cell proliferation, activation, survival and antibody production.

Subunit / interactions. Monomer and homodimer. Exists as a monomer in the absence of unmethylated cytidine-phosphate-guanosine (CpG) ligand. Proteolytic processing of an insertion loop (Z-loop) is required for homodimerization upon binding to the unmethylated CpG ligand leading to its activation. Interacts with MYD88 via their respective TIR domains. Interacts with BTK. Interacts (via transmembrane domain) with UNC93B1. Interacts with CD300LH; the interaction may promote full activation of TLR9-triggered innate responses. Interacts with CNPY3 and HSP90B1; this interaction is required for proper folding in the endoplasmic reticulum. Interacts with SMPDL3B. Interacts with CD82; this interaction is essential for TLR9-dependent myddosome formation in response to CpG stimulation. Interacts with ADCY7; leading to ADCY7 activation, synthesis of cyclic di-AMP (c-di-AMP) and formation of the NLRP3 inflammasome.

Subcellular location. Endoplasmic reticulum membrane. Early endosome membrane. Lysosome. Cytoplasmic vesicle. Phagosome. Golgi apparatus membrane.

Tissue specificity. Highly expressed in spleen, lymph node, tonsil and peripheral blood leukocytes, especially in plasmacytoid pre-dendritic cells. Levels are much lower in monocytes and CD11c+ immature dendritic cells. Also detected in lung and liver.

Post-translational modifications. Activated by proteolytic cleavage of the flexible loop between repeats LRR14 and LRR15 within the ectodomain. Cleavage requires UNC93B1. Proteolytically processed by first removing the majority of the ectodomain by either asparagine endopeptidase (AEP) or a cathepsin followed by a trimming event that is solely cathepsin mediated and required for optimal receptor signaling. Palmitoylated by ZDHHC3 in the Golgi regulates TLR9 trafficking from the Golgi to endosomes. Depalmitoylation by PPT1 controls the release of TLR9 from UNC93B1 in endosomes.

Similarity. Belongs to the Toll-like receptor family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9NR96-1	1, A	yes
Q9NR96-2	2, B
Q9NR96-3	3
Q9NR96-4	4
Q9NR96-5	5

RefSeq proteins (1): NP_059138* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000157	TIR_dom	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
IPR041283	LRR_12	Repeat

Pfam: PF01582, PF13516, PF13855, PF18837

UniProt features (79 total): repeat 26, glycosylation site 13, disulfide bond 8, binding site 6, sequence variant 6, splice variant 4, sequence conflict 4, topological domain 2, lipid moiety-binding region 2, helix 2, signal peptide 1, chain 1, transmembrane region 1, domain 1, turn 1, strand 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9L48	X-RAY DIFFRACTION	1.9
9L49	X-RAY DIFFRACTION	3
8AR3	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NR96-F1	86.96	0.65

Functional residue map

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

Ligand- & substrate-binding residues (6): 47–51; 72–77; 95–109; 132; 179–181; 208

Post-translational modifications (2): 258, 265

Disulfide bonds (8): 35–45, 98–110, 178–184, 255–268, 258–265, 470–500, 764–790, 766–809

Glycosylation sites (13): 64, 129, 200, 210, 242, 300, 340, 469, 474, 513, 567, 694, 731

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-1679131	Trafficking and processing of endosomal TLR
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-975110	TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling
R-HSA-975138	TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation
R-HSA-975155	MyD88 dependent cascade initiated on endosome

MSigDB gene sets: 323 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_DIGESTION, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_8_PRODUCTION

GO Biological Process (54): microglial cell activation (GO:0001774), toll-like receptor signaling pathway (GO:0002224), positive regulation of immunoglobulin production (GO:0002639), regulation of dendritic cell cytokine production (GO:0002730), MyD88-dependent toll-like receptor signaling pathway (GO:0002755), canonical NF-kappaB signal transduction (GO:0007249), male gonad development (GO:0008584), positive regulation of autophagy (GO:0010508), positive regulation of gene expression (GO:0010628), maintenance of gastrointestinal epithelium (GO:0030277), positive regulation of B cell proliferation (GO:0030890), detection of molecule of bacterial origin (GO:0032490), positive regulation of chemokine production (GO:0032722), positive regulation of granulocyte macrophage colony-stimulating factor production (GO:0032725), 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-10 production (GO:0032733), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-18 production (GO:0032741), positive regulation of interleukin-6 production (GO:0032755), positive regulation of interleukin-8 production (GO:0032757), positive regulation of tumor necrosis factor production (GO:0032760), toll-like receptor 9 signaling pathway (GO:0034162), positive regulation of toll-like receptor 9 signaling pathway (GO:0034165), defense response to bacterium (GO:0042742), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of MAPK cascade (GO:0043410), innate immune response (GO:0045087), regulation of B cell differentiation (GO:0045577), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of JNK cascade (GO:0046330), positive regulation of inflammatory response (GO:0050729), defense response to Gram-negative bacterium (GO:0050829), positive regulation of B cell activation (GO:0050871), defense response to virus (GO:0051607), negative regulation of ERK1 and ERK2 cascade (GO:0070373), cellular response to lipopolysaccharide (GO:0071222), cellular response to metal ion (GO:0071248), negative regulation of ATPase-coupled calcium transmembrane transporter activity (GO:1901895)

