PTGS2

Summary

PTGS2 (prostaglandin-endoperoxide synthase 2, HGNC:9605) is a protein-coding gene on chromosome 1q31.1, encoding Prostaglandin G/H synthase 2 (P35354). Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate, AA, C20:4(n-6)), with a particular role in the inflammatory response.

Prostaglandin-endoperoxide synthase (PTGS), also known as cyclooxygenase, is the key enzyme in prostaglandin biosynthesis, and acts both as a dioxygenase and as a peroxidase. There are two isozymes of PTGS: a constitutive PTGS1 and an inducible PTGS2, which differ in their regulation of expression and tissue distribution. This gene encodes the inducible isozyme. It is regulated by specific stimulatory events, suggesting that it is responsible for the prostanoid biosynthesis involved in inflammation and mitogenesis.

Source: NCBI Gene 5743 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 55 total
• Druggable target: yes — 192 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000963

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9605
Approved symbol	PTGS2
Name	prostaglandin-endoperoxide synthase 2
Location	1q31.1
Locus type	gene with protein product
Status	Approved
Aliases	COX2
Ensembl gene	ENSG00000073756
Ensembl biotype	protein_coding
OMIM	600262
Entrez	5743

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 2 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000367468, ENST00000466691, ENST00000490885, ENST00000559627, ENST00000680451, ENST00000681605

RefSeq mRNA: 1 — MANE Select: NM_000963 NM_000963

CCDS: CCDS1371

Canonical transcript exons

ENST00000367468 — 10 exons

Exon	Start	End
ENSE00002401108	186671791	186674762
ENSE00002570587	186680239	186680423
ENSE00003548045	186679322	186679438
ENSE00003548799	186677649	186677830
ENSE00003551831	186676833	186676916
ENSE00003563132	186679058	186679201
ENSE00003576370	186676467	186676713
ENSE00003652822	186675898	186676184
ENSE00003655093	186675249	186675396
ENSE00003667680	186678261	186678404

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 99.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 106.5173 / max 22952.2141, expressed in 1134 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16368	106.2792	1134
16367	0.2381	88

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
seminal vesicle	UBERON:0000998	99.59	gold quality
cartilage tissue	UBERON:0002418	99.27	gold quality
mucosa of urinary bladder	UBERON:0001259	98.91	gold quality
type B pancreatic cell	CL:0000169	98.50	gold quality
periodontal ligament	UBERON:0008266	98.37	gold quality
vena cava	UBERON:0004087	98.16	gold quality
visceral pleura	UBERON:0002401	94.17	gold quality
saphenous vein	UBERON:0007318	94.12	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.99	gold quality
gall bladder	UBERON:0002110	93.64	gold quality
mucosa of stomach	UBERON:0001199	92.57	gold quality
pleura	UBERON:0000977	91.17	gold quality
monocyte	CL:0000576	90.60	gold quality
bone marrow cell	CL:0002092	90.48	gold quality
mononuclear cell	CL:0000842	90.24	gold quality
leukocyte	CL:0000738	90.07	gold quality
lower lobe of lung	UBERON:0008949	89.75	gold quality
parietal pleura	UBERON:0002400	89.19	gold quality
bone marrow	UBERON:0002371	88.25	gold quality
islet of Langerhans	UBERON:0000006	87.74	gold quality
urethra	UBERON:0000057	87.38	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.08	gold quality
smooth muscle tissue	UBERON:0001135	86.09	gold quality
urinary bladder	UBERON:0001255	85.59	gold quality
lung	UBERON:0002048	85.59	gold quality
choroid plexus epithelium	UBERON:0003911	84.78	gold quality
epithelial cell of pancreas	CL:0000083	84.34	gold quality
upper lobe of lung	UBERON:0008948	84.23	gold quality
upper lobe of left lung	UBERON:0008952	84.01	gold quality
prostate gland	UBERON:0002367	83.58	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-10283	yes	828.28
E-MTAB-8559	yes	347.14
E-CURD-46	yes	21.07
E-GEOD-135922	yes	6.43
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AP1, APC, AR, ARID4B, ARNT, ATF1, ATF2, ATF4, ATP2B4, CDX1, CDX2, CEBPA, CEBPB, CEBPD, CEBPG, CREB1, CREBBP, CTNNB1, DDIT3, DNMT1, DNMT3B, DR1, E2F1, E2F4, EGR1, EGR2, ELF3, ELK1, ENO1, EP300, ESR1, ETS1, ETV4, ETV5, EZH2, FOS, FOXC1, FOXL2, FOXM1

miRNA regulators (miRDB)

