AGER

Summary

AGER (advanced glycosylation end-product specific receptor, HGNC:320) is a protein-coding gene on chromosome 6p21.32, encoding Advanced glycosylation end product-specific receptor (Q15109). Cell surface pattern recognition receptor that senses endogenous stress signals with a broad ligand repertoire including advanced glycation end products, S100 proteins, high-mobility group box 1 protein/HMGB1, amyloid beta/APP oligomers, nucleic acids, histones, phospholipids an….

The advanced glycosylation end product (AGE) receptor encoded by this gene is a member of the immunoglobulin superfamily of cell surface receptors. It is a multiligand receptor, and besides AGE, interacts with other molecules implicated in homeostasis, development, and inflammation, and certain diseases, such as diabetes and Alzheimer’s disease. Many alternatively spliced transcript variants encoding different isoforms, as well as non-protein-coding variants, have been described for this gene (PMID:18089847).

Source: NCBI Gene 177 — RefSeq curated summary.

At a glance

• GWAS associations: 38
• Clinical variants (ClinVar): 110 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001136

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:320
Approved symbol	AGER
Name	advanced glycosylation end-product specific receptor
Location	6p21.32
Locus type	gene with protein product
Status	Approved
Aliases	RAGE, SCARJ1, sRAGE
Ensembl gene	ENSG00000204305
Ensembl biotype	protein_coding
OMIM	600214
Entrez	177

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 34 protein_coding, 4 retained_intron

ENST00000375055, ENST00000375056, ENST00000375067, ENST00000375069, ENST00000375070, ENST00000375076, ENST00000438221, ENST00000450110, ENST00000469940, ENST00000473619, ENST00000484849, ENST00000488669, ENST00000538695, ENST00000851463, ENST00000851464, ENST00000851465, ENST00000851466, ENST00000851467, ENST00000851468, ENST00000851469, ENST00000851470, ENST00000851471, ENST00000851472, ENST00000851473, ENST00000851474, ENST00000851475, ENST00000851476, ENST00000851477, ENST00000851478, ENST00000851479, ENST00000851480, ENST00000966076, ENST00000966077, ENST00000966078, ENST00000966079, ENST00000966080, ENST00000966081, ENST00000966082

RefSeq mRNA: 9 — MANE Select: NM_001136 NM_001136, NM_001206929, NM_001206932, NM_001206934, NM_001206936, NM_001206940, NM_001206954, NM_001206966, NM_172197

CCDS: CCDS4746, CCDS4747, CCDS56417, CCDS56418, CCDS75429

Canonical transcript exons

ENST00000375076 — 11 exons

Exon	Start	End
ENSE00001633661	32184171	32184253
ENSE00001645680	32183881	32183987
ENSE00003508529	32183324	32183388
ENSE00003547166	32182841	32183023
ENSE00003571651	32183114	32183201
ENSE00003598645	32181606	32181632
ENSE00003666843	32181351	32181477
ENSE00003677357	32182247	32182388
ENSE00003683780	32182568	32182698
ENSE00003690347	32183555	32183750
ENSE00003845547	32180969	32181239

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.71.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.2172 / max 813.0710, expressed in 35 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72917	0.8757	29
72916	0.2210	16
72918	0.0851	10
72914	0.0199	5
72912	0.0083	2
72915	0.0071	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	99.71	gold quality
upper lobe of left lung	UBERON:0008952	99.55	gold quality
lung	UBERON:0002048	98.31	gold quality
right lobe of thyroid gland	UBERON:0001119	96.20	gold quality
left lobe of thyroid gland	UBERON:0001120	96.10	gold quality
thyroid gland	UBERON:0002046	95.53	gold quality
granulocyte	CL:0000094	94.99	gold quality
spleen	UBERON:0002106	93.53	gold quality
blood	UBERON:0000178	93.00	gold quality
right uterine tube	UBERON:0001302	92.27	gold quality
lower esophagus mucosa	UBERON:0035834	91.44	gold quality
mucosa of stomach	UBERON:0001199	89.66	gold quality
lymph node	UBERON:0000029	88.89	gold quality
pituitary gland	UBERON:0000007	88.74	gold quality
adenohypophysis	UBERON:0002196	87.96	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.75	gold quality
left uterine tube	UBERON:0001303	87.74	gold quality
cerebellar hemisphere	UBERON:0002245	87.57	gold quality
cerebellar cortex	UBERON:0002129	87.46	gold quality
cerebellum	UBERON:0002037	87.37	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.23	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.13	gold quality
muscle layer of sigmoid colon	UBERON:0035805	86.85	gold quality
monocyte	CL:0000576	86.56	gold quality
prostate gland	UBERON:0002367	86.49	gold quality
leukocyte	CL:0000738	86.47	gold quality
vermiform appendix	UBERON:0001154	86.32	gold quality
small intestine	UBERON:0002108	86.10	gold quality
lower esophagus	UBERON:0013473	86.10	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.09	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-CURD-126	yes	8746.11
E-MTAB-6653	yes	1927.64
E-MTAB-6308	yes	1282.14
E-HCAD-1	yes	1237.39
E-GEOD-130148	yes	993.87
E-MTAB-10662	yes	423.92
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): APP, CREB1, EGR1, MYOG, NFKB1, NFKB, NKX2-1, PAX7, PPARG, RELA, SP1, TTF1

miRNA regulators (miRDB)

29 targeting AGER, 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-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-6764-3P	98.44	67.64	1153
HSA-MIR-6824-3P	98.44	67.62	1154
HSA-MIR-4289	98.26	66.90	810
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-4700-3P	97.74	68.64	1014
HSA-MIR-6855-5P	97.51	66.03	830
HSA-MIR-597-5P	96.82	67.57	732
HSA-MIR-6742-5P	96.32	64.01	869
HSA-MIR-576-3P	96.14	65.63	773
HSA-MIR-6726-5P	95.97	63.72	841
HSA-MIR-920	95.97	63.95	811
HSA-MIR-5591-5P	95.85	64.76	1002
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-3170	95.84	64.32	721

Literature-anchored findings (GeneRIF, showing 40)