GO Molecular Function (6): interleukin-1 receptor binding (GO:0005149), siRNA binding (GO:0035197), pattern recognition receptor activity (GO:0038187), protein homodimerization activity (GO:0042803), unmethylated CpG binding (GO:0045322), protein binding (GO:0005515)

GO Cellular Component (19): Golgi membrane (GO:0000139), extracellular region (GO:0005576), cytoplasm (GO:0005737), lysosome (GO:0005764), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), endosome membrane (GO:0010008), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), early endosome membrane (GO:0031901), early phagosome (GO:0032009), endolysosome (GO:0036019), endolysosome membrane (GO:0036020), Golgi apparatus (GO:0005794), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), phagocytic vesicle (GO:0045335)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Toll-like Receptor Cascades	2
MyD88 dependent cascade initiated on endosome	2
IRS-mediated signalling	1
SARS-CoV Infections	1
Toll Like Receptor 9 (TLR9) Cascade	1
Toll Like Receptor 7/8 (TLR7/8) Cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cytokine production	6
cellular anatomical structure	3
endomembrane system	3
cytoplasm	3
positive regulation of type I interferon production	2
bounding membrane of organelle	2
intracellular membrane-bounded organelle	2
endosome	2
plasma membrane region	2
endosome membrane	2
leukocyte activation involved in inflammatory response	1
macrophage activation	1
glial cell activation	1
pattern recognition receptor signaling pathway	1
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune response	1
dendritic cell cytokine production	1
regulation of leukocyte mediated immunity	1
regulation of cytokine production involved in immune response	1
toll-like receptor signaling pathway	1
intracellular signaling cassette	1
gonad development	1
development of primary male sexual characteristics	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
epithelial structure maintenance	1
digestive system process	1
regulation of B cell proliferation	1
B cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of B cell activation	1
response to molecule of bacterial origin	1
detection of chemical stimulus	1
detection of external biotic stimulus	1
chemokine production	1

Protein interactions and networks

STRING

3404 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLR9	MYD88	P78397	999
TLR9	HMGB1	P09429	997
TLR9	IL1B	P01584	975
TLR9	CAMP	P49913	966
TLR9	IRAK1	P51617	966
TLR9	TRAF6	Q9Y4K3	949
TLR9	IRF7	Q92985	939
TLR9	UNC93B1	Q9H1C4	929
TLR9	TLR7	Q9NYK1	926
TLR9	NOD2	Q9HC29	915
TLR9	RIGI	O95786	902
TLR9	IFNA13	P01562	900
TLR9	IL1A	P01583	897
TLR9	IRF3	Q14653	894
TLR9	IL6	P05231	893

IntAct

13 interactions, top by confidence:

A	B	Type	Score
SIGLEC5	TLR9	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC6	TLR9	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC9	TLR9	psi-mi:“MI:0915”(physical association)	0.400
TLR9	TLR8	psi-mi:“MI:0915”(physical association)	0.400
TLR9	NCK1	psi-mi:“MI:0915”(physical association)	0.400
RBMX	TLR9	psi-mi:“MI:0915”(physical association)	0.400
TLR9	TLR9	psi-mi:“MI:0915”(physical association)	0.370
GSK3A	PRSS37	psi-mi:“MI:0914”(association)	0.350
GSK3B	PRSS37	psi-mi:“MI:0914”(association)	0.350
RYBP	FAM186A	psi-mi:“MI:0914”(association)	0.350
TLR9	ABCD4	psi-mi:“MI:0914”(association)	0.350
TLR9	CLGN	psi-mi:“MI:0914”(association)	0.350

BioGRID (72): TLR9 (Affinity Capture-MS), RNF216 (Two-hybrid), TLR9 (Two-hybrid), HSPA6 (Affinity Capture-MS), XRN1 (Affinity Capture-MS), MSH3 (Affinity Capture-MS), MTDH (Affinity Capture-MS), UNC45A (Affinity Capture-MS), BSCL2 (Affinity Capture-MS), PES1 (Affinity Capture-MS), KDM1A (Affinity Capture-MS), TPRN (Affinity Capture-MS), TMPO (Affinity Capture-MS), IFI16 (Affinity Capture-MS), NFYA (Affinity Capture-MS)

ESM2 similar proteins: A1A4H9, A2VDH3, A3KNN3, A6H789, A6H793, A8WHP9, O14498, O75325, O88186, P14770, P59034, P59035, Q13641, Q149C3, Q2EEY0, Q3UVD5, Q3UY51, Q4KLL3, Q4R8Y9, Q5I2M3, Q5I2M4, Q5I2M5, Q5I2M7, Q5I2M8, Q5NVQ6, Q5PQV5, Q5VT99, Q6UY18, Q6ZSA7, Q7M6Z0, Q80WD0, Q80WD1, Q80ZD7, Q86UN2, Q86UN3, Q86WK6, Q86WK7, Q8BHA1, Q8C2S7, Q8K0S5

