CXCR1

Summary

CXCR1 (C-X-C motif chemokine receptor 1, HGNC:6026) is a protein-coding gene on chromosome 2q35, encoding C-X-C chemokine receptor type 1 (P25024). Receptor to interleukin-8, which is a powerful neutrophils chemotactic factor.

The protein encoded by this gene is a member of the G-protein-coupled receptor family. This protein is a receptor for interleukin 8 (IL8). It binds to IL8 with high affinity, and transduces the signal through a G-protein activated second messenger system. Knockout studies in mice suggested that this protein inhibits embryonic oligodendrocyte precursor migration in developing spinal cord. This gene, IL8RB, a gene encoding another high affinity IL8 receptor, as well as IL8RBP, a pseudogene of IL8RB, form a gene cluster in a region mapped to chromosome 2q33-q36.

Source: NCBI Gene 3577 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 80 total
• Druggable target: yes — 9 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000634

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6026
Approved symbol	CXCR1
Name	C-X-C motif chemokine receptor 1
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	CKR-1, CDw128a, CD181
Ensembl gene	ENSG00000163464
Ensembl biotype	protein_coding
OMIM	146929
Entrez	3577

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000295683

RefSeq mRNA: 1 — MANE Select: NM_000634 NM_000634

CCDS: CCDS2409

Canonical transcript exons

ENST00000295683 — 2 exons

Exon	Start	End
ENSE00001074911	218162841	218165244
ENSE00001074913	218166908	218166962

Expression profiles

Bgee: expression breadth ubiquitous, 148 present calls, max score 97.86.

FANTOM5 (CAGE): breadth broad, TPM avg 8.8004 / max 1568.2835, expressed in 203 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
33932	7.4457	176
33933	1.3547	80

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	97.86	gold quality
granulocyte	CL:0000094	91.88	gold quality
type B pancreatic cell	CL:0000169	91.58	gold quality
olfactory bulb	UBERON:0002264	91.37	gold quality
periodontal ligament	UBERON:0008266	90.43	gold quality
spleen	UBERON:0002106	87.43	gold quality
bone marrow	UBERON:0002371	81.71	gold quality
diaphragm	UBERON:0001103	81.00	gold quality
bone marrow cell	CL:0002092	80.12	gold quality
bone element	UBERON:0001474	79.07	gold quality
vermiform appendix	UBERON:0001154	78.68	gold quality
gingival epithelium	UBERON:0001949	78.33	gold quality
epithelial cell of pancreas	CL:0000083	77.19	gold quality
right lung	UBERON:0002167	77.15	gold quality
upper lobe of left lung	UBERON:0008952	76.15	gold quality
decidua	UBERON:0002450	74.93	gold quality
leukocyte	CL:0000738	74.67	gold quality
nasal cavity epithelium	UBERON:0005384	74.57	silver quality
hair follicle	UBERON:0002073	74.18	gold quality
epithelium of nasopharynx	UBERON:0001951	74.02	gold quality
mucosa of paranasal sinus	UBERON:0005030	73.62	gold quality
mucosa of urinary bladder	UBERON:0001259	73.57	silver quality
caecum	UBERON:0001153	73.40	gold quality
upper lobe of lung	UBERON:0008948	73.13	gold quality
squamous epithelium	UBERON:0006914	73.07	gold quality
trabecular bone tissue	UBERON:0002483	73.05	silver quality
secondary oocyte	CL:0000655	72.89	silver quality
monocyte	CL:0000576	72.67	gold quality
mononuclear cell	CL:0000842	72.62	gold quality
palpebral conjunctiva	UBERON:0001812	72.51	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.71

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, NFKB, PPARG, SPI1

miRNA regulators (miRDB)

40 targeting CXCR1, 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-4283	100.00	66.42	2097
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-1295B-5P	99.03	67.50	810
HSA-MIR-3124-3P	98.87	68.95	2123
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-1237-3P	98.55	67.65	1423
HSA-MIR-3138	98.41	67.53	744
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-4772-3P	98.04	65.60	1203
HSA-MIR-4303	98.01	68.13	2304
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-1271-3P	97.56	64.85	865
HSA-MIR-550A-3-5P	97.56	65.35	823
HSA-MIR-550A-5P	97.56	65.35	823
HSA-MIR-4253	97.48	65.11	692
HSA-MIR-6862-5P	97.48	64.84	713

Literature-anchored findings (GeneRIF, showing 40)