• mRNA and protein expression in Caco-2 cells (PMID:11700025)
• this study we have investigated a possible role of RAGE and amphoterin in the retinoic acid-induced differentiation of neuroblastoma cells. (PMID:11739380)
• susceptibility to the development of chronic periodontitis could be influenced by the 1704G/T polymorphism of the RAGE gene, independently of diabetes (PMID:11811511)
• Polymorphisms 1704G/T, 2184A/G, and 2245G/A in the rage gene are not associated with diabetic retinopathy in NIDDM (PMID:11884895)
• allele frequencies and genotype distribution combinations of four polymorphisms in the RAGE gene (6p21.3, G82S, 1704G/T, 2184A/G and 2245A/G) of 272 subjects (130 patients with plaque psoriasis and 142 healthy control). (PMID:12029499)
• increased prevalence of the 82S allele in patients with rheumatoid arthritis compared with control subjects (PMID:12070776)
• There is an association of Gly82Ser polymorphism in this gene with diabetic retinopathy in type II diabetic Asian Indian patients. (PMID:12477623)
• Data show that vascular endothelial cells and pericytes express three novel splice variants of receptor for advanced glycation end-products (RAGE) mRNA. (PMID:12495433)
• co-expression of RAGE and amphoterin is closely associated with invasion and metastasis of colorectal cancer (PMID:12579287)
• These data reinforce the importance of receptor for advanced glycation end products (RAGE)-ligand interactions in modulating properties of CD4+ T cells that infiltrate the central nervous system (PMID:12598893)
• association between -374 T/A RAGE polymorphism and cardiovascular disease and albumin excretion in type 1 diabetics with poor metabolic control suggests gene-environment interaction in development of diabetic nephropathy and cardiovascular complications (PMID:12606536)
• The RAGE is expressed in dying neurons and suggest that RAGE may have a role in neuronal cell death mediated by ischemic stress. (PMID:12618340)
• Advanced glycation end products and receptor for advanced glycation end products are found in AA amyloidosis. (PMID:12651613)
• AGEs can augment inflammatory responses by up-regulating COX-2 via RAGE and multiple signaling pathways, thereby leading to monocyte activation and vascular cell dysfunction (PMID:12837757)
• Results suggest a possible role of S100 protein- and RAGE-mediated signal transduction in the development of specific cancers. (PMID:12859967)
• In vitro binding studies using a series of C-terminal deletion mutants of human RAGE revealed the importance of the membrane-proximal cytoplasmic region of RAGE for the direct ERK-RAGE interaction. (PMID:12935895)
• No association betwween -429T/C and -37T/A polymorphism in RAGE gene promoter with diabetic retinopathy in NIDDM in Chinese patients (PMID:12941744)
• identified three novel RAGE transcripts all encoding truncated soluble forms of RAGE. The relative expression ratios for the full-length RAGE transcript to the sum of its splice-variants encoding the soluble variants varied strongly among tissues. (PMID:14580673)
• Oleate, not ligands of the receptor for advanced glycation end-products, acts as an enhancer of human smooth muscle cell proliferation. (PMID:14595542)
• Our study failed to demonstrate an association between either - 429 T/C or - 374 T/A gene polymorphism of the RAGE gene and diabetic retinopathy in Caucasians with type 2 diabetes (PMID:14704946)
• RAGE G1704T polymorphisms may be useful in identifying the risk for developing diabetic nephropathy in type 2 diabetic patients. (PMID:14747204)
• AGE might be involved in the growth and invasion of melanoma through interactions with RAGE and represent promising candidates for assessing the future therapeutic potential of this therapy in treating patients with melanoma. (PMID:15009731)
• results suggest that the decrease in monocyte RAGE expression can be at least partly accounted for by the ligand engagement and may be a factor contributing to the development of diabetic vascular complications (PMID:15019601)
• AGER mediates S100A13 protein translocation in response to extracellular S100 (PMID:15033494)
• Patients with type 2 diabetes and the 63bp deletion in the promoter of RAGE seem to be protected from diabetic nephropathy. (PMID:15052533)
• Only cells expressing RAGE at the cell surface showed hypersensitivity to Abeta. (PMID:15053925)
• Findings using advanced glycosylation end products (AGEs) with strong RAGE-binding properties indicate that AGEs may not uniformly play a role in cellular activation. (PMID:15127201)
• Review. RAGE is an amplification step in vascular inflammation and acceleration of atherosclerosis. (PMID:15155381)
• the RAGE pathway plays a critical proinflammatory role in vasculitic neuropathy. (PMID:15170618)
• Advanced glycation end products (AGE) by binding to AGE receptor (RAGE) per se could control mesangial cell growth. (PMID:15180953)
• Corellation of expression of tissue factor (TF) and the receptor for advanced glycation end products (RAGEs) and vascular complications in diabetic patients (PMID:15203887)
• RAGE expression is upregulated on monocytes from patients with chronic kidney disease (PMID:15213278)
• RAGE and MMP-9 are expressed concordant with the metastatic ability of the human pancreatic cancer cells. Could be key to regulating metastatic ability of pancreatic cancer. (PMID:15239215)
• AGER has a role as a pleiotropic antagonistic gene (review) (PMID:15247020)
• AGER1 suppressed AGE mediated NF-kappaB and MAPK/p44/p42 activities and suppressed AGE-mediated mesangial cell inflammatory injury through negative regulation of RAGE (PMID:15289604)
• Thiazolidinedione antidiabetics modulate vascular endothelial RAGE expression. (PMID:15448098)
• Down-regulation of RAGE may be considered as a critical step in tissue reorganization and the formation of lung tumours. (PMID:15539404)
• 374T/A polymorphism of the RAGE gene may reduce susceptibility to coronary artery disease (PMID:15547674)
• RAGE may have multiple functions in the human brain, mediated by the individual or coordinated efforts of the different RAGE isoforms (PMID:15555779)
• data demonstrate that the RAGE-NF-kappaB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches (PMID:15599399)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-79k12.1	ENSDARG00000079175
mus_musculus	Ager	ENSMUSG00000015452
rattus_norvegicus	Ager	ENSRNOG00000000439

Paralogs (3): MCAM (ENSG00000076706), ALCAM (ENSG00000170017), BCAM (ENSG00000187244)

Protein

Protein identifiers

Advanced glycosylation end product-specific receptor — Q15109 (reviewed: Q15109)

Alternative names: Receptor for advanced glycosylation end products

All UniProt accessions (6): A0A1U9X785, A8MS87, B5A982, Q15109, Q5SSZ2, Q5SSZ3

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface pattern recognition receptor that senses endogenous stress signals with a broad ligand repertoire including advanced glycation end products, S100 proteins, high-mobility group box 1 protein/HMGB1, amyloid beta/APP oligomers, nucleic acids, histones, phospholipids and glycosaminoglycans. Advanced glycosylation end products are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. These ligands accumulate at inflammatory sites during the pathogenesis of various diseases including diabetes, vascular complications, neurodegenerative disorders and cancers, and RAGE transduces their binding into pro-inflammatory responses. Upon ligand binding, uses TIRAP and MYD88 as adapters to transduce the signal ultimately leading to the induction of inflammatory cytokines IL6, IL8 and TNFalpha through activation of NF-kappa-B. Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key pro-inflammatory mediators. Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling. Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons. ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space. Participates in endothelial albumin transcytosis together with HMGB1 through the RAGE/SRC/Caveolin-1 pathway, leading to endothelial hyperpermeability. Mediates the loading of HMGB1 in extracellular vesicles (EVs) that shuttle HMGB1 to hepatocytes by transferrin-mediated endocytosis and subsequently promote hepatocyte pyroptosis by activating the NLRP3 inflammasome. Binds to DNA and promotes extracellular hypomethylated DNA (CpG DNA) uptake by cells via the endosomal route to activate inflammatory responses. Mediates phagocytosis by non-professional phagocytes (NPP) and this is enhanced by binding to ligands including RNA, DNA, HMGB1 and histones. Promotes NPP-mediated phagocytosis of Saccharomyces cerevisiae spores by binding to RNA attached to the spore wall. Also promotes NPP-mediated phagocytosis of apoptotic cells. Following DNA damage, recruited to DNA double-strand break sites where it colocalizes with the MRN repair complex via interaction with double-strand break repair protein MRE11. Enhances the endonuclease activity of MRE11, promoting the end resection of damaged DNA. Promotes DNA damage repair in trophoblasts which enhances trophoblast invasion and contributes to placental development and maintenance. Protects cells from DNA replication stress by localizing to damaged replication forks where it stabilizes the MCM2-7 complex and promotes faithful progression of the replication fork. Mediates the production of reactive oxygen species (ROS) in human endothelial cells.