Diamond homologs: A8WGA3, B1H134, B1H234, D3ZTV3, D4ABX8, F1NUK7, G5EFX6, O42235, O43155, O55226, O60938, O75093, O88279, O88280, O94769, O94991, P04629, P13224, P14770, P24014, P50608, P50609, P56400, P59383, P83503, Q04785, Q06828, Q3UHC2, Q5R6T0, Q5RAC4, Q5RI43, Q6RKD8, Q6WRH9, Q70AK3, Q7Z2Q7, Q80TR4, Q80XU8, Q810B7, Q810C1, Q8BGT1

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
BGLF5	“down-regulates quantity by destabilization”	TLR9	“post transcriptional regulation”
LMP1	“down-regulates quantity by repression”	TLR9	“transcriptional regulation”
RNF216	“down-regulates quantity by destabilization”	TLR9	ubiquitination
TLR9	“up-regulates activity”	MYD88	binding
TLR9	“up-regulates activity”	TIRAP	binding
TLR9	“up-regulates activity”	TICAM1	binding
TLR9	“up-regulates activity”	TICAM2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	111
Likely benign	17
Benign	9

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
916573	NM_017442.4(TLR9):c.548C>G (p.Pro183Arg)	Likely pathogenic

SpliceAI

201 predictions. Top by Δscore:

Variant	Effect	Δscore
3:52224311:CC:C	acceptor_gain	1.0000
3:52224312:CC:C	acceptor_gain	1.0000
3:52224310:ACCC:A	acceptor_loss	0.9900
3:52224312:CCT:C	acceptor_loss	0.9900
3:52224313:C:CA	acceptor_loss	0.9900
3:52224313:C:CC	acceptor_gain	0.9900
3:52225526:CCATG:C	donor_gain	0.9900
3:52225638:C:CT	acceptor_gain	0.9900
3:52225639:A:T	acceptor_gain	0.9900
3:52224309:AACC:A	acceptor_gain	0.9800
3:52224310:ACC:A	acceptor_gain	0.9700
3:52224311:CCC:C	acceptor_gain	0.9700
3:52224308:AAACC:A	acceptor_gain	0.9600
3:52225521:TCCTA:T	donor_loss	0.9600
3:52225522:CCTA:C	donor_loss	0.9600
3:52225523:CTA:C	donor_loss	0.9600
3:52225524:TACC:T	donor_loss	0.9600
3:52225525:A:C	donor_loss	0.9600
3:52225526:C:A	donor_loss	0.9600
3:52225634:G:T	acceptor_gain	0.9600
3:52224313:C:T	acceptor_gain	0.9500
3:52224315:G:GC	acceptor_gain	0.9400
3:52224310:ACCCT:A	acceptor_gain	0.9200
3:52225520:GTCCT:G	donor_loss	0.9100
3:52225525:A:AC	donor_gain	0.9100
3:52225526:C:CC	donor_gain	0.9100
3:52225633:C:CT	acceptor_gain	0.8900
3:52224312:CCTGT:C	acceptor_gain	0.8400
3:52225631:A:T	acceptor_gain	0.8400
3:52224311:CCCT:C	acceptor_gain	0.8200

AlphaMissense

6741 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:52224025:G:C	N97K	0.995
3:52224025:G:T	N97K	0.995
3:52223284:A:C	N344K	0.993
3:52223284:A:T	N344K	0.993
3:52223362:G:C	N318K	0.992
3:52223362:G:T	N318K	0.992
3:52223113:G:C	N401K	0.991
3:52223113:G:T	N401K	0.991
3:52223554:A:C	N254K	0.990
3:52223554:A:T	N254K	0.990
3:52223933:A:G	L128P	0.990
3:52221688:G:C	F876L	0.989
3:52221688:G:T	F876L	0.989
3:52221690:A:G	F876L	0.989
3:52223287:G:C	F343L	0.989
3:52223287:G:T	F343L	0.989
3:52223289:A:G	F343L	0.989
3:52222871:T:A	N482I	0.988
3:52223626:G:C	N230K	0.988
3:52223626:G:T	N230K	0.988
3:52221947:C:G	C790S	0.987
3:52221948:A:T	C790S	0.987
3:52223917:G:C	N133K	0.987
3:52223917:G:T	N133K	0.987
3:52223627:T:A	N230I	0.986
3:52223785:G:C	N177K	0.986
3:52223785:G:T	N177K	0.986
3:52224182:C:G	C45S	0.986
3:52224183:A:T	C45S	0.986
3:52222183:G:C	N711K	0.985

dbSNP variants (sampled 300 via entrez): RS1000657662 (3:52227345 G>T), RS1000694260 (3:52220941 C>G,T), RS1000997311 (3:52227135 G>A), RS1001378722 (3:52223514 A>G), RS1002938758 (3:52225982 GCAC>G), RS1003285767 (3:52227544 C>T), RS1003453327 (3:52224792 G>A), RS1003773252 (3:52221110 C>G), RS1004391176 (3:52226773 C>T), RS1004728466 (3:52226240 A>G), RS1005568000 (3:52223381 A>G), RS1006284456 (3:52223124 G>C), RS1007188630 (3:52224399 C>G), RS1007241182 (3:52224698 C>G), RS1007724971 (3:52223700 G>A)

Disease associations

OMIM: gene MIM:605474 | disease phenotypes: MIM:189960

GenCC curated gene-disease

Mondo (1): esophageal atresia/tracheoesophageal fistula (MONDO:0008586)

Orphanet (1): Esophageal atresia (Orphanet:1199)