• Data show that CXCR1 is expressed in neutrophils in inflamed human stomach and gut tissues. (PMID:12002274)
• Identification of a signal transduction switch in this receptor (PMID:12077146)
• Phagocytosing neutrophils down-regulate its expression (PMID:12239185)
• CXCR1 and CXCR2 internalization and recycling are tightly regulated by receptor domains and by actin-related kinases. (PMID:12442335)
• Level of expression of the adhesion molecule/complement receptor CD11b/CD18 and the chemokine receptor IL-8 receptor-A was also higher after vaginal delivery. (PMID:12576754)
• Neutrophil recruitment to inflammatory sites is mediated by two related receptors: CXCR1 and CXCR2. Both receptors share two ligands, interleukin-8 (CXCL8) and GCP-2 (CXCL6). (PMID:12628493)
• The specific distribution and regulation of chemokine receptors CXCR1, CXCR4, CCR5, and CCR2b in endometrial epithelium and blastocyst suggest a role for these receptors in the apposition and adhesion phases of human implantation. (PMID:12651900)
• Subjects with atopic disease are found to have higher numbers of CXCR1+CD4+ T cells in peripheral blood and in T cell populations expanded from nasal mucosa tissue. (PMID:14688334)
• the data suggest that constitutive expression of CXCR1 and CXCR2 play an important role regulating the IL-8-mediated metastatic phenotype in human malignant melanoma cells. (PMID:14713106)
• neutrophil migration in response to CXCR1 or CXCR2 agonists is not dependent on endocytosis of CXCR1 or CXCR2 (PMID:15028716)
• Role of N-terminal domain in ligand selectivity and affinity of chemokine receptor CXCR1 (PMID:15133028)
• extra- and intracellular CXCR1 and CXCR2 are differentially expressed and regulated on T lymphocytes and mast cells (PMID:15265017)
• CXCR1 identifies a subset of CD8 T cells poised for immediate cytotoxicity and early recruitment into sites of innate immune system activation. (PMID:15292066)
• IL-8 and CXCR1 participate in the altered megakarocyte growth that features myeloid metaplasia with myelofibrosis (PMID:15454487)
• Activation of neutrophils and down-regulation of CXCR1 were predominantly caused by IL-8 (PMID:15545821)
• CD38 is stimulated by sequential activation of IL8 receptor, IP(3)-mediated Ca(2+) rise, and cGMP/protein kinase G and plays an essential role in IL8-induced migration of LAK cells (PMID:15556942)
• CXCL8 modulates human intestinal epithelial cells through a CXCR1 dependent pathway (PMID:15579377)
• In eutopic endometrium of women with endometriosis, significant increase in both proliferative and secretory phases for epithelial CXCR2 expression, and in proliferative phase for CXCR1 expression. May be involved in pathogenesis of endometriosis. (PMID:15618253)
• Our results link low-grade IL-8-mediated cartilaginous inflammation in OA to altered chondrocyte differentiation and disease progression through PiT-1 expression and sodium-dependent Pi uptake mediated by CXCR1 signaling. (PMID:15641067)
• The expression of CXC chemokine receptor 1 mRNA was significantly more increased than in controls. (PMID:15764156)
• the relative expression levels of CXCR-1 and -2 mRNA were rather lower than expected in the affected esophageal mucosa of patients with reflux esophagitis (PMID:15793866)
• Proliferating NK cells were simultaneously positive for CXCR1 in all aggressive NK cell leukemia patients examined. (PMID:15902300)
• CXCR1-CXCR2 heterodimers are as likely to form in cells co-expressing these two chemokine receptors as the corresponding homodimers. (PMID:15946947)
• Gene polymorphisms active in the EGFR pathway may be associated with the sensitivity of colorectal cancer patients to platinum-based chemotherapy. (PMID:16098254)
• the complete coding region of the CXCR1 gene in worldwide human populations and five representative nonhuman primate species; results indicate accelerated protein evolution in the human lineage (PMID:16205979)
• In CXCR1-expressing cells FAK phosphorylation was adhesion-independent.Overall, several aspects of CXCL8-induced FAK phosphorylation and migration are regulated in a receptor-specific manner. (PMID:16406804)
• Intrinsic abnormalities concerning IL-8 and its receptor system may be present in eutopic endometrium of women affected by adenomyosis. IL-8 receptors may be involved in pathogenesis and/or pathophysiology of adenomyosis. (PMID:16500343)
• CXCR-1 and CXCR-2 chemokine receptors of synovial fluid neutrophils may have diverse functions in the course of inflammatory arthritides (PMID:16987681)
• No association is found for chemokine (C-X-C motif) receptor 1 (CXCR1) single nucleotide polymorphisms in patients with increased susceptibility to bronchiectasis. (PMID:17026468)
• no association of polymorphisms with melanoma susceptibility (PMID:17169533)
• data herein indicate that the second extracellular loop (2ECL) of the receptors CXCR1,CXCR2, and CXCL8 is critical for the distinct rate of internalization of each (PMID:17204468)
• An interaction between this cytokine and glial cells may help explain the pathophysiological mechanisms leading to cognitive impairment in our study group. (PMID:17207897)
• Mesenchymal stem cells express chemokine receptor CXCR1 and migrate upon stimulation with IL-8. (PMID:17295203)
• A haplotype of the human CXCR1 gene is protective against rapid disease progression in HIV-1+ patients, probably acting through modulation of CD4 and CXCR4 expression. (PMID:17360650)
• RANTES, MCP-1, CCR2, CCR5, CXCR1 and CXCR4 gene polymorphisms do not have a role in progression of hepatitis B virus infection (PMID:17596666)
• Findings indicate that beta-endorphin and Met-enkephalin are contained in primary granules of PMN, and that CXCR1/2 ligands induce p38-dependent translocation and release of these opioid peptides to inhibit inflammatory pain. (PMID:17604950)
• When reflux was excluded, 54% of the patients had CXCR1 sequence variants. The UTI prone children expressed less CXCR1 protein than the pediatric controls (p<0.0001) and two sequence variants were shown to impair transcription (PMID:17786197)
• The development of a model for the structure of the IL-8/CXCL8 receptor CXCR1, using a combination of homology modeling and a molecular dynamics simulation was pesented. (PMID:17876799)
• Intracellular cross-talk between the GPCR CXCR1 and CXCR2: role of carboxyl terminus phosphorylation sites (PMID:17996233)
• Cyr61 promotes interleukin-8-dependent chemotaxis, transendothelial migration, and intravasation by induction of CXCR1/CXCR2 through integrin alphavbeta3/Src/PI3K/Akt-dependent pathway. (PMID:18025257)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cxcr2	ENSDARG00000054975
mus_musculus	Cxcr1	ENSMUSG00000048480
rattus_norvegicus	Cxcr1	ENSRNOG00000048239

Paralogs (23): CCR6 (ENSG00000112486), CCRL2 (ENSG00000121797), CCR2 (ENSG00000121807), CXCR4 (ENSG00000121966), CCR7 (ENSG00000126353), ACKR4 (ENSG00000129048), ACKR3 (ENSG00000144476), ACKR2 (ENSG00000144648), RGR (ENSG00000148604), CXCR5 (ENSG00000160683), CCR5 (ENSG00000160791), CCR1 (ENSG00000163823), CX3CR1 (ENSG00000168329), CXCR6 (ENSG00000172215), XCR1 (ENSG00000173578), CCR9 (ENSG00000173585), CCR8 (ENSG00000179934), CXCR2 (ENSG00000180871), GALR2 (ENSG00000182687), CCR3 (ENSG00000183625), CCR4 (ENSG00000183813), CCR10 (ENSG00000184451), CXCR3 (ENSG00000186810)

Protein

Protein identifiers

C-X-C chemokine receptor type 1 — P25024 (reviewed: P25024)

Alternative names: CDw128a, High affinity interleukin-8 receptor A, IL-8 receptor type 1

All UniProt accessions (1): P25024

UniProt curated annotations — full annotation on UniProt →

Function. Receptor to interleukin-8, which is a powerful neutrophils chemotactic factor. Binding of IL-8 to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system.

Subunit / interactions. Interacts with IL8. Interacts with GNAI2.

Subcellular location. Cell membrane.

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (1): NP_000625* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000174	Chemokine_CXCR_1/2	Family
IPR000276	GPCR_Rhodpsn	Family
IPR001355	Chemokine_CXCR1	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR050119	CCR1-9-like	Family

Pfam: PF00001

UniProt features (45 total): helix 12, topological domain 8, transmembrane region 7, sequence variant 7, turn 4, glycosylation site 2, strand 2, chain 1, disulfide bond 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8IC0	ELECTRON MICROSCOPY	3.41
1ILP	SOLUTION NMR
1ILQ	SOLUTION NMR
2LNL	SOLID-STATE NMR
6XMN	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P25024-F1	78.08	0.25

Antibody-complex structures (SAbDab): 1 — 8IC0

Functional residue map

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

Disulfide bonds (1): 110–187

Glycosylation sites (2): 3, 16

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-380108	Chemokine receptors bind chemokines
R-HSA-418594	G alpha (i) signalling events
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 125 (showing top): FERRANDO_TAL1_NEIGHBORS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_DENDRITIC_CELL_MIGRATION, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, GOCC_CELL_SURFACE, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_LEUKOCYTE_CHEMOTAXIS, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, GOBP_TAXIS, GOBP_LEUKOCYTE_MIGRATION, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS

GO Biological Process (12): dendritic cell chemotaxis (GO:0002407), immune response (GO:0006955), cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186), positive regulation of cytosolic calcium ion concentration (GO:0007204), calcium-mediated signaling (GO:0019722), neutrophil chemotaxis (GO:0030593), receptor internalization (GO:0031623), chemotaxis (GO:0006935), signal transduction (GO:0007165), interleukin-8-mediated signaling pathway (GO:0038112), chemokine-mediated signaling pathway (GO:0070098)

GO Molecular Function (8): interleukin-8 receptor activity (GO:0004918), G protein-coupled receptor activity (GO:0004930), chemokine receptor activity (GO:0004950), C-C chemokine receptor activity (GO:0016493), C-C chemokine binding (GO:0019957), interleukin-8 binding (GO:0019959), protein binding (GO:0005515), C-X-C chemokine receptor activity (GO:0016494)

GO Cellular Component (4): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), secretory granule membrane (GO:0030667), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Peptide ligand-binding receptors	1
GPCR downstream signalling	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
cytokine-mediated signaling pathway	2
G protein-coupled receptor signaling pathway	2
chemokine binding	2
chemokine receptor activity	2
C-X-C chemokine binding	2
leukocyte chemotaxis	1
dendritic cell migration	1
immune system process	1
response to stimulus	1
G protein-coupled receptor activity	1
regulation of biological quality	1
intracellular signaling cassette	1
granulocyte chemotaxis	1
neutrophil migration	1
receptor-mediated endocytosis	1
response to chemical	1
taxis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular response to interleukin-8	1
cellular response to chemokine	1
C-X-C chemokine receptor activity	1
interleukin-8 binding	1
interleukin-8-mediated signaling pathway	1
transmembrane signaling receptor activity	1
G protein-coupled chemoattractant receptor activity	1
cytokine receptor activity	1
chemokine-mediated signaling pathway	1
C-C chemokine binding	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
secretory granule	1

Protein interactions and networks

STRING

2074 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CXCR1	CXCL8	P10145	998
CXCR1	CXCL6	P80162	996
CXCR1	CXCL1	P09341	996
CXCR1	CXCL5	P42830	996
CXCR1	PPBP	P02775	993
CXCR1	CCL2	P13500	989
CXCR1	CXCL2	P19875	989
CXCR1	CX3CL1	P78423	985
CXCR1	CXCR2	P25025	980
CXCR1	CXCL12	P48061	979
CXCR1	CXCL10	P02778	970
CXCR1	CXCL13	O43927	965
CXCR1	CXCL3	P19876	963
CXCR1	CCL3	P10147	945
CXCR1	CCR2	P41597	920

IntAct

140 interactions, top by confidence:

A	B	Type	Score
CXCR1	FATE1	psi-mi:“MI:0915”(physical association)	0.560
TUSC5	CXCR1	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	CXCR1	psi-mi:“MI:0915”(physical association)	0.560
CXCR1	CLDND1	psi-mi:“MI:0915”(physical association)	0.560
CXCR1	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	ARHGEF12	psi-mi:“MI:0407”(direct interaction)	0.440
WHRN	CXCR1	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	SHANK1	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	CXCR1	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	PALS2	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	GRID2IP	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	TJP1	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	LIMK2	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
CXCR1	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
PDZRN4	CXCR1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (10): CXCR1 (Two-hybrid), CXCR1 (Two-hybrid), CXCR1 (Two-hybrid), TUSC5 (Two-hybrid), GNAI2 (Affinity Capture-Western), GNAI2 (Affinity Capture-Western), UBE2C (Two-hybrid), CXCR1 (Two-hybrid), TUBA1A (Two-hybrid), PDCD6IP (Two-hybrid)

ESM2 similar proteins: A4FUQ5, B1PHQ8, B9VR26, O35786, O70129, O88536, O88537, O97571, P0C7U4, P0C7U5, P21109, P21730, P25024, P25025, P25089, P25090, P30992, P30993, P32248, P33766, P35344, P35407, P51686, P55919, P55920, P79175, P79177, P79188, P79189, P79190, P79191, P79234, P79235, P79236, P79237, P79240, P79242, P79243, P97468, P97520

Diamond homologs: A0A4W3GG95, A0A6I8PUB9, B2GV46, B5X337, D4A7K7, E7FEL0, E9QJ73, F8VQN3, O00270, O08726, O08858, O14842, O14843, O15529, O42179, O43603, O46685, O60755, O77408, O88410, O88626, O88634, O88853, P21109, P23944, P25024, P25025, P35344, P35383, P35414, P41231, P41232, P46092, P46093, P49652, P49682, P49683, P50132, P51675, P51679

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CXCL8	up-regulates	CXCR1	binding
REEP5	“up-regulates activity”	CXCR1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
Ras activation upon Ca2+ influx through NMDA receptor	5	50.1×	3e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	47.7×	3e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	47.7×	3e-06
Assembly and cell surface presentation of NMDA receptors	10	44.5×	4e-12
Long-term potentiation	5	41.7×	5e-06
Neurexins and neuroligins	10	34.5×	3e-11
Protein-protein interactions at synapses	6	28.0×	3e-06
Neuronal System	7	5.4×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	74.5×	3e-14
protein localization to synapse	6	58.9×	1e-07
receptor clustering	7	56.0×	9e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	6	38.1×	9e-07
bicellular tight junction assembly	6	25.4×	8e-06
protein-containing complex assembly	10	14.6×	2e-07
cell-cell adhesion	10	13.0×	5e-07
protein localization to plasma membrane	7	9.8×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	65
Likely benign	9
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

247 predictions. Top by Δscore:

Variant	Effect	Δscore
2:218165241:CTAA:C	acceptor_gain	0.9900
2:218165245:C:CC	acceptor_gain	0.9900
2:218165242:TAA:T	acceptor_gain	0.9800
2:218166904:CTA:C	donor_loss	0.9800
2:218166905:TACCT:T	donor_loss	0.9800
2:218166906:A:C	donor_loss	0.9800
2:218166907:CCT:C	donor_loss	0.9800
2:218165341:C:A	donor_gain	0.9700
2:218165253:T:TC	acceptor_gain	0.9500
2:218165245:C:CA	acceptor_loss	0.9400
2:218165246:T:A	acceptor_loss	0.9400
2:218165243:AA:A	acceptor_gain	0.9200
2:218165253:T:C	acceptor_gain	0.9000
2:218166906:A:AC	donor_gain	0.8800
2:218166907:C:CC	donor_gain	0.8800
2:218165340:T:TA	donor_gain	0.8700
2:218165247:G:C	acceptor_loss	0.8400
2:218166906:A:T	donor_gain	0.7900
2:218166905:TA:T	donor_gain	0.7800
2:218166907:C:CG	donor_gain	0.7700
2:218165371:T:TA	donor_gain	0.7600
2:218166902:TCCTA:T	donor_gain	0.7600
2:218166903:CCTAC:C	donor_gain	0.7600
2:218166904:CTACC:C	donor_gain	0.7600
2:218165455:G:GC	acceptor_gain	0.7100
2:218166471:TG:T	acceptor_gain	0.6900
2:218166908:C:G	donor_gain	0.6900
2:218166469:CATG:C	acceptor_gain	0.6800
2:218166470:ATGA:A	acceptor_gain	0.6800
2:218166902:T:TA	donor_gain	0.6800