Subunit / interactions. Constitutive homodimer; disulfide-linked. Forms homooligomers. Interacts with S100A1 and APP. Interacts with S100B, S100A12 and S100A14. Interacts with TIRAP. Interacts with HMGB1. Interacts with LGP2; this interaction plays an important role in AGER-mediated pro-inflammatory responses and cytokine release. Interacts with double-strand break repair protein MRE11 which is a core component of the MRN complex. The interaction enhances MRE11 endonuclease activity and promotes DNA repair. Interacts with the MCM2-7 complex via interaction with complex member MCM2; the interaction is increased following DNA replication stress and stabilizes the MCM2-7 complex at replication forks. Interacts with longistatin, a protein from the saliva of the tick, Haemaphysalis longicornis; the interaction attenuates AGER-mediated production of reactive oxygen species (ROS), activation of NF-kappa-B and expression of adhesion molecules and cytokines in human endothelial cells.

Subcellular location. Cell membrane. Cell projection. Phagocytic cup. Early endosome. Nucleus Cell membrane Secreted Cell membrane.

Tissue specificity. Endothelial cells. Increased expression in pre-term labor and preeclampsia placentas compared to controls.

Post-translational modifications. Phosphorylated on its cytoplasmic domain by PKCzeta/PRKCZ upon ligand binding. Phosphorylated by ATM following DNA damage. Targeted by the ubiquitin E3 ligase subunit FBXO10 to mediate its ubiquitination and degradation.

Induction. Induced in T cells by antigen stimulation and by the S100B ligand. Induced in trophoblasts by DNA damage.

Miscellaneous. Detected in lung, brain, heart and kidney.

Isoforms (10)

UniProt ID	Names	Canonical?
Q15109-1	1	yes
Q15109-2	2, RAGESEC
Q15109-3	3
Q15109-4	4
Q15109-5	5, del exon3-7
Q15109-6	6
Q15109-7	7, del exon3
Q15109-8	8
Q15109-9	9, del exon8-9
Q15109-10	10, delta-ICD, variant 20

RefSeq proteins (9): NP_001127, NP_001193858, NP_001193861, NP_001193863, NP_001193865, NP_001193869, NP_001193883, NP_001193895, NP_751947 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003006	Ig/MHC_CS	Conserved_site
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013162	CD80_C2-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR051116	Surface_Rcpt/Adhesion_Mol	Family

Pfam: PF08205, PF13927

UniProt features (74 total): strand 33, splice variant 11, turn 5, disulfide bond 4, helix 3, domain 3, glycosylation site 2, topological domain 2, sequence variant 2, mutagenesis site 2, signal peptide 1, chain 1, modified residue 1, transmembrane region 1, sequence conflict 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

33 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5D7F	X-RAY DIFFRACTION	1.3
3O3U	X-RAY DIFFRACTION	1.5
6XQ1	X-RAY DIFFRACTION	1.51
6XQ3	X-RAY DIFFRACTION	1.71
6XQ5	X-RAY DIFFRACTION	1.8
6XQ7	X-RAY DIFFRACTION	1.8
6XQ8	X-RAY DIFFRACTION	1.82
3CJJ	X-RAY DIFFRACTION	1.85
6XQ6	X-RAY DIFFRACTION	1.9
7LML	X-RAY DIFFRACTION	2.15
4P2Y	X-RAY DIFFRACTION	2.3
6XQ9	X-RAY DIFFRACTION	2.3
9S2X	X-RAY DIFFRACTION	2.35
4LP4	X-RAY DIFFRACTION	2.4
4YBH	X-RAY DIFFRACTION	2.4
7LMW	X-RAY DIFFRACTION	2.5
4XYN	X-RAY DIFFRACTION	2.55
4OF5	X-RAY DIFFRACTION	2.8
4OFV	X-RAY DIFFRACTION	3.1
4OI8	X-RAY DIFFRACTION	3.1
4OI7	X-RAY DIFFRACTION	3.1
4LP5	X-RAY DIFFRACTION	3.8
8I9M	ELECTRON MICROSCOPY	5.19
2E5E	SOLUTION NMR
2ENS	SOLUTION NMR
2L7U	SOLUTION NMR
2LE9	SOLUTION NMR
2LMB	SOLUTION NMR
2M1K	SOLUTION NMR
2MJW	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15109-F1	83.74	0.58

Functional residue map

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

Post-translational modifications (1): 391

Disulfide bonds (4): 38–99, 144–208, 259, 301

Glycosylation sites (2): 25, 81

Mutagenesis-validated functional residues (2):

Position	Phenotype
374	less monoubiquitinated product and resistant to degradation.
391	complete loss of phosphorylation by pkc/prkcz and by atm.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation
R-HSA-879415	Advanced glycosylation endproduct receptor signaling
R-HSA-933542	TRAF6 mediated NF-kB activation

MSigDB gene sets: 361 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, GOBP_DENDRITIC_CELL_DIFFERENTIATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS

GO Biological Process (67): response to hypoxia (GO:0001666), microglial cell activation (GO:0001774), regulation of T cell mediated cytotoxicity (GO:0001914), DNA replication (GO:0006260), DNA repair (GO:0006281), phagocytosis (GO:0006909), inflammatory response (GO:0006954), cell surface receptor signaling pathway (GO:0007166), learning or memory (GO:0007611), response to wounding (GO:0009611), glucose mediated signaling pathway (GO:0010255), neuron projection development (GO:0031175), negative regulation of interleukin-10 production (GO:0032693), positive regulation of chemokine production (GO:0032722), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), positive regulation of heterotypic cell-cell adhesion (GO:0034116), positive regulation of activated T cell proliferation (GO:0042104), transcytosis (GO:0045056), positive regulation of JNK cascade (GO:0046330), astrocyte activation (GO:0048143), regulation of synaptic plasticity (GO:0048167), regulation of inflammatory response (GO:0050727), induction of positive chemotaxis (GO:0050930), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), positive regulation of ERK1 and ERK2 cascade (GO:0070374), positive regulation of monocyte chemotactic protein-1 production (GO:0071639), protein localization to membrane (GO:0072657), regulation of spontaneous synaptic transmission (GO:0150003), transport across blood-brain barrier (GO:0150104), regulation of long-term synaptic potentiation (GO:1900271), negative regulation of long-term synaptic potentiation (GO:1900272), negative regulation of long-term synaptic depression (GO:1900453), regulation of p38MAPK cascade (GO:1900744), positive regulation of p38MAPK cascade (GO:1900745), regulation of non-canonical NF-kappaB signal transduction (GO:1901222), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), positive regulation of amyloid precursor protein catabolic process (GO:1902993)

GO Molecular Function (14): amyloid-beta binding (GO:0001540), DNA binding (GO:0003677), RNA binding (GO:0003723), transmembrane signaling receptor activity (GO:0004888), scavenger receptor activity (GO:0005044), laminin receptor activity (GO:0005055), signaling receptor activity (GO:0038023), histone binding (GO:0042393), identical protein binding (GO:0042802), S100 protein binding (GO:0044548), protein-containing complex binding (GO:0044877), advanced glycation end-product receptor activity (GO:0050785), molecular adaptor activity (GO:0060090), protein binding (GO:0005515)