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST001241_15	Bipolar disorder	2.000000e-06
GCST002149_14	Schizophrenia	1.000000e-08
GCST004521_123	Autism spectrum disorder or schizophrenia	3.000000e-12
GCST004521_201	Autism spectrum disorder or schizophrenia	4.000000e-08
GCST004902_20	Parkinson’s disease	3.000000e-08
GCST006269_705	General cognitive ability	1.000000e-09
GCST006948_16	Feeling nervous	2.000000e-09
GCST012203_2	Colon cancer	1.000000e-08
GCST012205_2	Distal colorectal cancer	5.000000e-07
GCST012226_616	Waist circumference adjusted for body mass index	2.000000e-09
GCST012228_59	Waist-hip index	7.000000e-09
GCST90020024_1202	A body shape index	2.000000e-12
GCST90020025_1953	Waist-to-hip ratio adjusted for BMI	1.000000e-13
GCST90020027_111	Waist-hip index	3.000000e-14
GCST90020029_1190	Waist circumference adjusted for body mass index	2.000000e-14

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0009597	feeling nervous measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C531835	Esophageal atresia with or without tracheoesophageal fistula (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2111471 (PROTEIN FAMILY), CHEMBL4106182 (PROTEIN FAMILY), CHEMBL5804 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 136,595 (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
CHEMBL1535	HYDROXYCHLOROQUINE	4	42,638
CHEMBL140	CURCUMIN	3	93,882
CHEMBL508338	THIMEROSAL	3
CHEMBL4650329	AFIMETORAN	2	49
CHEMBL5417170	MHV-370	2	26

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs352139	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Crohn Disease;Inflammatory Bowel Diseases
rs352139	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Psoriasis

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs352139	TLR9	3	3.50	2	Tumor necrosis factor alpha (TNF-alpha) inhibitors

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Toll-like receptor family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
hydroxychloroquine	Antagonist	7.1	pIC50

Binding affinities (BindingDB)

1063 measured of 1071 human assays (1247 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

5540 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.46	IC50	3.5	nM	CHEMBL3356618
8.41	IC50	3.9	nM	CHEMBL3357062
8.34	IC50	4.6	nM	CHEMBL2144205
8.30	IC50	5	nM	CHEMBL5169681
8.15	IC50	7	nM	CHEMBL5094930
8.07	IC50	8.6	nM	CHEMBL3357064
7.96	IC50	11	nM	CHEMBL3357065
7.96	IC50	11	nM	CHEMBL3356617
7.96	IC50	11	nM	CHEMBL4065452
7.89	IC50	13	nM	CHEMBL3357070
7.89	IC50	13	nM	CHEMBL6134015
7.82	IC50	15	nM	CHEMBL4065452
7.82	IC50	15	nM	CHEMBL5176310
7.82	IC50	15	nM	CHEMBL6108908
7.80	IC50	16	nM	CHEMBL3356616
7.80	IC50	16	nM	CHEMBL5855721
7.80	IC50	16	nM	CHEMBL6083133
7.77	IC50	17	nM	CHEMBL5177422
7.77	IC50	17	nM	CHEMBL6083131
7.72	IC50	19	nM	CHEMBL5193639
7.72	IC50	19	nM	CHEMBL5845501
7.70	IC50	20	nM	CHEMBL3356615
7.70	IC50	20	nM	CHEMBL4278635
7.70	IC50	20	nM	CHEMBL4276673
7.70	IC50	20	nM	CHEMBL4279467
7.70	IC50	20	nM	CHEMBL4282131
7.70	IC50	20	nM	CHEMBL457704
7.70	IC50	20	nM	CHEMBL6074579
7.70	IC50	20	nM	CHEMBL6078096
7.64	IC50	23	nM	CHEMBL5857884
7.60	IC50	25	nM	CHEMBL3905103
7.57	IC50	27	nM	CHEMBL3356611
7.55	IC50	28	nM	CHEMBL3357069
7.55	IC50	28	nM	CHEMBL5187807
7.55	IC50	28	nM	CHEMBL5183377
7.52	IC50	30	nM	CHEMBL4290314
7.52	IC50	30	nM	CHEMBL4279648
7.52	IC50	30	nM	CHEMBL4281194
7.52	IC50	30	nM	CHEMBL4278682
7.52	IC50	30	nM	CHEMBL4286933
7.52	IC50	30	nM	CHEMBL515364
7.50	IC50	32	nM	CHEMBL5092293
7.50	IC50	32	nM	CHEMBL5075053
7.50	IC50	32	nM	CHEMBL6052992
7.46	IC50	35	nM	CHEMBL3356614
7.46	IC50	35	nM	CHEMBL5197857
7.46	IC50	35	nM	CHEMBL5992876
7.43	IC50	37	nM	CHEMBL4082132
7.43	IC50	37	nM	CHEMBL5974999
7.42	IC50	38	nM	CHEMBL5175416