131 targeting PTGS2, 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-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-545-3P	99.95	70.74	2783

Literature-anchored findings (GeneRIF, showing 40)

• Increased expression of iNOS and production of prostanoids in colon cancer parallels the increase in COX-2, confirming the importance of this enzyme in colon cancer. (PMID:11705852)
• Findings collectively suggest the possibility that COX-2 is mainly produced in follicles in a preovulatory phase, while after ovulation, COX-2 is produced in interstitial cells in human ovary. (PMID:11712072)
• Cyclooxygenase-1 is up-regulated in cervical carcinomas: autocrine/paracrine regulation of cyclooxygenase-2, prostaglandin e receptors, and angiogenic factors by cyclooxygenase-1. (PMID:11809691)
• induction in monocytes by peroxisome proliferator activated receptor gamma and oxidized alkyl phospholipids from oxidized low density lipoprotein (PMID:11809750)
• increased expression associated with chemotherapy resistance and poor survival in cervical cancer (PMID:11844819)
• Up-regulation of prostaglandin E2 synthesis by interleukin-1beta in human orbital fibroblasts involves coordinate induction of prostaglandin-endoperoxide H synthase-2 and glutathione-dependent prostaglandin E2 synthase expression (PMID:11847219)
• Aromatase and COX-2 expression in human breast cancers. (PMID:11850206)
• Inhibition of cyclooxygenase 2 blocks human cytomegalovirus replication (PMID:11867761)
• in intestinal myofibroblasts, IL-1-mediated induction of COX-2 expression is a complex process that requires input from multiple signaling pathways. (PMID:11880271)
• COX-2 is an independent prognostic factor for poor survival (relative risk, 2.74; 95% CI, 1.38 to 5.47) in ovarian carcinoma. (PMID:11891188)
• co-stimulatory mechanisms may exist that increase the expression of cox-2 and laminin-5 at the invasive front of lung adenocarcinomas and that EGFR signaling could be one of the mechanisms (PMID:11891209)
• the effects of several paracrine and/or autocrine signaling pathways in the regulation of expression of aromatase, COX-1, and COX-2 in breast cells has identified complex relationships (PMID:11897504)
• overexpresssion in HER-2 positive breast cancer with involvement of AP-1 and PEA3 (PMID:11901151)
• 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors (PMID:11906292)
• Overexpression of cyclooxygenase-2 (COX-2) in human primitive neuroectodermal tumors (PMID:11911965)
• Reduced prostate cancer growth after exposure to saw palmetto extract may relate to decreased expression of Cox-2 (PMID:11913955)
• greater expression seen in adenocarcinoma rather than squamous cell carcinoma of lung; no correlation seen between increased expression and major clinicopathologic factors (PMID:11920472)
• highly expressed in adenoma and adenocarcinoma in intraductal papillary-mucinous tumors of the pancreas (PMID:11920515)
• overexpression of COX-2 and iNOS were revealed in epithelial cells of lymphocytic thyroiditis and thyroid tumors (PMID:11939728)
• In advanced gallbladder carcinoma, enhanced expression of cyclooxygenase-2 is observed in the adjacent stroma. (PMID:11948128)
• COX-2 is upregulated in endometrial cancer and facilitates tumor growth via angiogenesis produced in associated with VEGF and TP (PMID:11957147)
• Cyclooxygenase-2, player or spectator in cyclooxygenase-2 inhibitor-induced apoptosis in prostate cancer cells (PMID:11959891)
• Cyclooxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), and Her-2/neu are expressed in ovarian cancer. (PMID:11972392)
• COX-2 appears to be constitutively and selectively present in medullary epithelial cells of the human thymus. (PMID:11981837)
• The MEK/ERK pathway mediates COX-2-selective NSAID-induced apoptosis and induced COX-2 protein expression in colorectal carcinoma cells (PMID:11992399)
• Serous cystadenocarcinomas also had an unexpectedly high expression of COX-2. (PMID:11994539)
• malignant endometrial epithelial cells secrete PGE(2) that induces COX-2 expression in normal endometrial stromal cells in a paracrine fashion through activation of transcription and stabilization of COX-2 mRNA (PMID:12006564)
• induction of promoter activity by deoxycholic acid (PMID:12016158)
• results suggest that NFkappaB is involved in the IL-1beta-induced COX-2 expression in the mesenchymal cells of human amnion (PMID:12021045)
• expression is induced during human megekaryopoiesis and characterizes newly formed platelets (PMID:12032335)
• expression induced by interleukin-1beta and amyloid beta 42 peptide is potentiated by hypoxia in primary human neural cells (PMID:12050157)
• cyclooxygenase gene expression in human preimplantation embryos. (PMID:12050227)
• data collectively imply COX-2 may play an important role during premalignant hyperproliferation, as well as the later stages of invasive carcinoma and metastasis in various human epithelial cancers (PMID:12051953)
• Cholesterol-sensitive transcriptional pathways that regulate COX-2 expression are present in vascular tissue. (PMID:12067908)
• Cox-2 could participate in the carcinogenic process of oral mucosa (PMID:12070598)
• PI3K destabilizes cyclooxygenase 2 mRNA (PMID:12072439)
• increased expression associated with development of lung cancer and possibly acquisition of invasive/metastatis phenotype (PMID:12086404)
• Inhibitory effect of a selective cyclooxygenase-2 inhibitor on liver metastasis of colon cancer. (PMID:12124799)
• COX-2 may be involved in inflammatory responses in chronic pancreatitis and in the progression of this chronic inflammatory disease. (PMID:12131767)
• ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions. (PMID:12143054)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ptgs2a	ENSDARG00000004539
danio_rerio	ptgs2b	ENSDARG00000010276
mus_musculus	Ptgs2	ENSMUSG00000032487
rattus_norvegicus	Ptgs2	ENSRNOG00000002525