GO Cellular Component (13): fibrillar center (GO:0001650), phagocytic cup (GO:0001891), extracellular region (GO:0005576), nucleus (GO:0005634), early endosome (GO:0005769), plasma membrane (GO:0005886), cell surface (GO:0009986), apical plasma membrane (GO:0016324), cell junction (GO:0030054), postsynapse (GO:0098794), endosome (GO:0005768), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1
Toll Like Receptor 3 (TLR3) Cascade	1
Interleukin-1 signaling	1
TRIF (TICAM1)-mediated TLR4 signaling	1
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1
MyD88 cascade initiated on plasma membrane	1
Innate Immune System	1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
positive regulation of cytokine production	3
protein binding	3
binding	3
response to stress	2
DNA metabolic process	2
nucleic acid binding	2
signaling receptor activity	2
response to decreased oxygen levels	1
leukocyte activation involved in inflammatory response	1
macrophage activation	1
glial cell activation	1
regulation of leukocyte mediated cytotoxicity	1
T cell mediated cytotoxicity	1
regulation of T cell mediated immunity	1
DNA biosynthetic process	1
DNA damage response	1
endocytosis	1
defense response	1
signal transduction	1
behavior	1
cognition	1
hexose mediated signaling	1
cellular response to glucose stimulus	1
neuron development	1
plasma membrane bounded cell projection organization	1
negative regulation of cytokine production	1
interleukin-10 production	1
regulation of interleukin-10 production	1
chemokine production	1
regulation of chemokine production	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
interleukin-12 production	1
regulation of interleukin-12 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1

Protein interactions and networks

STRING

1978 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AGER	HMGB1	P09429	999
AGER	S100A12	P80511	997
AGER	S100B	P04271	995
AGER	S100A4	P26447	981
AGER	S100A11	P31949	960
AGER	TLR4	O00206	940
AGER	S100A7	P31151	876
AGER	S100A6	P06703	840
AGER	TTR	P02766	824
AGER	ITGB2	P05107	813
AGER	HSPA4	P34932	806
AGER	TLR2	O60603	801
AGER	ALB	P02768	797
AGER	LRP1	Q07954	794
AGER	TLR9	Q9NR96	789

IntAct

81 interactions, top by confidence:

A	B	Type	Score
AGER	S100B	psi-mi:“MI:0407”(direct interaction)	0.720
S100B	AGER	psi-mi:“MI:0407”(direct interaction)	0.720
AGER	MAPKAPK5	psi-mi:“MI:0915”(physical association)	0.660
AGER	MAPKAPK5	psi-mi:“MI:2364”(proximity)	0.660
AGER	MAPKAPK5	psi-mi:“MI:0403”(colocalization)	0.660
PRKCZ	AGER	psi-mi:“MI:0915”(physical association)	0.610
AGER	PRKCZ	psi-mi:“MI:0915”(physical association)	0.610
AGER	DIAPH1	psi-mi:“MI:0915”(physical association)	0.580
AGER	CREB3	psi-mi:“MI:0915”(physical association)	0.560
GRB2	AGER	psi-mi:“MI:0915”(physical association)	0.560
AGER	TIRAP	psi-mi:“MI:0914”(association)	0.560
AGER	TIRAP	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (31): NRP1 (Affinity Capture-MS), CSTF2 (Affinity Capture-MS), CREB3 (Two-hybrid), AGER (Affinity Capture-Western), AGER (Affinity Capture-Western), AGER (Affinity Capture-Western), FGFR1 (Affinity Capture-Western), S100B (Affinity Capture-Western), FGF2 (Affinity Capture-Western), AGER (Affinity Capture-Western), AGER (Affinity Capture-Western), AGER (Affinity Capture-Western), AGER (Two-hybrid), AGER (Two-hybrid), AGER (Proximity Label-MS)

ESM2 similar proteins: A0A140LHF2, A6H8M9, A7LCJ3, A8E0Y8, D3YX43, D3YZF7, O14498, O15197, O70394, O70540, P01877, P0C0K6, P0C788, P0DP72, P35590, P40223, P43121, P50895, P70289, Q00657, Q06418, Q06805, Q15109, Q28173, Q5BK54, Q5NVQ6, Q5TJE4, Q61790, Q61826, Q62151, Q62230, Q63495, Q64612, Q6UVK1, Q6UWB1, Q7Z442, Q86VR7, Q8IZF5, Q8R2Y2, Q8VHY0

Diamond homologs: A2AJ76, A4IFA6, A6NJW4, A8WHP9, O14498, P14770, P59034, P59035, Q13641, Q15109, Q28173, Q4R8Y9, Q5NVQ6, Q5RKR3, Q62151, Q63495, Q6GU68, Q6UXK2, Q6WRH9, Q96RW7, A2AAJ9, A6H793, E7FE13, F1MLX5, P13224, P56400, Q58EX2, Q6UY18, Q6V4S5, Q9BY71, Q9JJM7, A4IGL7, B3MH43, B4MR28, B4QC63, D3YYU8, F1M0Z1, G5EF96, G5EGI7, O15146

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
S100A8	“up-regulates activity”	AGER	binding
S100A9	“up-regulates activity”	AGER	binding
“Calprotectin complex”	“up-regulates activity”	AGER	binding
ATM	“up-regulates activity”	AGER	phosphorylation
TIRAP	“up-regulates activity”	AGER	binding
HMGB1	“up-regulates activity”	AGER	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	6	41.5×	2e-06
Signaling by Receptor Tyrosine Kinases	5	11.7×	1e-03
Cytokine Signaling in Immune system	5	9.3×	2e-03
Neutrophil degranulation	7	7.3×	7e-04
Innate Immune System	6	7.0×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of canonical NF-kappaB signal transduction	7	18.8×	3e-05
positive regulation of ERK1 and ERK2 cascade	5	15.8×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	70
Likely benign	13
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1463 predictions. Top by Δscore:

Variant	Effect	Δscore
6:32181350:CCT:C	donor_gain	1.0000
6:32181478:C:A	acceptor_loss	1.0000
6:32181479:T:C	acceptor_loss	1.0000
6:32182387:CC:C	acceptor_gain	1.0000
6:32182388:CC:C	acceptor_gain	1.0000
6:32182566:A:AC	donor_gain	1.0000
6:32182566:ACAT:A	donor_gain	1.0000
6:32182567:C:CC	donor_gain	1.0000
6:32182567:CATC:C	donor_gain	1.0000
6:32182569:T:TA	donor_gain	1.0000
6:32182697:CT:C	acceptor_gain	1.0000
6:32182706:T:C	acceptor_gain	1.0000
6:32182706:T:TC	acceptor_gain	1.0000
6:32183112:AC:A	donor_gain	1.0000
6:32183113:CC:C	donor_gain	1.0000
6:32183113:CCCTT:C	donor_gain	1.0000
6:32183553:A:AC	donor_gain	1.0000
6:32183554:C:CT	donor_gain	1.0000
6:32183649:C:CT	acceptor_gain	1.0000
6:32181235:CCTTC:C	acceptor_loss	0.9900
6:32181236:CTTC:C	acceptor_gain	0.9900
6:32181237:TTC:T	acceptor_gain	0.9900
6:32181237:TTCC:T	acceptor_loss	0.9900
6:32181239:CCTGA:C	acceptor_loss	0.9900
6:32181240:C:CC	acceptor_gain	0.9900
6:32181240:C:G	acceptor_loss	0.9900
6:32181241:T:G	acceptor_loss	0.9900
6:32181346:CTCA:C	donor_loss	0.9900
6:32181347:TCA:T	donor_loss	0.9900
6:32181348:CACCT:C	donor_loss	0.9900