PubChem BioAssay actives

265 with measured affinity, of 729 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]-7-(3-pyrrolidin-1-ylpropyl)-5,6-dihydropyrrolo[2,3-d]pyrimidine	1171366: Antagonist activity at human TLR9 transfected in HEK293 cells after 6 hrs by NF-kappaB luciferase reporter assay	ic50	0.0035	uM
2-[4-(4-methylpiperazin-1-yl)phenyl]-7-(3-pyrrolidin-1-ylpropyl)-5,6-dihydropyrrolo[2,3-d]pyrimidine	1171366: Antagonist activity at human TLR9 transfected in HEK293 cells after 6 hrs by NF-kappaB luciferase reporter assay	ic50	0.0039	uM
6,7-dimethoxy-2-[4-(4-methylpiperazin-1-yl)phenyl]-N-(2-morpholin-4-ylethyl)quinazolin-4-amine	1171366: Antagonist activity at human TLR9 transfected in HEK293 cells after 6 hrs by NF-kappaB luciferase reporter assay	ic50	0.0046	uM
N-[6-(4-cyclopentylpiperazin-1-yl)-9-(3-pyrrolidin-1-ylpropyl)purin-2-yl]-4-(methylaminomethyl)benzamide	1846684: Antagonist activity at TLR9 (unknown origin)	ic50	0.0050	uM
6-(4-cyclopentylpiperazin-1-yl)-N-[[4-[(dimethylamino)methyl]phenyl]methyl]-9-(3-pyrrolidin-1-ylpropyl)purin-2-amine	1814740: Antagonist activity at human TLR9 expressed in HEK-blue-HTLR7 cells assessed as inhibition of CpGB-induced NFkappaB activation measured after overnight incubation by SEAP-based spectrophotometry assay	ic50	0.0070	uM
4-[3-[2-[4-(4-methylpiperazin-1-yl)phenyl]-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]propyl]morpholine	1171366: Antagonist activity at human TLR9 transfected in HEK293 cells after 6 hrs by NF-kappaB luciferase reporter assay	ic50	0.0086	uM
6-(3-pyrrolidin-1-ylpropoxy)-2-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1,3-benzoxazole	1924741: Antagonist activity at human TLR9 expressed in HEK293 cells coexpressing firefly luciferase assessed as inhibition of CpGB-induced NFkappaB activation preincubated for 30 mins followed by Oligo CpG stimulation by Steady-Glo luciferase assay	ic50	0.0110	uM
4-[4-[2-[4-(4-methylpiperazin-1-yl)phenyl]-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]butyl]morpholine	1171366: Antagonist activity at human TLR9 transfected in HEK293 cells after 6 hrs by NF-kappaB luciferase reporter assay	ic50	0.0110	uM
4-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]-7-(2-pyrrolidin-1-ylethyl)-5,6-dihydropyrrolo[2,3-d]pyrimidine	1171366: Antagonist activity at human TLR9 transfected in HEK293 cells after 6 hrs by NF-kappaB luciferase reporter assay	ic50	0.0110	uM
2-[4-[4-[7-(3-morpholin-4-ylpropyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl]phenyl]piperazin-1-yl]ethanol	1171366: Antagonist activity at human TLR9 transfected in HEK293 cells after 6 hrs by NF-kappaB luciferase reporter assay	ic50	0.0130	uM
2-(2,4-dimethoxyphenyl)-7-(4-propan-2-ylpiperazin-1-yl)-3-(pyrrolidin-1-ylmethyl)imidazo[1,2-a]pyridine	1874521: Antagonist activity at human TLR9 expressed in HEK-blue hTLR9 cells assessed as inhibition of CpGB-induced NFkappaB activation preincubated with compound for 1 hrs followed by CpGB addition and measured next day by SEAP-based spectrophotometry assay	ic50	0.0150	uM
4-[3-[4-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]propyl]morpholine	1171366: Antagonist activity at human TLR9 transfected in HEK293 cells after 6 hrs by NF-kappaB luciferase reporter assay	ic50	0.0160	uM
7-(4-cyclopentylpiperazin-1-yl)-2-[4-methoxy-2-(3-pyrrolidin-1-ylpropoxy)phenyl]imidazo[1,2-a]pyridine	1874521: Antagonist activity at human TLR9 expressed in HEK-blue hTLR9 cells assessed as inhibition of CpGB-induced NFkappaB activation preincubated with compound for 1 hrs followed by CpGB addition and measured next day by SEAP-based spectrophotometry assay	ic50	0.0170	uM
2-(2,4-dimethoxyphenyl)-N-(3-pyrrolidin-1-ylpropyl)imidazo[1,2-a]pyridin-7-amine	1874521: Antagonist activity at human TLR9 expressed in HEK-blue hTLR9 cells assessed as inhibition of CpGB-induced NFkappaB activation preincubated with compound for 1 hrs followed by CpGB addition and measured next day by SEAP-based spectrophotometry assay	ic50	0.0190	uM
2-[4-(4-methylpiperazin-1-yl)phenyl]-N-(2-morpholin-4-ylethyl)quinazolin-4-amine	1924740: Antagonist activity at human TLR9 expressed in HEK-Blue hTLR9 cells assessed as activation of NFkappaB incubated for 16 hrs by luciferase reporter gene assay	ic50	0.0200	uM
4-(4-cyclopentylpiperazin-1-yl)-6-methoxy-2-(4-methylpiperazin-1-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline	1422466: Antagonist activity at human TLR9 expressed in HEK-Blue cells assessed as reduction in CpGB-induced NF-kappaB levels after 24 hrs by spectrophotometric analysis	ic50	0.0200	uM
6-methoxy-N,N-dimethyl-4-piperazin-1-yl-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-2-amine	1422466: Antagonist activity at human TLR9 expressed in HEK-Blue cells assessed as reduction in CpGB-induced NF-kappaB levels after 24 hrs by spectrophotometric analysis	ic50	0.0200	uM
[4-[2-(dimethylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]piperazin-1-yl]-phenylmethanone	1422466: Antagonist activity at human TLR9 expressed in HEK-Blue cells assessed as reduction in CpGB-induced NF-kappaB levels after 24 hrs by spectrophotometric analysis	ic50	0.0200	uM
4-(4-cyclopentylpiperazin-1-yl)-6-methoxy-N,N-dimethyl-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-2-amine	1422466: Antagonist activity at human TLR9 expressed in HEK-Blue cells assessed as reduction in CpGB-induced NF-kappaB levels after 24 hrs by spectrophotometric analysis	ic50	0.0200	uM
4-[2-[4-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]ethyl]morpholine	1171366: Antagonist activity at human TLR9 transfected in HEK293 cells after 6 hrs by NF-kappaB luciferase reporter assay	ic50	0.0200	uM
2-[4-(4-methylpiperazin-1-yl)phenyl]-N-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydroquinazolin-4-amine	1171366: Antagonist activity at human TLR9 transfected in HEK293 cells after 6 hrs by NF-kappaB luciferase reporter assay	ic50	0.0270	uM
4-[3-[2-[7-(4-cyclopentylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl]-5-methoxyphenoxy]propyl]morpholine	1874521: Antagonist activity at human TLR9 expressed in HEK-blue hTLR9 cells assessed as inhibition of CpGB-induced NFkappaB activation preincubated with compound for 1 hrs followed by CpGB addition and measured next day by SEAP-based spectrophotometry assay	ic50	0.0280	uM
2-(2,4-dimethoxyphenyl)-7-(4-propan-2-ylpiperazin-1-yl)imidazo[1,2-a]pyridine	1874527: Antagonist activity at TLR9 in human pDCs inhibition of CpGB-induced NFkappaB activation by measuring IFN-alpha levels preincubated with compound for 1 hrs followed by CpGB addition and measured after 18 hrs by ELISA analysis	ic50	0.0280	uM
4-[3-[2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]propyl]morpholine	1171366: Antagonist activity at human TLR9 transfected in HEK293 cells after 6 hrs by NF-kappaB luciferase reporter assay	ic50	0.0280	uM
4-[4-(cyclopentylmethyl)piperazin-1-yl]-6-methoxy-N,N-dimethyl-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-2-amine	1422466: Antagonist activity at human TLR9 expressed in HEK-Blue cells assessed as reduction in CpGB-induced NF-kappaB levels after 24 hrs by spectrophotometric analysis	ic50	0.0300	uM
4-(4-cyclopentylpiperazin-1-yl)-6-methoxy-N-[3-(4-methylpiperazin-1-yl)propyl]-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-2-amine	1422466: Antagonist activity at human TLR9 expressed in HEK-Blue cells assessed as reduction in CpGB-induced NF-kappaB levels after 24 hrs by spectrophotometric analysis	ic50	0.0300	uM