AlphaMissense

2284 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:218164816:A:C	S132R	0.996
2:218164816:A:T	S132R	0.996
2:218164818:T:G	S132R	0.996
2:218164903:C:A	W103C	0.996
2:218164903:C:G	W103C	0.996
2:218164459:G:C	F251L	0.994
2:218164459:G:T	F251L	0.994
2:218164461:A:G	F251L	0.994
2:218164905:A:G	W103R	0.994
2:218164905:A:T	W103R	0.994
2:218165053:G:C	S53R	0.994
2:218165053:G:T	S53R	0.994
2:218165055:T:G	S53R	0.994
2:218164883:C:G	C110S	0.992
2:218164884:A:T	C110S	0.992
2:218164276:A:C	F312L	0.990
2:218164276:A:T	F312L	0.990
2:218164278:A:G	F312L	0.990
2:218164442:G:T	P257H	0.990
2:218164883:C:T	C110Y	0.990
2:218164934:G:C	P93R	0.990
2:218164318:G:C	S298R	0.989
2:218164318:G:T	S298R	0.989
2:218164320:T:G	S298R	0.989
2:218164808:C:G	R135P	0.989
2:218164843:A:C	S123R	0.989
2:218164843:A:T	S123R	0.989
2:218164845:T:G	S123R	0.989
2:218164882:G:C	C110W	0.989
2:218164331:C:T	G294E	0.988

dbSNP variants (sampled 300 via entrez): RS1000800851 (2:218163151 T>A,C,G), RS1000827249 (2:218162806 G>C), RS1000982366 (2:218167682 C>T), RS1001165300 (2:218164192 A>C), RS1001459719 (2:218168821 T>C), RS1002799878 (2:218165539 C>A,T), RS1003010912 (2:218164524 A>G), RS1003606250 (2:218163344 T>G), RS1003860782 (2:218166507 A>G), RS1005302201 (2:218163505 T>C), RS1005456699 (2:218163379 G>A), RS1005489141 (2:218163619 C>A), RS1007314261 (2:218166150 T>A,C), RS1007380714 (2:218166871 C>A), RS1007741237 (2:218166363 G>A,C)

Disease associations

OMIM: gene MIM:146929 | disease phenotypes: MIM:609423

GenCC curated gene-disease

Mondo (2): susceptibility to HIV infection (MONDO:0004951), cholangiocarcinoma (MONDO:0019087)

Orphanet (1): Cholangiocarcinoma (Orphanet:70567)

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000964_14	Ulcerative colitis	1.000000e-10
GCST001725_74	Inflammatory bowel disease	4.000000e-12
GCST001896_9	Smooth-surface caries	2.000000e-06
GCST004131_76	Inflammatory bowel disease	2.000000e-07
GCST005688_3	Idiopathic intracranial hypertension	5.000000e-07
GCST005973_24	White blood cell count	3.000000e-11
GCST005974_12	Neutrophil count	4.000000e-13
GCST007637_44	Diffusing capacity of carbon monoxide	2.000000e-06
GCST90002379_31	Basophil count	1.000000e-23
GCST90002389_2	Lymphocyte percentage of white cells	5.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0005090	basophil count
EFO:0007993	lymphocyte percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018281	Cholangiocarcinoma	C04.557.470.200.025.450

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2096909 (PROTEIN FAMILY), CHEMBL4029 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

9 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 293,253 (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
CHEMBL175	DEXIBUPROFEN	4	12,118
CHEMBL75435	DEXKETOPROFEN	4	5,327
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL139	DICLOFENAC	4	125,009
CHEMBL64391	ITRACONAZOLE	4	606
CHEMBL191413	REPARIXIN	3	653
CHEMBL50	QUERCETIN	3	74,559
CHEMBL216981	NAVARIXIN ANHYDROUS	2	932
CHEMBL427526	(R)-IBUPROPHEN	1	17,724

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Chemokine receptors

Most potent curated ligand interactions (8 total), top 8:

Ligand	Action	Affinity	Parameter
[125I]CXCL8 (human)	Full agonist	9.6	pKd
navarixin	Antagonist	8.41	pIC50
CXCL8	Agonist	8.1	pKd
mini-TyrRS	Full agonist	8.1	pKi
[125I]mini-TyrRS	Full agonist	7.7	pKd
vCXCL1	Agonist	7.36	pIC50
CXCL6	Full agonist	7.0	pKi
AZD5069	Antagonist	6.9	pIC50

Binding affinities (BindingDB)