Paralogs (1): PTGS1 (ENSG00000095303)

Protein

Protein identifiers

Prostaglandin G/H synthase 2 — P35354 (reviewed: P35354)

Alternative names: Cyclooxygenase-2, PHS II, Prostaglandin H2 synthase 2, Prostaglandin-endoperoxide synthase 2

All UniProt accessions (3): P35354, A0A7P0T828, Q6ZYK7

UniProt curated annotations — full annotation on UniProt →

Function. Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate, AA, C20:4(n-6)), with a particular role in the inflammatory response. The cyclooxygenase activity oxygenates AA to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide prostaglandin H2 (PGH2), the precursor of all 2-series prostaglandins and thromboxanes. This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons. Similarly catalyzes successive cyclooxygenation and peroxidation of dihomo-gamma-linoleate (DGLA, C20:3(n-6)) and eicosapentaenoate (EPA, C20:5(n-3)) to corresponding PGH1 and PGH3, the precursors of 1- and 3-series prostaglandins. In an alternative pathway of prostanoid biosynthesis, converts 2-arachidonoyl lysophopholipids to prostanoid lysophopholipids, which are then hydrolyzed by intracellular phospholipases to release free prostanoids. Metabolizes 2-arachidonoyl glycerol yielding the glyceryl ester of PGH2, a process that can contribute to pain response. Generates lipid mediators from n-3 and n-6 polyunsaturated fatty acids (PUFAs) via a lipoxygenase-type mechanism. Oxygenates PUFAs to hydroperoxy compounds and then reduces them to corresponding alcohols. Plays a role in the generation of resolution phase interaction products (resolvins) during both sterile and infectious inflammation. Metabolizes docosahexaenoate (DHA, C22:6(n-3)) to 17R-HDHA, a precursor of the D-series resolvins (RvDs). As a component of the biosynthetic pathway of E-series resolvins (RvEs), converts eicosapentaenoate (EPA, C20:5(n-3)) primarily to 18S-HEPE that is further metabolized by ALOX5 and LTA4H to generate 18S-RvE1 and 18S-RvE2. In vascular endothelial cells, converts docosapentaenoate (DPA, C22:5(n-3)) to 13R-HDPA, a precursor for 13-series resolvins (RvTs) shown to activate macrophage phagocytosis during bacterial infection. In activated leukocytes, contributes to oxygenation of hydroxyeicosatetraenoates (HETE) to diHETES (5,15-diHETE and 5,11-diHETE). Can also use linoleate (LA, (9Z,12Z)-octadecadienoate, C18:2(n-6)) as substrate and produce hydroxyoctadecadienoates (HODEs) in a regio- and stereospecific manner, being (9R)-HODE ((9R)-hydroxy-(10E,12Z)-octadecadienoate) and (13S)-HODE ((13S)-hydroxy-(9Z,11E)-octadecadienoate) its major products. During neuroinflammation, plays a role in neuronal secretion of specialized preresolving mediators (SPMs) 15R-lipoxin A4 that regulates phagocytic microglia.