[4-(aminomethyl)phenyl]-[4-[2-(dimethylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]piperazin-1-yl]methanone	1422466: Antagonist activity at human TLR9 expressed in HEK-Blue cells assessed as reduction in CpGB-induced NF-kappaB levels after 24 hrs by spectrophotometric analysis	ic50	0.0300	uM
[4-[2-(dimethylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]piperazin-1-yl]-(4-fluorophenyl)methanone	1422466: Antagonist activity at human TLR9 expressed in HEK-Blue cells assessed as reduction in CpGB-induced NF-kappaB levels after 24 hrs by spectrophotometric analysis	ic50	0.0300	uM
6-methoxy-4-(4-methylpiperazin-1-yl)-N-[3-(4-methylpiperazin-1-yl)propyl]-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-2-amine	1422466: Antagonist activity at human TLR9 expressed in HEK-Blue cells assessed as reduction in CpGB-induced NF-kappaB levels after 24 hrs by spectrophotometric analysis	ic50	0.0300	uM
N’,N’-dimethyl-N-[2-[4-(4-methylpiperazin-1-yl)phenyl]quinazolin-4-yl]ethane-1,2-diamine	389404: Antagonist activity at human TLR9 expressed in HEK293 cells assessed as blockade of CpG oligonucleotide-induced immune response by NF-kappaB luciferase reporter gene assay	ic50	0.0300	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	1846687: Antagonist activity at R848 stimulated TRL9 in HEK-Blue hTLR9 cells assessed as inhibition of NF kappa B/Ap-1 activation measured after 20 hrs by SEAP reporter assay	ic50	0.0320	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	1846687: Antagonist activity at R848 stimulated TRL9 in HEK-Blue hTLR9 cells assessed as inhibition of NF kappa B/Ap-1 activation measured after 20 hrs by SEAP reporter assay	ic50	0.0320	uM
2-deuterio-5-[(2R,6S)-2-methyl-6-[[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)spiro[1H-2-benzofuran-3,3’-azetidine]-1’-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile	1817772: Inhibition of human TLR9 expressed in HEK-Blue hTLR9 cells assessed as inhibition of TLR9 by cell based assay	ic50	0.0320	uM
4-[(2R,6S)-2-methyl-6-[[6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)spiro[1H-2-benzofuran-3,3’-azetidine]-1’-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile	1817772: Inhibition of human TLR9 expressed in HEK-Blue hTLR9 cells assessed as inhibition of TLR9 by cell based assay	ic50	0.0320	uM
4-[3-[5-methoxy-2-(7-piperazin-1-ylimidazo[1,2-a]pyridin-2-yl)phenoxy]propyl]morpholine	1874521: Antagonist activity at human TLR9 expressed in HEK-blue hTLR9 cells assessed as inhibition of CpGB-induced NFkappaB activation preincubated with compound for 1 hrs followed by CpGB addition and measured next day by SEAP-based spectrophotometry assay	ic50	0.0350	uM
5,6-dimethyl-2-[4-(4-methylpiperazin-1-yl)phenyl]-N-(2-morpholin-4-ylethyl)pyrimidin-4-amine	1171366: Antagonist activity at human TLR9 transfected in HEK293 cells after 6 hrs by NF-kappaB luciferase reporter assay	ic50	0.0350	uM
1-methyl-N-[3-[6-(3-pyrrolidin-1-ylpropoxy)-1,3-benzoxazol-2-yl]phenyl]piperidin-4-amine	1452739: Antagonist activity at human TLR9 expressed in HEK293 cells assessed as inhibition of CpGB-induced NF-kappaB activation after 24 hrs by spectrophotometry based SEAP reporter gene assay	ic50	0.0370	uM
2-(2,4-dimethoxyphenyl)-N-(3-imidazol-1-ylpropyl)imidazo[1,2-a]pyridin-7-amine	1874521: Antagonist activity at human TLR9 expressed in HEK-blue hTLR9 cells assessed as inhibition of CpGB-induced NFkappaB activation preincubated with compound for 1 hrs followed by CpGB addition and measured next day by SEAP-based spectrophotometry assay	ic50	0.0380	uM
5-[(2S,6R)-2-[[3-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]spiro[5H-furo[3,4-b]pyridine-7,3’-azetidine]-1’-yl]methyl]-6-methylmorpholin-4-yl]-2-deuterioquinoline-8-carbonitrile	1817772: Inhibition of human TLR9 expressed in HEK-Blue hTLR9 cells assessed as inhibition of TLR9 by cell based assay	ic50	0.0390	uM
7-(4-cyclopentylpiperazin-1-yl)-2-(2,4-dimethoxyphenyl)-3-(pyrrolidin-1-ylmethyl)imidazo[1,2-a]pyridine	1874521: Antagonist activity at human TLR9 expressed in HEK-blue hTLR9 cells assessed as inhibition of CpGB-induced NFkappaB activation preincubated with compound for 1 hrs followed by CpGB addition and measured next day by SEAP-based spectrophotometry assay	ic50	0.0390	uM
4-(4-cyclopentylpiperazin-1-yl)-N-[(4-fluorophenyl)methyl]-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-2-amine	1422466: Antagonist activity at human TLR9 expressed in HEK-Blue cells assessed as reduction in CpGB-induced NF-kappaB levels after 24 hrs by spectrophotometric analysis	ic50	0.0400	uM
6-methoxy-N,N-dimethyl-4-(4-methylpiperazin-1-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-2-amine	1422466: Antagonist activity at human TLR9 expressed in HEK-Blue cells assessed as reduction in CpGB-induced NF-kappaB levels after 24 hrs by spectrophotometric analysis	ic50	0.0400	uM
6-(4-ethylpiperazin-1-yl)-N-[(4-fluorophenyl)methyl]-9-(3-pyrrolidin-1-ylpropyl)purin-2-amine	1814740: Antagonist activity at human TLR9 expressed in HEK-blue-HTLR7 cells assessed as inhibition of CpGB-induced NFkappaB activation measured after overnight incubation by SEAP-based spectrophotometry assay	ic50	0.0400	uM
2-(2,6-dimethyl-4-pyridinyl)-4-methyl-6-piperidin-4-yl-9H-carbazole	1768802: Inhibition of human TLR9 in HEK-Blue hTLR9 cells assessed as reduction in ODN2006-activated NF-KappaB by SEAP reporter assay	ic50	0.0400	uM
5-[(2S,6R)-2-[[6-(3-amino-3-methylazetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3’-azetidine]-1’-yl]methyl]-6-methylmorpholin-4-yl]-2-deuterioquinoline-8-carbonitrile	1817772: Inhibition of human TLR9 expressed in HEK-Blue hTLR9 cells assessed as inhibition of TLR9 by cell based assay	ic50	0.0400	uM
4-[[2-(2,4-dimethoxyphenyl)-7-(4-propan-2-ylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl]methyl]morpholine	1874521: Antagonist activity at human TLR9 expressed in HEK-blue hTLR9 cells assessed as inhibition of CpGB-induced NFkappaB activation preincubated with compound for 1 hrs followed by CpGB addition and measured next day by SEAP-based spectrophotometry assay	ic50	0.0400	uM
2-(4-methoxyphenyl)-7-(4-propan-2-ylpiperazin-1-yl)imidazo[1,2-a]pyridine	1874521: Antagonist activity at human TLR9 expressed in HEK-blue hTLR9 cells assessed as inhibition of CpGB-induced NFkappaB activation preincubated with compound for 1 hrs followed by CpGB addition and measured next day by SEAP-based spectrophotometry assay	ic50	0.0440	uM
2-(2,4-dimethoxyphenyl)-7-piperazin-1-ylimidazo[1,2-a]pyridine	1874521: Antagonist activity at human TLR9 expressed in HEK-blue hTLR9 cells assessed as inhibition of CpGB-induced NFkappaB activation preincubated with compound for 1 hrs followed by CpGB addition and measured next day by SEAP-based spectrophotometry assay	ic50	0.0460	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	1684820: Inhibition of human TLR9 expressed in HEK-Blue cells assessed as inhibition of ODN2006-induced NF-kappaB and AP-1 activation measured after 20 hrs by quanti-blue based SEAP reporter gene assay	ic50	0.0470	uM
4-[(dimethylamino)methyl]-N-[3-[6-(3-pyrrolidin-1-ylpropoxy)-1,3-benzoxazol-2-yl]phenyl]benzamide	1452739: Antagonist activity at human TLR9 expressed in HEK293 cells assessed as inhibition of CpGB-induced NF-kappaB activation after 24 hrs by spectrophotometry based SEAP reporter gene assay	ic50	0.0480	uM