24 measured of 24 human assays (24 total across all organisms); most potent 24 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-[4-chloro-2-hydroxy-3-(4-methylpiperazin-1-yl)sulfonylanilino]-4-[[(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]cyclobutane-1,2-dione	IC50	30 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
2-hydroxy-N-methyl-3-[[2-[[(S)-(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]-N-(2,2,2-trifluoroethyl)benzamide	IC50	36 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
methyl 2-[[2-hydroxy-3-[[2-[[(S)-(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]benzoyl]-methylamino]acetate	IC50	42 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
methyl (2R)-1-[2-hydroxy-3-[[2-[[(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]benzoyl]pyrrolidine-2-carboxylate	IC50	43 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
2-hydroxy-N-methyl-3-[[2-[[(S)-(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]-N-(2,2,2-trifluoroethyl)benzamide	IC50	85 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
methyl (2R)-1-[2-hydroxy-3-[[2-[[(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]benzoyl]pyrrolidine-2-carboxylate	IC50	108 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
6-chloro-2-hydroxy-N,N-dimethyl-3-[[2-[[(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]benzamide	IC50	113 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
methyl (2S)-1-[2-hydroxy-3-[[2-[[(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]benzoyl]pyrrolidine-2-carboxylate	IC50	171 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
3-[(2-hydroxy-1-methyl-2H-pyridin-3-yl)amino]-4-[[(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]cyclobutane-1,2-dione	IC50	384 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
2-hydroxy-N,N-dimethyl-3-[[2-[[(5-methylfuran-2-yl)-[(2S)-oxolan-2-yl]methyl]amino]-3,4-dioxocyclobutyl]amino]benzamide	IC50	483 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
2-hydroxy-N-methyl-3-[[2-[[(R)-(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]-N-(2,2,2-trifluoroethyl)benzamide	IC50	508 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
methyl (2S)-1-[2-fluoro-3-[[2-[[(5-methylfuran-2-yl)-[(2R)-thiolan-2-yl]methyl]amino]-3,4-dioxocyclobutyl]amino]benzoyl]pyrrolidine-2-carboxylate	IC50	552 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
methyl 2-[[2-[2-hydroxy-3-[[2-[[(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]phenyl]-2-oxoethyl]amino]acetate	IC50	580 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
3-[[(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-4-[(2-oxo-1H-pyridin-3-yl)amino]cyclobutane-1,2-dione	IC50	652 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
ethyl (2S)-1-[2-fluoro-3-[[2-[[(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]benzoyl]pyrrolidine-2-carboxylate	IC50	711 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
methyl 1-[2-fluoro-3-[[2-[[(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]benzoyl]pyrrolidine-2-carboxylate	IC50	812 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
6-chloro-2-hydroxy-N,N-dimethyl-3-[[2-[[(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]benzenesulfonamide	IC50	1100 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
3-[[2,3-dioxo-4-[[oxolan-2-yl(phenyl)methyl]amino]cyclobutyl]amino]-2-hydroxy-N,N-dimethylbenzamide	IC50	1150 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
2-hydroxy-N,N-dimethyl-3-[[2-[[(5-methylfuran-2-yl)-[(2R)-oxolan-2-yl]methyl]amino]-3,4-dioxocyclobutyl]amino]benzamide	IC50	1320 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
2-hydroxy-N,N-dimethyl-3-[[2-[[(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]benzamide	IC50	1560 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
propan-2-yl (2S)-1-[2-fluoro-3-[[2-[[(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]benzoyl]pyrrolidine-2-carboxylate	IC50	1890 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
2-hydroxy-N,N-dimethyl-3-[[2-[[(5-methylfuran-2-yl)-(2-methyloxolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]benzamide	IC50	2080 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
methyl (2S)-1-[2-fluoro-3-[[2-[[(5-methylfuran-2-yl)-(thiolan-2-yl)methyl]amino]-3,4-dioxocyclobutyl]amino]benzoyl]pyrrolidine-2-carboxylate	IC50	3810 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
methyl (2S)-1-[2-fluoro-3-[[2-[[(R)-(5-methylfuran-2-yl)-[(2S)-thiolan-2-yl]methyl]amino]-3,4-dioxocyclobutyl]amino]benzoyl]pyrrolidine-2-carboxylate	IC50	8910 nM	US-9388149: Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases

ChEMBL bioactivities

438 potent at pChembl≥5 of 491 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL4442431
9.40	Kd	0.3981	nM	CHEMBL4562140
9.00	IC50	1	nM	REPARIXIN
8.74	IC50	1.8	nM	CHEMBL190899
8.52	Ki	3	nM	CHEMBL246108
8.48	IC50	3.3	nM	CHEMBL3609016
8.41	IC50	3.9	nM	NAVARIXIN ANHYDROUS
8.41	Kd	3.9	nM	CHEMBL218115
8.30	Ki	5	nM	CHEMBL516184
8.28	IC50	5.3	nM	REPARIXIN
8.22	Ki	6	nM	CHEMBL473959
8.22	Ki	6	nM	CHEMBL491330
8.22	Ki	6	nM	CHEMBL523984
8.17	IC50	6.8	nM	CHEMBL254370
8.15	IC50	7	nM	CHEMBL3609018
8.15	Ki	7	nM	CHEMBL245699
8.14	IC50	7.3	nM	CHEMBL246108
8.12	Ki	7.6	nM	CHEMBL396573
8.12	Ki	7.5	nM	CHEMBL464013
8.10	IC50	8	nM	CHEMBL403547
8.10	IC50	8	nM	CHEMBL254942
8.10	Ki	8	nM	CHEMBL518857
8.05	Ki	9	nM	CHEMBL245501
8.05	Ki	9	nM	CHEMBL515262
8.00	Ki	10	nM	CHEMBL247150
8.00	Ki	10	nM	CHEMBL394899
8.00	Ki	10	nM	CHEMBL523645
7.96	IC50	11	nM	CHEMBL376414
7.96	Ki	11	nM	CHEMBL247149
7.92	IC50	12	nM	DICLOFENAC
7.89	IC50	13	nM	CHEMBL254943
7.89	Ki	13	nM	CHEMBL518201
7.89	Ki	13	nM	CHEMBL462155
7.85	Ki	14	nM	CHEMBL247356
7.85	Ki	14	nM	CHEMBL246107
7.85	Ki	14	nM	CHEMBL455431
7.85	Ki	14	nM	CHEMBL464012
7.85	Ki	14	nM	CHEMBL462331
7.82	IC50	15	nM	CHEMBL254942
7.82	Ki	15	nM	CHEMBL510437
7.82	Ki	15	nM	CHEMBL508938
7.82	IC50	15	nM	CHEMBL218964
7.80	IC50	16	nM	NAVARIXIN ANHYDROUS
7.80	Ki	16	nM	CHEMBL442799
7.80	Ki	16	nM	CHEMBL514001
7.80	Ki	16	nM	CHEMBL462024
7.75	Ki	18	nM	NAVARIXIN ANHYDROUS
7.75	Ki	18	nM	CHEMBL518696
7.70	IC50	20	nM	CHEMBL3913959
7.70	IC50	20	nM	CHEMBL403547