Subunit / interactions. Homodimer.

Subcellular location. Microsome membrane. Endoplasmic reticulum membrane. Nucleus inner membrane. Nucleus outer membrane.

Post-translational modifications. S-nitrosylation by NOS2 (iNOS) activates enzyme activity. S-nitrosylation may take place on different Cys residues in addition to Cys-526. Acetylated at Ser-565 by SPHK1. During neuroinflammation, acetylation by SPHK1 promotes neuronal secretion of specialized preresolving mediators (SPMs), especially 15-R-lipoxin A4, which results in an increase of phagocytic microglia.

Activity regulation. The cyclooxygenase activity is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, ibuprofen, flurbiprofen, celecoxib, flufenamic, mefenamic and tolfenamic acids as well as by hydroperoxide scavenger erythrocyte glutathione peroxidase GPX1. Aspirin triggers enzyme acetylation turning off its ability to generate pro-inflammatory prostaglandins, but switches on its capacity to produce anti-inflammatory lipid mediators involved in inflammation resolution. Aspirin enhances lipoxygenase-type activity toward production of epimers with R stereochemistry such as 15R-HETE, 18R-HEPE, 15R-HEPE and 17R-HDHA. Atorvastatin, a cholesterol-lowering drug, triggers enzyme S-nitrosylation increasing production of 13-series resolvins (RvTs).

Cofactor. Binds 1 heme b (iron(II)-protoporphyrin IX) group per subunit.

Induction. By cytokines and mitogens. Up-regulated by IL1B. Up-regulated by lipopolysaccharide (LPS).

Pathway. Lipid metabolism; prostaglandin biosynthesis.

Miscellaneous. The conversion of arachidonate to prostaglandin H2 is a 2 step reaction: a cyclooxygenase (COX) reaction which converts arachidonate to prostaglandin G2 (PGG2) and a peroxidase reaction in which PGG2 is reduced to prostaglandin H2 (PGH2). The cyclooxygenase reaction occurs in a hydrophobic channel in the core of the enzyme. The peroxidase reaction occurs at a heme-containing active site located near the protein surface. The nonsteroidal anti-inflammatory drugs (NSAIDs) binding site corresponds to the cyclooxygenase active site. Conversion of arachidonate to prostaglandin H2 is mediated by 2 different isozymes: the constitutive PTGS1 and the inducible PTGS2. PTGS1 is expressed constitutively and generally produces prostanoids acutely in response to hormonal stimuli to fine-tune physiological processes requiring instantaneous, continuous regulation (e.g. hemostasis). PTGS2 is inducible and typically produces prostanoids that mediate responses to physiological stresses such as infection and inflammation. PTGS1 and PTGS2 are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin and ibuprofen. Aspirin is able to produce an irreversible inactivation of the enzyme through a serine acetylation. Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces fatal thrombotic events, as well as the development of colon cancer and Alzheimer’s disease. PTGS2 is the principal isozyme responsible for production of inflammatory prostaglandins. New generation PTGSs inhibitors strive to be selective for PTGS2, to avoid side effects such as gastrointestinal complications and ulceration.

Similarity. Belongs to the prostaglandin G/H synthase family.

RefSeq proteins (1): NP_000954* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR010255	Haem_peroxidase_sf	Homologous_superfamily
IPR019791	Haem_peroxidase_animal	Family
IPR037120	Haem_peroxidase_sf_animal	Homologous_superfamily
IPR050783	Oxylipin_biosynth_metab	Family

Pfam: PF03098

Enzyme classification (BRENDA):

• EC 1.14.99.1 — prostaglandin-endoperoxide synthase (BRENDA: 16 organisms, 64 substrates, 225 inhibitors, 101 Km, 3 kcat entries)

Substrate kinetics (BRENDA)