AlphaMissense

2558 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:32183887:C:A	W51C	0.997
6:32183887:C:G	W51C	0.997
6:32183151:C:A	W157C	0.996
6:32183151:C:G	W157C	0.996
6:32183889:A:G	W51R	0.994
6:32183889:A:T	W51R	0.994
6:32183153:A:G	W157R	0.992
6:32183153:A:T	W157R	0.992
6:32183614:C:G	C99S	0.992
6:32183615:A:T	C99S	0.992
6:32182577:C:A	W271C	0.991
6:32182577:C:G	W271C	0.991
6:32183888:C:G	W51S	0.988
6:32183620:A:C	F97C	0.985
6:32183927:C:G	C38S	0.983
6:32183928:A:T	C38S	0.983
6:32183615:A:G	C99R	0.979
6:32183620:A:G	F97S	0.979
6:32183191:C:G	C144S	0.977
6:32183192:A:T	C144S	0.977
6:32183727:C:A	W61C	0.977
6:32183727:C:G	W61C	0.977
6:32183152:C:G	W157S	0.975
6:32183613:G:C	C99W	0.974
6:32182909:C:G	C208S	0.972
6:32182910:A:T	C208S	0.972
6:32182316:A:C	Y299D	0.971
6:32183614:C:T	C99Y	0.971
6:32183566:A:T	V115D	0.970
6:32182579:A:G	W271R	0.968

dbSNP variants (sampled 300 via entrez): RS1000 (6:32186118 T>C), RS1000138351 (6:32183571 G>A), RS1000286697 (6:32184644 C>A), RS1000337149 (6:32184909 C>T), RS1000832365 (6:32181882 T>G), RS1001 (6:32186196 A>G), RS1001508058 (6:32184697 G>A), RS1001536575 (6:32182071 G>A), RS1002 (6:32186240 G>A,C), RS1002593015 (6:32181775 T>C), RS1004095 (6:32185632 A>C), RS1004567640 (6:32183889 A>C,G), RS1005044410 (6:32184592 G>A,C), RS1005073824 (6:32184328 T>A), RS1006659094 (6:32183764 A>G)

Disease associations

OMIM: gene MIM:600214 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): COPD, severe early onset (MONDO:0011751)

Orphanet (0):

HPO phenotypes

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

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST000542_3	Pulmonary function	3.000000e-14
GCST000544_6	Pulmonary function	3.000000e-15
GCST001784_28	Pulmonary function (smoking interaction)	1.000000e-21
GCST001942_21	Prostate cancer	5.000000e-09
GCST002942_14	Percentage gas trapping	4.000000e-09
GCST002945_48	Emphysema imaging phenotypes	5.000000e-09
GCST002977_1	Soluble receptor for advanced glycation end-product levels	2.000000e-08
GCST002977_2	Soluble receptor for advanced glycation end-product levels	3.000000e-16
GCST003232_1	Response to Pazopanib in cancer (hepatotoxicity)	8.000000e-09
GCST004131_25	Inflammatory bowel disease	2.000000e-31
GCST004133_79	Ulcerative colitis	5.000000e-65
GCST004147_3	Chronic obstructive pulmonary disease	6.000000e-10
GCST004185_37	Lung function (FEV1/FVC)	3.000000e-25
GCST004521_10	Autism spectrum disorder or schizophrenia	2.000000e-13
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_118	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_126	Autism spectrum disorder or schizophrenia	2.000000e-10
GCST004521_154	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_17	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_170	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_173	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_213	Autism spectrum disorder or schizophrenia	5.000000e-13
GCST004521_226	Autism spectrum disorder or schizophrenia	4.000000e-12
GCST004521_276	Autism spectrum disorder or schizophrenia	5.000000e-10
GCST004521_296	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_81	Autism spectrum disorder or schizophrenia	1.000000e-14
GCST005542_1	Sarcoidosis (non-Lofgren’s syndrome without extrapulmonary manifestations)	7.000000e-06
GCST007429_16	Lung function (FVC)	8.000000e-15

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004713	FEV/FVC ratio
EFO:0007628	gas trapping measurement
EFO:0007626	emphysema imaging measurement
EFO:0007622	sRAGE measurement
EFO:0004312	vital capacity
EFO:0009718	peak expiratory flow
EFO:0004314	forced expiratory volume
EFO:0007819	advanced glycation end-product measurement
EFO:0008173	interleukin 16 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2176846 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 300 (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
CHEMBL3989929	AZELIRAGON	3	300

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — Immunoglobulin like domain containing proteins

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

Ligand	Action	Affinity	Parameter
azeliragon	Antagonist	6.0	pIC50

ChEMBL bioactivities

87 potent at pChembl≥5 of 97 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	Kd	0.1	nM	CHEMBL4101927
9.52	Kd	0.3	nM	CHEMBL4101927
9.26	Kd	0.55	nM	CHEMBL1335502
9.00	Kd	1	nM	CHEMBL4077165
9.00	Kd	1	nM	CHEMBL1477694
9.00	Kd	1	nM	CHEMBL5176926
8.96	Kd	1.1	nM	CHEMBL4077165
8.92	Kd	1.2	nM	CHEMBL1342645
8.85	Kd	1.4	nM	CHEMBL6043937
8.70	Kd	2	nM	CHEMBL4063929
8.70	Kd	2	nM	CHEMBL4072531
8.70	Kd	2	nM	CHEMBL5815349
8.52	Kd	3	nM	CHEMBL4100986
8.51	Kd	3.1	nM	CHEMBL4100986
8.40	Kd	4	nM	CHEMBL4075539
8.40	Kd	4	nM	CHEMBL1463447
8.22	Kd	6	nM	CHEMBL1463447
8.19	Kd	6.5	nM	CHEMBL5812329
8.01	Kd	9.7	nM	CHEMBL5753345
8.01	Kd	9.8	nM	CHEMBL5795267
7.90	Kd	12.7	nM	AZELIRAGON
7.82	Kd	15	nM	CHEMBL4066660
7.82	Kd	15	nM	CHEMBL5200484
7.75	Kd	18	nM	CHEMBL1477694
7.65	Kd	22.3	nM	CHEMBL5752083
7.60	Ki	25	nM	CHEMBL4075936
7.52	Kd	30	nM	CHEMBL4085254
7.50	Kd	32	nM	CHEMBL1547178
7.37	Kd	43	nM	QUINOLINIC ACID
7.12	Kd	75	nM	CHEMBL6008871
7.11	Kd	78	nM	CHEMBL1566222
7.00	Kd	99.8	nM	CHEMBL5747024
6.91	Kd	123	nM	CHEMBL1547178
6.83	Ki	148	nM	CHEMBL4075936
6.66	Kd	219	nM	CHEMBL5996265
6.64	Ki	230	nM	CHEMBL4075936
6.59	Kd	257	nM	CHEMBL5741459
6.30	Kd	500	nM	AZELIRAGON
6.30	Kd	500	nM	CHEMBL6022471
6.26	IC50	550	nM	CHEMBL3216782
6.18	IC50	660	nM	CHEMBL2205559
6.04	IC50	910	nM	CHEMBL2205572
5.98	IC50	1040	nM	CHEMBL2205549
5.95	IC50	1120	nM	CHEMBL2205556
5.94	IC50	1140	nM	CHEMBL2205561
5.92	IC50	1210	nM	CHEMBL2205550
5.91	IC50	1240	nM	CHEMBL2205569
5.80	IC50	1580	nM	CHEMBL2205553
5.76	IC50	1720	nM	CHEMBL2205558
5.76	IC50	1750	nM	CHEMBL4095634