PubChem BioAssay actives

322 with measured affinity, of 658 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
sodium methylsulfonyl-[(2R)-2-[4-(trifluoromethylsulfonyloxy)phenyl]propanoyl]azanide	1513651: Inhibition of CXCR1 (unknown origin)	ic50	0.0001	uM
N-[2-[(2,3-difluorophenyl)methylsulfanyl]-6-[(2R,3S)-3,4-dihydroxybutan-2-yl]oxypyrimidin-4-yl]azetidine-1-sulfonamide	2012285: Binding affinity to CXCL1 (unknown origin) expressed in human Polymorphonuclear neutrophil cells	kd	0.0004	uM
(2R)-2-[4-(2-methylpropyl)phenyl]-N-methylsulfonylpropanamide	2033691: Displacement of 125I-IL-8 from CXCR1 (unknown origin)	ic50	0.0010	uM
(2R)-N-methoxy-2-[4-(2-methylpropyl)phenyl]propanamide	248424: Inhibition of CXCL8-induced chemotaxis in human polymorphonuclear cells	ic50	0.0018	uM
3-[[3,4-dioxo-2-[[(1R)-1-(4-propan-2-ylfuran-2-yl)propyl]amino]cyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	307570: Displacement of [125I]IL8 from human CXCR1 expressed in CHO cells by SPA	ki	0.0030	uM
[6-[[[5-[(4-fluorophenyl)carbamoyl]-2-pyridinyl]-(furan-2-ylmethyl)amino]methyl]-3-pyridinyl]boronic acid	1243335: Antagonist activity at CXCR1 (unknown origin) transfected in RBL cells assessed as inhibition of IL-8-mediated intracellular calcium release preincubated for 30 mins followed by IL-8 addition by FLUO-4AM-based fluorescent microplate reader analysis	ic50	0.0033	uM
3-[[2-[[(1R)-1-(furan-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	1915497: Binding affinity to human CXCR1 assessed as dissociation constant incubated for 6 to 24 hrs by radioligand binding assay	kd	0.0039	uM
2-hydroxy-N,N-dimethyl-3-[[2-[[(1R)-1-(5-methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]benzamide	707880: Binding affinity to CXCR1	ic50	0.0039	uM
3-[[2-[[(1S,2S)-2-fluoro-1-(4-methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	418196: Binding affinity to CXCR1	ki	0.0050	uM
3-[[2-[[(1S)-2,2-difluoro-1-(5-methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	418196: Binding affinity to CXCR1	ki	0.0060	uM
3-[[2-[[(1S)-2,2-difluoro-1-(4-methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	418196: Binding affinity to CXCR1	ki	0.0060	uM
3-[[3,4-dioxo-2-[[(1S)-2,2,2-trifluoro-1-(furan-2-yl)ethyl]amino]cyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	418196: Binding affinity to CXCR1	ki	0.0060	uM
3-[[3,4-dioxo-2-[[(1R)-1-phenylpropyl]amino]cyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	1915499: Inhibition of human CXCR1	ic50	0.0068	uM
3-[[2-[[(1R)-1-(4-ethylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	307570: Displacement of [125I]IL8 from human CXCR1 expressed in CHO cells by SPA	ki	0.0070	uM
[6-[[benzyl-[5-[(4-fluorophenyl)carbamoyl]pyrimidin-2-yl]amino]methyl]-3-pyridinyl]boronic acid	1243335: Antagonist activity at CXCR1 (unknown origin) transfected in RBL cells assessed as inhibition of IL-8-mediated intracellular calcium release preincubated for 30 mins followed by IL-8 addition by FLUO-4AM-based fluorescent microplate reader analysis	ic50	0.0070	uM
2-hydroxy-N,N-dimethyl-3-[[4-[[(1R)-1-(5-methylfuran-2-yl)propyl]amino]-1,2,5-thiadiazol-3-yl]amino]-6-(trifluoromethyl)benzamide	418198: Displacement of IL8 from CXCR1 receptor	ki	0.0075	uM
3-[[2-[[(1R)-1-(4-butan-2-ylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	307570: Displacement of [125I]IL8 from human CXCR1 expressed in CHO cells by SPA	ki	0.0076	uM
2-hydroxy-N,N-dimethyl-3-[[1-oxido-4-[(1R)-1-(4-propan-2-ylfuran-2-yl)propyl]imino-1,2,5-thiadiazol-1-ium-3-yl]amino]benzamide	313443: Antagonist activity at CXCR1/CXCR2 in human PMN cells assessed as inhibition of GROalpha-mediated myeloperoxidase release	ic50	0.0080	uM
3-[[4-[(1R)-1-(furan-2-yl)-2,2-dimethylpropyl]imino-1-oxido-1,2,5-thiadiazol-1-ium-3-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	313443: Antagonist activity at CXCR1/CXCR2 in human PMN cells assessed as inhibition of GROalpha-mediated myeloperoxidase release	ic50	0.0080	uM
3-[[2-[[(1S)-1-(1,3-benzodioxol-5-yl)-2,2,2-trifluoroethyl]amino]-3,4-dioxocyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	418196: Binding affinity to CXCR1	ki	0.0080	uM
2-hydroxy-N,N-dimethyl-3-[[2-[[(1R)-1-(4-methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]benzamide	307570: Displacement of [125I]IL8 from human CXCR1 expressed in CHO cells by SPA	ki	0.0090	uM
3-[[3,4-dioxo-2-[[(1S)-2,2,2-trifluoro-1-(5-methylfuran-2-yl)ethyl]amino]cyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	418196: Binding affinity to CXCR1	ki	0.0090	uM
3-[[2-[[(R)-cyclopropyl-(4-propan-2-ylfuran-2-yl)methyl]amino]-3,4-dioxocyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	307570: Displacement of [125I]IL8 from human CXCR1 expressed in CHO cells by SPA	ki	0.0100	uM
3-[[2-[[(1R)-1-(4-tert-butylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	307570: Displacement of [125I]IL8 from human CXCR1 expressed in CHO cells by SPA	ki	0.0100	uM
3-[[3,4-dioxo-2-[[(1S)-2,2,3,3,3-pentafluoro-1-(5-methylfuran-2-yl)propyl]amino]cyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	418196: Binding affinity to CXCR1	ki	0.0100	uM
2-hydroxy-N,N-dimethyl-3-[[2-[[(1R)-2-methyl-1-(4-propan-2-ylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]benzamide	307570: Displacement of [125I]IL8 from human CXCR1 expressed in CHO cells by SPA	ki	0.0110	uM
3-[[2-[[(1R)-2,2-dimethyl-1-(5-methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	274659: Displacement of [125I]hCXCL8 from human CXCR1 receptor expressed in BaF3 cells	ic50	0.0110	uM
Diclofenac	426476: Inhibition of wild type CXCR1 transfected in mouse L1.2 cells assessed as inhibition of CXCL8-induced cell migration pretreated for 15 mins measured after 4 hrs	ic50	0.0120	uM