18 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ARACHIDONATE	0.0009–0.015	33
ARACHIDONIC ACID	0.001–0.16	11
TRANS-5-PHENYL-4-PENTENYL-1-HYDROPEROXIDE	0.02–0.437	8
N,N,N’,N’-TETRAMETHYL-P-PHENYLENEDIAMINE	0.0083–0.0854	5
ALPHA-LINOLENIC ACID	0.0031–0.082	4
CIS-4,7,10,13,16,19-DOCOSAHEXAENOIC ACID	0.0011–0.07	4
CIS-5,8,11,14,17-EICOSAPENTAENOIC ACID	0.0012–0.039	4
CIS-5,8,11,14-EICOSATETRAENOIC ACID	0.0017–0.013	4
CIS-7,10,13,16-DOCOSATETRAENOIC ACID	0.0027–0.061	4
CIS-8,11,14-EICOSATRIENOIC ACID	0.002–0.036	4
O2	0.005–0.011	4
GAMMA-LINOLENIC ACID	0.0048–0.162	3
CIS-11,14-EICOSADIENOIC ACID	0.0052–0.0091	2
GUAIACOL	0.08–0.29	2
H2O2	1.3–5.5	2

Catalyzed reactions (Rhea), 12 shown:

• (5Z,8Z,11Z,14Z)-eicosatetraenoate + AH2 + 2 O2 = prostaglandin H2 + A + H2O (RHEA:23728)
• (5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 = 11R-hydroperoxy-(5Z,8Z,12E,14Z)-eicosatetraenoate (RHEA:42280)
• (5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 = (15R)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate (RHEA:42284)
• (5Z,8Z,11Z,14Z)-eicosatetraenoate + 2 O2 = prostaglandin G2 (RHEA:42596)
• prostaglandin G2 + AH2 = prostaglandin H2 + A + H2O (RHEA:42600)
• 2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol + 2 O2 = 2-glyceryl-prostaglandin G2 (RHEA:45288)
• 2-glyceryl-prostaglandin G2 + AH2 = 2-glyceryl-prostaglandin H2 + A + H2O (RHEA:45292)
• (5S)-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoate + AH2 + O2 = (5S,11R)-dihydroxy-(6E,8Z,12E,14Z)-eicosatetraenoate + A + H2O (RHEA:48804)
• (5S)-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoate + AH2 + O2 = (5S,15S)-dihydroxy-(6E,8Z,11Z,13E)-eicosatetraenoate + A + H2O (RHEA:48808)
• (5S)-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoate + AH2 + O2 = (5S,15R)-dihydroxy-(6E,8Z,11Z,13E)-eicosatetraenoate + A + H2O (RHEA:48812)
• (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + AH2 + O2 = 17R-hydroxy-(4Z,7Z,10Z,13Z,15E,19Z)-docosahexaenoate + A + H2O (RHEA:48816)
• (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + AH2 + O2 = 13-hydroxy-(4Z,7Z,10Z,14E,16Z,19Z)-docosahexaenoate + A + H2O (RHEA:48820)

UniProt features (90 total): helix 31, strand 14, mutagenesis site 11, turn 7, disulfide bond 5, sequence variant 5, glycosylation site 4, binding site 3, modified residue 2, active site 2, sequence conflict 2, signal peptide 1, chain 1, domain 1, site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5F19	X-RAY DIFFRACTION	2.04
5IKR	X-RAY DIFFRACTION	2.34
5F1A	X-RAY DIFFRACTION	2.38
5IKQ	X-RAY DIFFRACTION	2.41
5IKT	X-RAY DIFFRACTION	2.45
5IKV	X-RAY DIFFRACTION	2.51
5KIR	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35354-F1	93.37	0.91

Functional residue map

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

Catalytic / active sites (3): 193 (proton acceptor); 371 (for cyclooxygenase activity); 516 (aspirin-acetylated serine)

Ligand- & substrate-binding residues (3): 106; 341; 374 (axial binding residue)

Post-translational modifications (2): 565, 526

Disulfide bonds (5): 21–32, 22–145, 26–42, 44–54, 555–561

Glycosylation sites (4): 53, 130, 396, 580

Mutagenesis-validated functional residues (11):

Position	Phenotype
189	increases two-electron hydroperoxide reduction. has no effect on cyclooxygenase activity.
189	impairs two-electron hydroperoxide reduction and cyclooxygenase activity.
189	impairs two-electron hydroperoxide reduction.
193	reduces two-electron hydroperoxide reduction and cyclooxygenase activity. catalyzes predominantly one-electron hydropero
371	decreased protein stability. increased decrease of protein stability; when associated with a-516.
516	no effect on protein stability. increased decrease of protein stability; when associated with a-371.
516	decreased enzyme activity with arachidonic acid. loss of cyclooxygenase activity; when associated with v-519.
519	loss of cyclooxygenase activity. loss of cyclooxygenase activity; when associated with t-516.
526	prevents activation by nitric oxid (no).
555	abolishes enzyme activity.
561	does not affect activation by nitric oxid (no).