PubChem BioAssay actives

58 with measured affinity, of 291 total; 47 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-acetamido-5-chloro-2-methoxy-N-(1,3-thiazol-2-yl)benzamide	1475149: Binding affinity to human RAGE cytoplasmic domain by tryptophan fluorescence assay	kd	0.0003	uM
3-[4-(4-(18F)fluoro-2-fluorophenyl)-1,3-thiazol-2-yl]aminophenol	1896074: Binding affinity to RAGE (unknown origin) assessed as dissociation constant	kd	0.0010	uM
1-carbazol-9-yl-3-(2-methylbenzimidazol-1-yl)propan-2-ol	1475149: Binding affinity to human RAGE cytoplasmic domain by tryptophan fluorescence assay	kd	0.0010	uM
3-[[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]amino]phenol	1475149: Binding affinity to human RAGE cytoplasmic domain by tryptophan fluorescence assay	kd	0.0010	uM
methyl 4,5-dihydroxy-2-[(2-methyl-2,3-dihydro-1,4-benzodioxine-3-carbonyl)amino]benzoate	1475149: Binding affinity to human RAGE cytoplasmic domain by tryptophan fluorescence assay	kd	0.0020	uM
1-(benzimidazol-1-yl)-3-indol-1-ylpropan-2-ol	1475149: Binding affinity to human RAGE cytoplasmic domain by tryptophan fluorescence assay	kd	0.0020	uM
2-(1H-benzimidazol-2-yl)-5-methyl-4-(3-methylbutyl)-4H-pyrazol-3-one	1475149: Binding affinity to human RAGE cytoplasmic domain by tryptophan fluorescence assay	kd	0.0030	uM
1-(3-carbazol-9-yl-2-hydroxypropyl)-3-methylbenzimidazol-2-one	1475149: Binding affinity to human RAGE cytoplasmic domain by tryptophan fluorescence assay	kd	0.0040	uM
2-methoxy-N-(6-methyl-2-pyridinyl)-4-methylsulfanylbenzamide	1475149: Binding affinity to human RAGE cytoplasmic domain by tryptophan fluorescence assay	kd	0.0060	uM
3-[4-[2-butyl-1-[4-(4-chlorophenoxy)phenyl]imidazol-4-yl]phenoxy]-N,N-diethylpropan-1-amine	1908571: Binding affinity to recombinant human RAGE assessed as dissociation constant	kd	0.0127	uM
N-benzyl-N-cyclohexyl-4-fluorobenzamide	1475147: Binding affinity to human RAGE domain V by autoradiography	kd	0.0150	uM
N-benzyl-N-cyclohexyl-4-(18F)fluoro(18F)benzamide	1896074: Binding affinity to RAGE (unknown origin) assessed as dissociation constant	kd	0.0150	uM
N-benzyl-4-chloro-N-cyclohexylbenzamide	1475145: Displacement of [I125]amyloid beta (1 to 40) from human RAGE domain V expressed in CHO cells	ki	0.0250	uM
(2S)-2-amino-5-[(4-methyl-5-oxoimidazolidin-2-ylidene)amino]pentanoic acid	1475138: Binding affinity to human C-terminal His-tagged RAGE domain V (24 to 125 residues) expressed in Escherichia coli BL21(DE3) by tryptophan fluorescence assay	kd	0.0300	uM
N-[2-(3-chloro-2-methylanilino)-2-oxoethyl]-2-fluorobenzamide	1475149: Binding affinity to human RAGE cytoplasmic domain by tryptophan fluorescence assay	kd	0.0320	uM
pyridine-2,3-dicarboxylic acid	1475140: Binding affinity to human His-tagged RAGE domain VC1 expressed in Escherichia coli by fluorescence titration method	kd	0.0430	uM
tert-butyl N-[(1R)-1-[1-butyl-5-[3-(diethylamino)propoxy]benzimidazol-2-yl]-2-[4-[2-(4-chlorophenyl)ethoxy]phenyl]ethyl]carbamate	1475146: Inhibition of S110B binding to RAGE (unknown origin) by ELISA	ic50	0.5000	uM
9H-fluoren-9-ylmethyl N-[3-(1-benzylpiperidin-4-yl)-1-[2-butoxy-4-[3-(diethylamino)propoxy]anilino]-1-oxopropan-2-yl]carbamate	1475146: Inhibition of S110B binding to RAGE (unknown origin) by ELISA	ic50	0.5000	uM
5-butyl-4-[4-(4-chlorophenoxy)phenyl]-N-[4-[3-(diethylamino)propoxy]phenyl]-1,3-thiazol-2-amine;trihydrochloride	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	0.5500	uM
5-butyl-4-[4-(4-chlorophenoxy)phenyl]-2-[4-[(1-ethylpiperidin-3-yl)methoxy]phenyl]-1,3-thiazole	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	0.6600	uM
5-butyl-4-[4-(4-chlorophenoxy)phenyl]-2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1,3-thiazole	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	0.9100	uM
5-butyl-4-[4-(4-chlorophenoxy)phenyl]-2-[4-(2-piperidin-1-ylethoxy)phenyl]-1,3-thiazole	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	1.0400	uM
3-[4-[5-butyl-2-[4-(4-chlorophenoxy)phenyl]-1,3-thiazol-4-yl]phenoxy]-N,N-diethylpropan-1-amine	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	1.1200	uM
4-butyl-2-[4-(4-chlorophenoxy)phenyl]-5-[4-[(1-ethylpiperidin-3-yl)methoxy]phenyl]-1,3-thiazole	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	1.1400	uM
5-butyl-4-[4-(4-chlorophenoxy)phenyl]-2-[4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-1,3-thiazole	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	1.2100	uM
5-butyl-4-[4-(4-chlorophenoxy)phenyl]-2-[4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl]-1,3-thiazole	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	1.2400	uM
2-[4-[5-butyl-4-[4-(4-chlorophenoxy)phenyl]-1,3-thiazol-2-yl]phenoxy]-N,N-diethylethanamine	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	1.5800	uM
3-[4-[5-butyl-4-[4-(4-chlorophenoxy)phenyl]-1,3-thiazol-2-yl]phenoxy]-N,N-diethylpropan-1-amine	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	1.7200	uM
2-(diethylamino)ethyl 4-[[(2R)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-3-butoxybenzoate	1475146: Inhibition of S110B binding to RAGE (unknown origin) by ELISA	ic50	1.7500	uM
5-butyl-4-[4-(4-chlorophenoxy)phenyl]-2-[4-(3-piperidin-1-ylpropoxy)phenyl]-1,3-thiazole	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	1.8400	uM
N-[2-butoxy-4-[3-(diethylamino)propoxy]phenyl]-1-methyl-3-[4-[4-(trifluoromethyl)phenoxy]phenyl]pyrazole-5-carboxamide	1127242: Inhibition of biotinylated human RAGE assessed as bound amyloid beta level after 60 mins by ELISA	ic50	1.9000	uM