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CPG-oligonucleotide	affects cotreatment, increases expression, increases reaction, decreases expression, decreases response to substance (+2 more)	4
Paraquat	affects cotreatment, affects reaction, increases expression, decreases reaction, increases reaction (+1 more)	3
CpG ODN 2216	increases activity	2
Benzo(a)pyrene	affects methylation, increases mutagenesis	2
Chloroquine	increases reaction, decreases reaction, increases activity, increases expression, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
2-anisidine	affects expression	1
hydroxyhydroquinone	decreases expression, decreases reaction	1
4-aminobenzhydrazide	decreases reaction, decreases expression	1
epigallocatechin gallate	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
lipopolysaccharide, E. coli O26-B6	increases expression	1
CpG ODN 2006	decreases reaction, increases activity, affects binding	1
CpG ODN 2395	decreases reaction, increases activity, affects binding	1
theaflavin-3,3’-digallate	affects expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Cisplatin	decreases expression, decreases response to substance	1
Hydroxychloroquine	decreases expression	1
Lipopolysaccharides	increases expression	1
Melatonin	decreases reaction, increases expression	1
Oxygen	increases reaction, decreases reaction, increases expression	1
Ozone	increases expression	1
Rotenone	increases expression	1
Silver Compounds	affects cotreatment, increases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