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-2142770	Synthesis of 15-eicosatetraenoic acid derivatives
R-HSA-2162123	Synthesis of Prostaglandins (PG) and Thromboxanes (TX)
R-HSA-6783783	Interleukin-10 signaling
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-9018677	Biosynthesis of DHA-derived SPMs
R-HSA-9018679	Biosynthesis of EPA-derived SPMs
R-HSA-9025094	Biosynthesis of DPAn-3 SPMs
R-HSA-9027604	Biosynthesis of electrophilic ω-3 PUFA oxo-derivatives

MSigDB gene sets: 675 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, BROWNE_HCMV_INFECTION_4HR_UP, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, PID_S1P_S1P1_PATHWAY, MCLACHLAN_DENTAL_CARIES_UP, GOBP_REGULATION_OF_BLOOD_PRESSURE, HARRIS_HYPOXIA, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, MODULE_255, GOBP_INFLAMMATORY_RESPONSE, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, FISCHER_G1_S_CELL_CYCLE, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS

GO Biological Process (35): prostaglandin biosynthetic process (GO:0001516), response to oxidative stress (GO:0006979), embryo implantation (GO:0007566), regulation of blood pressure (GO:0008217), response to nematode (GO:0009624), response to selenium ion (GO:0010269), positive regulation of vascular endothelial growth factor production (GO:0010575), cyclooxygenase pathway (GO:0019371), lipoxygenase pathway (GO:0019372), positive regulation of prostaglandin biosynthetic process (GO:0031394), positive regulation of fever generation (GO:0031622), prostaglandin secretion (GO:0032310), regulation of cell population proliferation (GO:0042127), long-chain fatty acid biosynthetic process (GO:0042759), positive regulation of nitric oxide biosynthetic process (GO:0045429), decidualization (GO:0046697), regulation of inflammatory response (GO:0050727), brown fat cell differentiation (GO:0050873), cellular response to hypoxia (GO:0071456), cellular response to non-ionic osmotic stress (GO:0071471), cellular response to fluid shear stress (GO:0071498), positive regulation of transforming growth factor beta production (GO:0071636), positive regulation of cell migration involved in sprouting angiogenesis (GO:0090050), positive regulation of fibroblast growth factor production (GO:0090271), positive regulation of brown fat cell differentiation (GO:0090336), positive regulation of platelet-derived growth factor production (GO:0090362), regulation of neuroinflammatory response (GO:0150077), negative regulation of intrinsic apoptotic signaling pathway in response to osmotic stress (GO:1902219), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631), fatty acid biosynthetic process (GO:0006633), prostaglandin metabolic process (GO:0006693), negative regulation of apoptotic process (GO:0043066), prostanoid biosynthetic process (GO:0046457), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (12): peroxidase activity (GO:0004601), prostaglandin-endoperoxide synthase activity (GO:0004666), oxidoreductase activity, acting on single donors with incorporation of molecular oxygen (GO:0016701), oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen (GO:0016702), enzyme binding (GO:0019899), heme binding (GO:0020037), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), dioxygenase activity (GO:0051213)

GO Cellular Component (10): nuclear inner membrane (GO:0005637), nuclear outer membrane (GO:0005640), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), neuron projection (GO:0043005), nucleus (GO:0005634), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Biosynthesis of specialized proresolving mediators (SPMs)	3
Arachidonate metabolism	2
Signaling by Interleukins	2
Biosynthesis of DPA-derived SPMs	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxidoreductase activity	3
cellular anatomical structure	3
prostaglandin biosynthetic process	2
nuclear membrane	2
nuclear outer membrane-endoplasmic reticulum membrane network	2
cytoplasm	2
intracellular membrane-bounded organelle	2
prostaglandin metabolic process	1
prostanoid biosynthetic process	1
response to stress	1
multicellular organism development	1
female pregnancy	1
reproductive process	1
blood circulation	1
regulation of biological quality	1
response to other organism	1
response to chemical	1
positive regulation of cytokine production	1
vascular endothelial growth factor production	1
regulation of vascular endothelial growth factor production	1
arachidonate metabolic process	1
fatty acid metabolic process	1
icosanoid metabolic process	1
regulation of prostaglandin biosynthetic process	1
positive regulation of unsaturated fatty acid biosynthetic process	1
fever generation	1
positive regulation of acute inflammatory response	1
regulation of fever generation	1
positive regulation of heat generation	1
prostaglandin transport	1
signal release	1
icosanoid secretion	1
lipid export from cell	1
cell population proliferation	1
regulation of cellular process	1
long-chain fatty acid metabolic process	1
fatty acid biosynthetic process	1
nitric oxide biosynthetic process	1
positive regulation of biosynthetic process	1
regulation of nitric oxide biosynthetic process	1