N-[2-butoxy-4-[3-(diethylamino)propoxy]phenyl]-3-[4-(4-fluorophenoxy)phenyl]-1-methylpyrazole-5-carboxamide	1127242: Inhibition of biotinylated human RAGE assessed as bound amyloid beta level after 60 mins by ELISA	ic50	1.9000	uM
5-butyl-2-[4-(4-chlorophenoxy)phenyl]-4-[4-[(1-ethylpiperidin-3-yl)methoxy]phenyl]-1,3-thiazole	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	1.9100	uM
3-[4-[4-butyl-2-[4-(4-chlorophenoxy)phenyl]-1,3-thiazol-5-yl]phenoxy]-N,N-diethylpropan-1-amine	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	2.0100	uM
N-[2-butoxy-4-[3-(diethylamino)propoxy]phenyl]-3-(4-cyclohexyloxyphenyl)-1-methylpyrazole-5-carboxamide	1127242: Inhibition of biotinylated human RAGE assessed as bound amyloid beta level after 60 mins by ELISA	ic50	2.5000	uM
2-[4-[5-butyl-4-[4-(4-chlorophenoxy)phenyl]-1,3-thiazol-2-yl]phenoxy]-N,N-dimethylethanamine	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	3.1800	uM
3-[4-[4-[1-[4-(4-chlorophenoxy)phenyl]-2-ethylimidazol-4-yl]piperidin-1-yl]butyl]-1H-indole-5-carbonitrile	1908573: Inhibition of biotinylated human RAGE/amyloid beta interaction incubated for 120 mins by ELISA assay	ic50	3.4900	uM
3-[[4-[2-butyl-1-[4-(4-chlorophenoxy)phenyl]imidazol-4-yl]piperidin-1-yl]methyl]-1H-indole-5-carbonitrile	1908573: Inhibition of biotinylated human RAGE/amyloid beta interaction incubated for 120 mins by ELISA assay	ic50	4.0400	uM
3-[4-[4-[1-butyl-5-[4-(4-chlorophenoxy)phenyl]pyrazol-3-yl]piperidin-1-yl]butyl]-1H-indole-5-carbonitrile	1908573: Inhibition of biotinylated human RAGE/amyloid beta interaction incubated for 120 mins by ELISA assay	ic50	4.1500	uM
4,6-bis(4-chlorophenyl)-N-[2-[2-(diethylamino)ethoxy]phenyl]pyrimidin-2-amine	708563: Inhibition of human recombinant biotinylated receptor for advanced glycation end product expressed in Escherichia coli DE3 assessed as inhibition of binding to amyloid beta (1 to 42) after 60 mins by TMB-ELISA	ic50	4.6000	uM
N-[2-butoxy-4-[3-(diethylamino)propoxy]phenyl]-3-[4-(4-chloro-3-methoxyphenoxy)phenyl]-1-methylpyrazole-5-carboxamide	1127242: Inhibition of biotinylated human RAGE assessed as bound amyloid beta level after 60 mins by ELISA	ic50	5.3000	uM
N-[2-butoxy-4-[3-(diethylamino)propoxy]phenyl]-1-methyl-3-(4-phenoxyphenyl)pyrazole-5-carboxamide	1127242: Inhibition of biotinylated human RAGE assessed as bound amyloid beta level after 60 mins by ELISA	ic50	5.4000	uM
N-[5-butyl-4-[4-(4-chlorophenoxy)phenyl]-1,3-thiazol-2-yl]-4-[3-(diethylamino)propoxy]benzamide;hydrochloride	719012: Antagonist activity at human biotinylated RAGE assessed as inhibition of amyloid beta binding after 60 mins by ELISA	ic50	5.5900	uM
3-[4-[4-[1-[4-(4-chlorophenoxy)phenyl]-2-pentylimidazol-4-yl]piperidin-1-yl]butyl]-1-methylindole-5-carbonitrile	1908573: Inhibition of biotinylated human RAGE/amyloid beta interaction incubated for 120 mins by ELISA assay	ic50	6.0300	uM
N-[2-butoxy-4-[3-(diethylamino)propoxy]phenyl]-3-[4-(4-methoxyphenoxy)phenyl]-1-methylpyrazole-5-carboxamide	1127242: Inhibition of biotinylated human RAGE assessed as bound amyloid beta level after 60 mins by ELISA	ic50	7.8000	uM
3-[4-[4-[5-butyl-4-[4-(4-chlorophenoxy)phenyl]-1,3-thiazol-2-yl]piperidin-1-yl]butyl]-1-methylindole-5-carbonitrile	1908573: Inhibition of biotinylated human RAGE/amyloid beta interaction incubated for 120 mins by ELISA assay	ic50	8.2600	uM
3-[4-[4-[1-[4-(4-chlorophenoxy)phenyl]-2-cyclobutylimidazol-4-yl]piperidin-1-yl]butyl]-1H-indole-5-carbonitrile	1908573: Inhibition of biotinylated human RAGE/amyloid beta interaction incubated for 120 mins by ELISA assay	ic50	8.2900	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, increases expression	3
Lipopolysaccharides	increases expression, decreases reaction	3
protocatechualdehyde	decreases reaction, increases expression, decreases expression	2
sodium arsenite	decreases expression, increases abundance, increases expression	2
acteoside	decreases reaction, increases expression, decreases expression	2
Resveratrol	affects binding, decreases activity, decreases reaction, increases expression, decreases expression (+1 more)	2
Estradiol	increases expression, increases reaction, decreases reaction	2
Glucose	affects binding, decreases reaction, increases reaction, increases expression	2
Tobacco Smoke Pollution	affects methylation, increases abundance, decreases expression	2
Toluene 2,4-Diisocyanate	affects reaction, decreases reaction, increases expression, affects localization	2
aristolochic acid I	increases expression	1
nornicotine	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
butyraldehyde	decreases expression	1
pentanal	decreases expression	1
pyrazolanthrone	decreases reaction, increases expression	1
2-chloro-5-nitrobenzanilide	affects binding, decreases activity, decreases reaction, increases expression	1
LR-90	decreases reaction, increases expression	1
er-xian decoction	decreases reaction, increases expression	1
4-methyl-N1-(3-phenylpropyl)benzene-1,2-diamine	decreases reaction, increases expression, decreases expression	1
FPS-ZM1	decreases reaction, increases expression, decreases activity	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Fulvestrant	decreases reaction, increases expression	1
Lycopene	decreases reaction, increases expression	1
Acetaminophen	decreases expression	1
Aldehydes	decreases expression	1
Anisomycin	increases expression	1
Arsenic	increases abundance, increases expression	1