2-hydroxy-N,N-dimethyl-3-[[4-[[(1R)-1-(5-methylfuran-2-yl)propyl]amino]-1,2,5-thiadiazol-3-yl]amino]benzamide	418198: Displacement of IL8 from CXCR1 receptor	ki	0.0130	uM
N-(2-cyanoethyl)-3-[[4-[[(1R)-2,2-dimethyl-1-(5-methylfuran-2-yl)propyl]amino]-1,2,5-thiadiazol-3-yl]amino]-2-hydroxy-N-methylbenzamide	418198: Displacement of IL8 from CXCR1 receptor	ki	0.0130	uM
3-[[4-[(1R)-1-(4,5-dimethylfuran-2-yl)-2-methylpropyl]imino-1-oxido-1,2,5-thiadiazol-1-ium-3-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	313443: Antagonist activity at CXCR1/CXCR2 in human PMN cells assessed as inhibition of GROalpha-mediated myeloperoxidase release	ic50	0.0130	uM
2-hydroxy-N,N-dimethyl-3-[[2-[[(1R)-1-[4-(4-morpholin-4-ylbutyl)furan-2-yl]propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]benzamide	307570: Displacement of [125I]IL8 from human CXCR1 expressed in CHO cells by SPA	ki	0.0140	uM
3-[[4-[[(1R)-2,2-dimethyl-1-(5-methylfuran-2-yl)propyl]amino]-1,2,5-thiadiazol-3-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	418198: Displacement of IL8 from CXCR1 receptor	ki	0.0140	uM
2-hydroxy-N,N-dimethyl-3-[[4-[[(1R)-2-methyl-1-(5-methylthiophen-2-yl)propyl]amino]-1,2,5-thiadiazol-3-yl]amino]benzamide	418198: Displacement of IL8 from CXCR1 receptor	ki	0.0140	uM
N-(2-cyanoethyl)-3-[[4-[[(1R)-1-(furan-2-yl)-2,2-dimethylpropyl]amino]-1,2,5-thiadiazol-3-yl]amino]-2-hydroxy-N-methylbenzamide	418198: Displacement of IL8 from CXCR1 receptor	ki	0.0140	uM
3-[[2-[[(1R)-2,2-dimethyl-1-(4-propan-2-ylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	307570: Displacement of [125I]IL8 from human CXCR1 expressed in CHO cells by SPA	ki	0.0140	uM
2-hydroxy-N,N-dimethyl-3-[[4-[[(1R)-2-methyl-1-(5-methylfuran-2-yl)propyl]amino]-1,2,5-thiadiazol-3-yl]amino]benzamide	418198: Displacement of IL8 from CXCR1 receptor	ki	0.0150	uM
3-[[4-[[(1R)-1-(furan-2-yl)-2,2-dimethylpropyl]amino]-1,2,5-thiadiazol-3-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	418198: Displacement of IL8 from CXCR1 receptor	ki	0.0150	uM
3-[[3,4-dioxo-2-(pentan-3-ylamino)cyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	1915499: Inhibition of human CXCR1	ic50	0.0150	uM
3-[[3,4-dioxo-2-[[(1S)-2,2,2-trifluoro-1-(4-propan-2-ylfuran-2-yl)ethyl]amino]cyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	307570: Displacement of [125I]IL8 from human CXCR1 expressed in CHO cells by SPA	ki	0.0160	uM
3-[[4-[[(R)-cyclopropyl(phenyl)methyl]amino]-1,2,5-thiadiazol-3-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	418198: Displacement of IL8 from CXCR1 receptor	ki	0.0160	uM
3-[[2-[[(1S,2S)-2-fluoro-1-(5-methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	418196: Binding affinity to CXCR1	ki	0.0160	uM
[3-[[4-[[(1R)-2,2-dimethyl-1-(5-methylfuran-2-yl)propyl]amino]-1,2,5-thiadiazol-3-yl]amino]-2-hydroxyphenyl]-morpholin-4-ylmethanone	418198: Displacement of IL8 from CXCR1 receptor	ki	0.0180	uM
3-[[4-[[(1R)-1-(3,5-difluorophenyl)propyl]amino]-1,2,5-thiadiazol-3-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	418198: Displacement of IL8 from CXCR1 receptor	ki	0.0200	uM
3-[[2-[[(1S)-1-(4-chlorofuran-2-yl)-2,2,2-trifluoroethyl]amino]-3,4-dioxocyclobuten-1-yl]amino]-2-hydroxy-N,N-dimethylbenzamide	418196: Binding affinity to CXCR1	ki	0.0200	uM
3-[2-hydroxy-3-[(3S)-3-hydroxypyrrolidine-1-carbonyl]anilino]-4-[[(1R)-1-phenylpropyl]amino]cyclobut-3-ene-1,2-dione	432704: Displacement of human [125I]IL-8 from human CXCR1	ki	0.0210	uM
2-hydroxy-N,N-dimethyl-3-[[4-[[(1R)-1-phenylpropyl]amino]-1,2,5-thiadiazol-3-yl]amino]benzamide	418198: Displacement of IL8 from CXCR1 receptor	ki	0.0210	uM
1-(2-bromophenyl)-3-(2-hydroxy-4-nitrophenyl)urea	707881: Antagonist activity at CXCR1 assessed as inhibition of CXCL8 binding by cell based assay	ic50	0.0220	uM
1-(2-bromophenyl)-3-(2,4-dihydroxyphenyl)urea	242303: Inhibitory concentration against interleukin-8 receptor of human neutrophils by using [125I]IL-8 (0.125 nM) as radioligand	ic50	0.0220	uM
(2R)-1-[3-[[3-[[N’-(2-bromophenyl)-N-cyanocarbamimidoyl]amino]-6-chloro-2-hydroxyphenyl]sulfonylamino]pentan-3-yl]pyrrolidine-2-carboxylic acid	276236: Displacement of [125I]IL8 from CXCR1 expressed in CHO cells	ic50	0.0220	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	decreases expression, decreases reaction, increases expression	5
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
reparixin	affects binding, decreases activity	2
Calcium	increases abundance, increases activity, affects abundance, affects binding	2
Estradiol	affects expression, affects cotreatment, increases expression, decreases expression	2
Tetradecanoylphorbol Acetate	increases reaction, affects cotreatment, decreases localization, increases expression	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
cinnamaldehyde	increases expression	1
oleandrin	increases expression	1
nickel chloride	increases expression	1
indirubin	increases expression	1
zomepirac glucuronide	increases expression	1
resorcinol	increases expression	1
lysophosphatidic acid	decreases expression, affects binding, decreases reaction	1
benzamide	affects binding, decreases activity	1
tolmetin glucuronide	increases expression	1
sphingosine 1-phosphate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
ginsenoside compound K	increases expression, decreases reaction	1
monomethylarsonous acid	affects localization	1
lipopolysaccharide, E. coli O26-B6	decreases expression	1
doramapimod	decreases expression, decreases reaction	1
teriflunomide	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Oxaliplatin	affects cotreatment, affects response to substance	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects response to substance, affects abundance	1
Arsenicals	affects abundance, affects response to substance	1