132 unique, capped per target: 125 binding, 7 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1247821	Binding	Inhibition of TLR7/TLR9-mediated activation of aldrithiol-2-treated HIV1 Ada-stimulated human PBMC assessed as CD86 expressing cells at 100 uM after 20 hrs by flow cytometry	Chloroquine modulates HIV-1-induced plasmacytoid dendritic cell alpha interferon: implication for T-cell activation. — Antimicrob Agents Chemother
CHEMBL2169112	Functional	Agonist activity at human TLR9 expressed in Ramos blue cells assessed as stimulation of NF-kB/AP-1 activity at 20 uM incubated for 18 hrs using quanti blue assay based SEAP reporter gene assay	Immunomodulatory properties of novel nucleotide oligomerization domain 2 (nod2) agonistic desmuramyldipeptides. — J Med Chem

Cellosaurus cell lines

11 cell lines: 8 transformed cell line, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8CU	HEK-Blue-Lucia hTLR9 (NF/IL8)	Transformed cell line	Female
CVCL_D7A5	Leeporter HEK293 TLR9/NF-kB luciferase	Transformed cell line	Female
CVCL_E6V4	Genomeditech HEK-293 H_TLR9 Reporter	Transformed cell line	Female
CVCL_E8FD	THP1-Dual hTLR9	Cancer cell line	Male
CVCL_IM86	HEK-Blue hTLR9	Transformed cell line	Female
CVCL_RQ78	HEK 293/TLR9/NF-kB Luciferase Reporter	Transformed cell line	Female
CVCL_VI46	HEK-TLR9-YFP	Transformed cell line	Female
CVCL_XI46	CAL-1 TLR9 mCherry	Cancer cell line	Male
CVCL_XI47	THP-1 TLR9 mCherry	Cancer cell line	Male
CVCL_Y412	293XL/hTLR9-HA	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03792360	PHASE1	WITHDRAWN	Adipose Derived SVF for Aero-digestive & Enterocutaneous Fistulae
NCT02033772	Not specified	COMPLETED	Prospective Data Collection of Patients < 6 Months of Age Undergoing Thoracoscopic Surgery
NCT02364843	Not specified	TERMINATED	A Physiological Study to Determine the Enteral Threonine Requirements in Infants Aged 1 to 6 Months
NCT03455881	Not specified	UNKNOWN	Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients
NCT03730454	Not specified	ACTIVE_NOT_RECRUITING	Transanastomotic Tube for Proximal Esophageal Atresia With Distal Tracheoesophageal Fistula Repair