ChEMBL screening assays

33 unique, capped per target: 32 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2185357	Binding	Binding affinity to human recombinant biotinylated receptor for advanced glycation end product expressed in Escherichia coli DE3 after 1 min by surface plasmon resonance assay	Ligand-based design, synthesis, and biological evaluation of 2-aminopyrimidines, a novel series of receptor for advanced glycation end products (RAGE) inhibitors. — J Med Chem
CHEMBL2210067	Functional	Antagonist activity at RAGE transfected in CHO cells assessed as inhibition of amyloid beta 42-induced NFkappaB activation at 1 uM after 18 hrs by luciferase reporter gene assay	Synthesis and structure-activity relationships of tri-substituted thiazoles as RAGE antagonists for the treatment of Alzheimer’s disease. — Bioorg Med Chem Lett

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C3N7	WM115-RAGE	Cancer cell line	Female
CVCL_D1V5	Abcam A-549 AGER KO	Cancer cell line	Male
CVCL_D1ZT	Abcam HCT 116 AGER KO	Cancer cell line	Male
CVCL_D2N2	Abcam THP-1 AGER KO	Cancer cell line	Male
CVCL_SB91	HAP1 AGER (-) 1	Cancer cell line	Male
CVCL_XL13	HAP1 AGER (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00106821	PHASE4	COMPLETED	Efficacy of Tiotropium in Patients of African Descent With Chronic Obstructive Pulmonary Disease
NCT00115492	PHASE4	COMPLETED	Advair® DISKUS® Versus Serevent® DISKUS® For Chronic Obstructive Pulmonary Disease Exacerbations
NCT00132860	PHASE4	UNKNOWN	Prophylactic Antibiotic Treatment of Patients With Chronic Obstructive Lung Disease (COLD)
NCT00139932	PHASE4	COMPLETED	Tiotropium Bromide Alone vs Tiotropium Bromide and Formoterol Fumarate in Subjects With COPD (Study P04272)
NCT00144196	PHASE4	COMPLETED	12 Week Efficacy of Tiotropium Versus Placebo in Patients With Mild COPD According to Swedish Guidelines (SPIRIMILD)
NCT00144911	PHASE4	COMPLETED	ADVAIR® DISKUS® Inhaler (Fluticasone Propionate/Salmeterol) Versus SEREVENT® DISKUS® Inhaler (Salmeterol) For The Treatment Of Chronic Obstructive Pulmonary Disease Exacerbations. ADVAIR® DISKUS® Inhaler and SEREVENT® DISKUS® Inhaler Are Trademarks of the GSK Group of Companies.
NCT00152984	PHASE4	COMPLETED	Efficacy and Safety of Tiotropium in Patients With COPD and Concomitant Diagnosis of Asthma
NCT00153075	PHASE4	COMPLETED	Flow Rate Effect Respimat Inhaler Versus a Metered Dose Inhaler Using Berodual in Patients With Chronic Obstructive Pulmonary Disease (COPD)
NCT00181207	PHASE4	COMPLETED	Airway Clearance for Prevention of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
NCT00184977	PHASE4	COMPLETED	COPD on Primary Care Treatment (COOPT)
NCT00239408	PHASE4	COMPLETED	Spiriva (Tiotropium Bromide) Assessment of FEV1 - (SAFE-Portugal).
NCT00239421	PHASE4	COMPLETED	A Six-week Study Comparing the Efficacy and Safety of Tiotropium Plus Formoterol to Salmeterol Plus Fluticasone in Chronic Obstructive Pulmonary Disease (COPD)
NCT00239499	PHASE4	COMPLETED	Pilot Study Comparing Tiotropium (Spiriva) to Salmeterol (Serevent) Plus Fluticasone (Flixotide) in Chronic Obstructive Pulmonary Disease (COPD)
NCT00267917	PHASE4	COMPLETED	Evaluation of the Respimat Inhaler vs. a HFA MDI Using Berodual in Patients With COPD With Poor MDI Technique.
NCT00274079	PHASE4	COMPLETED	SPIRIVA in Ususal Care
NCT00291460	PHASE4	UNKNOWN	Inspiratory Muscle Training in Hypercapnic COPD
NCT00346749	PHASE4	TERMINATED	ADVAIR DISKUS® (Fluticasone Propionate/Salmeterol) Inhaler Versus SEREVENT DISKUS® (Salmeterol) Inhlaer On Inflammatory Cells And Markers In Chronic Obstructive Pulmonary Disease. ADVAIR DISKUS® and SEREVENT DISKUS® Inhalers Are Trademarks of the GSK Group of Companies.
NCT00351676	PHASE4	COMPLETED	Capturing Outcomes of Clinical Activities Performed by a Rounding Pharmacist Practising in a Team Environment
NCT00355342	PHASE4	COMPLETED	Bone Mineral Density Study In Patients With Chronic Obstructive Pulmonary Disease. DISKUS® Inhaler is a Trademark of the GSK Group of Companies.
NCT00358358	PHASE4	COMPLETED	Chronic Obstructive Pulmonary Disease Endpoints Study
NCT00359788	PHASE4	COMPLETED	A Trial Comparing Treatment With Tiotropium Inhalation Capsules to Combivent Inhalation Aerosol in COPD Patients.
NCT00361959	PHASE4	COMPLETED	SERETIDE 50/500mcg Versus Tiotropium Bromide On Exacerbation Rates In Severe Chronic Obstructive Pulmonary Disease
NCT00388882	PHASE4	COMPLETED	Trial Comparing Treatment With Tiotropium Inhalation Capsules to Combivent® Inhalation Aerosol in COPD Patients.
NCT00394485	PHASE4	TERMINATED	Tiotropium + Procaterol vs Tiotropium + Placebo in COPD Patients
NCT00412204	PHASE4	COMPLETED	Study to Evaluate the Effects of Tiotropium Bromide on Chronic Obstructive Pulmonary Disease (COPD) During Exercise
NCT00440245	PHASE4	COMPLETED	Bronchoprotection of Salbutamol in Asthma and Chronic Obstructive Pulmonary Disease
NCT00523991	PHASE4	COMPLETED	Trial Comparing Tiotropium Inhalation Capsules vs Placebo in Chronic Obstructive Pulmonary Disease (COPD).
NCT00525512	PHASE4	COMPLETED	Tiotropium In Exercise
NCT00527826	PHASE4	COMPLETED	Influence Of Salmeterol Xinafoate/Fluticasone Propionate (50/500 µg BID) On The Course Of The Disease And Exacerbation Frequency In COPD Patients Gold Stage III And IV
NCT00530842	PHASE4	COMPLETED	Effect of Tiotropium Plus Salmeterol vs. Fluticasone/Salmeterol on Static Lung Volumes and Exercise Endurance in COPD
NCT00563381	PHASE4	COMPLETED	Tiotropium Once Daily 18 Mcg Versus Salmeterol Twice Daily 50 Mcg on Time to First Exacerbation in COPD Patients.
NCT00569270	PHASE4	COMPLETED	Dynamic Hyperinflation and Tiotropium
NCT00578968	PHASE4	COMPLETED	Cardiac Limitations in Chronic Obstructive Pulmonary Disease: Benefits of Bronchodilation
NCT00592033	PHASE4	COMPLETED	Effect of Oxygen in Normoxaemic COPD Patients Who Desaturate During Exercise
NCT00633217	PHASE4	COMPLETED	Advair HFA For Chronic Obstructive Pulmonary Disease(COPD)
NCT00633776	PHASE4	WITHDRAWN	Perforomist Versus Foradil Evaluated by Inspiratory Capacity and High Resolution Computed Tomography (HRCT)
NCT00667797	PHASE4	COMPLETED	Costs & Outcomes of Hospitalization/Treatment With Levalbuterol & Albuterol in Asthma or Chronic Obstructive Pulmonary Disease (COPD) Subjects
NCT00680056	PHASE4	COMPLETED	Add-on Effects of Tiotropium Over Formoterol in Exercise Tolerance on Chronic Obstructive Pulmonary Disease Patients
NCT00680641	PHASE4	UNKNOWN	Simvastatin in Chronic Obstructive Pulmonary Disease (COPD)
NCT00720226	PHASE4	COMPLETED	Efficacy of Losartan in Preventing Progression of COPD