ChEMBL screening assays

120 unique, capped per target: 85 binding, 35 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003796	Binding	Displacement of [125I]IL8 from human CXCR1/2 expressed in CHO cells at 10 uM	Synthesis and structure-activity relationship of benzetimide derivatives as human CXCR3 antagonists. — Bioorg Med Chem Lett
CHEMBL3386571	Functional	Antagonist activity at CXCR1/CXCR2 in human PMNs assessed as inhibition of CXCL8-induced intracellular Ca2+ release by fluorescence based calcium flux assay	Discovery of 2-[5-(4-Fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl]phenylboronic Acid (SX-517): Noncompetitive Boronic Acid Antagonist of CXCR1 and CXCR2. — J Med Chem

Cellosaurus cell lines

10 cell lines: 7 cancer cell line, 2 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8EC	Abcam HCT 116 CXCR1 KO	Cancer cell line	Male
CVCL_B8UH	Abcam MCF-7 CXCR1 KO	Cancer cell line	Female
CVCL_B9GK	Abcam A-549 CXCR1 KO	Cancer cell line	Male
CVCL_D8JR	Ubigene HCT 116 CXCR1 KO	Cancer cell line	Male
CVCL_F1WH	293-IL-8RA	Transformed cell line	Female
CVCL_KA14	CHO-K1/Galpha15/CXCR1	Spontaneously immortalized cell line	Female
CVCL_KV00	cAMP Hunter CHO-K1 CXCR1 Gi	Spontaneously immortalized cell line	Female
CVCL_LA11	PathHunter U2OS CXCR1 Activated GPCR Internalization	Cancer cell line	Female
CVCL_LA12	PathHunter U2OS CXCR1 beta-arrestin	Cancer cell line	Female
CVCL_ZK09	Tango CXCR1-bla U2OS	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00168987	PHASE4	COMPLETED	Influence of an Oral Nutritional Supplement Rich in Omega-3 Fatty Acids on Functional State and Quality of Life in Malnourished Patients With Gastroenterological Tumors
NCT00280709	PHASE4	COMPLETED	Biliary Metal Stent Study: Metal Stents for Management of Distal Malignant Biliary Obstruction
NCT00797121	PHASE4	UNKNOWN	Preoperative Biliary Drainage for Resectable Hilar Cholangiocarcinoma
NCT01111591	PHASE4	UNKNOWN	Cyclooxygenase-2 Inhibitor for Adjuvant Anticancer Effect in Patients With Biliary-pancreas Cancer
NCT01256034	PHASE4	COMPLETED	Effects of Preoperative Immunonutrition in Patients Undergoing Pancreaticoduodenectomy
NCT01256047	PHASE4	COMPLETED	Effects of Preoperative Immunonutrition in Patients Undergoing Hepatectomy
NCT01642875	PHASE4	UNKNOWN	Early Oral Versus Enteral Nutrition After Pancreatoduodenectomy
NCT02027311	PHASE4	COMPLETED	Etomidate vs. Midazolam for Sedation During ERCP
NCT02174575	PHASE4	WITHDRAWN	Anesthetic Agents and Acute Kidney Injury After Liver Resection Surgery
NCT07486713	PHASE4	RECRUITING	Olutasidenib DDI Study in Patients With IDH1 Mutation Positive Malignancies
NCT00540735	PHASE3	TERMINATED	Efficiency Evaluation of Photodynamic Therapy With Photofrin® on Unresectable Type III or IV Cholangiocarcinomas
NCT00653978	PHASE3	UNKNOWN	Unilateral Versus Bilateral Stents for Bismuth Type II and III Malignant Hilar Strictures
NCT00809081	PHASE3	UNKNOWN	Early Enteral Feeding After Pylorus Preserving Pancreatoduodenectomy
NCT00869635	PHASE3	COMPLETED	S-1 and Photodynamic Therapy in Cholangiocarcinoma
NCT00907413	PHASE3	TERMINATED	Photodynamic Therapy (PDT) Trial for Palliation of Cholangiocarcinoma
NCT01926236	PHASE3	COMPLETED	Active Symptom Control Alone or With mFOLFOX Chemotherapy for Locally Advanced/ Metastatic Biliary Tract Cancers
NCT02170090	PHASE3	ACTIVE_NOT_RECRUITING	Adjuvant Chemotherapy With Gemcitabine and Cisplatin Compared to Standard of Care After Curative Intent Resection of Biliary Tract Cancer
NCT02548195	PHASE3	UNKNOWN	Oxaliplatin+Gemcitabine vs Capecitabine as Adjuvant Therapy for Intrahepatic Cholangiocarcinoma
NCT02773485	PHASE3	UNKNOWN	Chemo Alone or in Combination With Radiation in Unresectable Cholangiocarcinoma
NCT02853474	PHASE3	COMPLETED	Early Palliative Care in Patients With Metastatic Upper Gastrointestinal Cancers Treated With First-line Chemotherapy
NCT02989857	PHASE3	COMPLETED	Study of AG-120 in Previously Treated Advanced Cholangiocarcinoma With IDH1 Mutations (ClarIDHy)
NCT03656536	PHASE3	TERMINATED	A Study to Evaluate the Efficacy and Safety of Pemigatinib Versus Chemotherapy in Unresectable or Metastatic Cholangiocarcinoma
NCT03773302	PHASE3	TERMINATED	Phase 3 Study of BGJ398 (Oral Infigratinib) in First Line Cholangiocarcinoma With FGFR2 Gene Fusions/Translocations
NCT03779035	PHASE3	UNKNOWN	Adjuvant Chemotherapy for Biliary Tract Cancer After Curative Resection
NCT04093362	PHASE3	TERMINATED	Futibatinib Versus Gemcitabine-Cisplatin Chemotherapy as First-Line Treatment of Patients With Advanced Cholangiocarcinoma Harboring FGFR2 Gene Rearrangements
NCT04157985	PHASE3	COMPLETED	Evaluating Length of Treatment With PD-1/PD-L1 Inhibitor in Advanced Solid Tumors
NCT05823311	PHASE3	RECRUITING	Lenvatinib, Tislelizumab Combined with Gemcitabine and Cisplatin (GPLET) in the Treatment of Advanced Cholangiocarcinoma
NCT05876754	PHASE3	RECRUITING	An Early Access Study of Ivosidenib in Patients With a Pretreated Locally Advanced or Metastatic Cholangiocarcinoma
NCT05948475	PHASE3	RECRUITING	Study of Tinengotinib VS. Physician’s Choice a Treatment of Subjects With FGFR-altered in Cholangiocarcinoma
NCT07155525	PHASE3	RECRUITING	Tissue Adhesive Glue Modified Cyanoacrylate (Glubran® 2) in Soft Pancreas
NCT07328919	PHASE3	NOT_YET_RECRUITING	Efficacy and Safety of TT-00420 (Tinengotinib) Tablets Versus Chemotherapy in Patients With Advanced Intrahepatic Cholangiocarcinoma Harboring FGFR2 Fusions/Rearrangements or Mutations
NCT00286013	PHASE2	COMPLETED	Feasibility of Radiotherapy and Concomitant Gemcitabine and Oxaliplatin in Locally Advanced Pancreatic Cancer and Distal Cholangiocarcinoma
NCT00290316	PHASE2	UNKNOWN	Accuracy of Endoscopic Ultrasound for Detection of Tumors of the Liver
NCT00350753	PHASE2	COMPLETED	Avastin and Tarceva for Upper Gastrointestinal Cancers
NCT00356161	PHASE2	UNKNOWN	HAI Via Interventionally Implanted Port Catheter Systems
NCT00660140	PHASE2	COMPLETED	Study of Gemcitabine and Carboplatin in the Treatment of Metastatic or Recurrent Cholangiocarcinoma/Gallbladder Cancer
NCT00713687	PHASE2	WITHDRAWN	Gemcitabine/Oxaliplatin and Photodynamic Therapy in Cholangiocarcinoma
NCT00779454	PHASE2	COMPLETED	Combined Biological Treatment and Chemotherapy for Patients With Inoperable Cholangiocarcinoma
NCT00832637	PHASE2	TERMINATED	Gemcitabine, Oxaliplatin, Tarceva &/or Cisplatin in HCC & Biliary Tree Cancers
NCT00948935	PHASE2	COMPLETED	Study of Gemcitabine, Irinotecan and Panitumumab in Patients With Advanced and Metastatic Biliary Tract Adenocarcinoma