Protein interactions and networks

STRING

5548 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTGS2	IL1B	P01584	929
PTGS2	IL6	P05231	927
PTGS2	NOS2	P35228	903
PTGS2	CXCL8	P10145	901
PTGS2	TNF	P01375	901
PTGS2	PTGER4	P35408	884
PTGS2	TP53	P04637	867
PTGS2	CASP3	P42574	863
PTGS2	CCL2	P13500	848
PTGS2	JUN	P05412	846
PTGS2	NFKBIA	P25963	843
PTGS2	PTGIS	Q16647	843
PTGS2	EGFR	P00533	832
PTGS2	PTGES	O14684	829
PTGS2	GAPDH	P00354	820

IntAct

15 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PTGS2	ATN1	psi-mi:“MI:0915”(physical association)	0.560
	PTGS2	psi-mi:“MI:0407”(direct interaction)	0.440
PTGS2	PTGS2	psi-mi:“MI:0915”(physical association)	0.400
PTGS2	HLA-A	psi-mi:“MI:0915”(physical association)	0.400
PTGS2	CASK	psi-mi:“MI:0915”(physical association)	0.370
PTGS2		psi-mi:“MI:0915”(physical association)	0.370
LMAN2L	ACP2	psi-mi:“MI:0914”(association)	0.350
CASP8	U2SURP	psi-mi:“MI:0914”(association)	0.350
LMAN2L	PTGS2	psi-mi:“MI:0914”(association)	0.350
LRRK2	SF3B1	psi-mi:“MI:0914”(association)	0.350

BioGRID (100): PTGS2 (Reconstituted Complex), PTGS2 (Reconstituted Complex), PTGS2 (Affinity Capture-RNA), PTGS2 (Affinity Capture-RNA), USP22 (Affinity Capture-Western), PTGS2 (Affinity Capture-Western), USP22 (Reconstituted Complex), PTGS2 (Biochemical Activity), PTGS2 (Affinity Capture-MS), APP (Affinity Capture-Western), PTGS2 (Affinity Capture-Western), TP53 (Affinity Capture-Western), TP53 (Reconstituted Complex), PTGS2 (Affinity Capture-Western), PTGS2 (Reconstituted Complex)

ESM2 similar proteins: A0A1S3ZX38, A0A2G3AC72, B0Y6R2, F9FAJ9, G4N2X9, G4N4J5, G5EB19, O02768, O19183, O61213, O62664, O62698, O62725, O97554, O97598, P05979, P11344, P14679, P22437, P23219, P27607, P35354, P35355, P54834, P55024, P55033, P70682, P79208, Q01603, Q05769, Q2FSF4, Q2QRV3, Q3ATL6, Q4WPX2, Q4WY82, Q5GQ66, Q61419, Q63921, Q6RET3, Q8AVF5

Diamond homologs: A1XQX0, A1XQX1, A1XQX2, A1XQX3, A1XQX8, A1XQY0, A1XQY1, A1XQY3, D0PRN2, D0PRN3, D0PRN4, E9PUN2, E9Q7X7, O02768, O19183, O62698, P0DI97, P35354, P58400, P58401, P79208, Q06561, Q07310, Q28142, Q28143, Q28146, Q3KN41, Q63372, Q63373, Q63374, Q63376, Q6P9K9, Q8C985, Q9CS84, Q9DDD0, Q9HDB5, Q9P2S2, Q9ULB1, Q9Y4C0, A0A1Y9G8H0

SIGNOR signaling

41 interactions.

A	Effect	B	Mechanism
PTGS2	up-regulates	“prostaglandin D2”	“chemical modification”
PTGS2	up-regulates	“prostaglandin F2alpha”	“chemical modification”
PTGS2	up-regulates	Prostacycline	“chemical modification”
“acetylsalicylic acid”	down-regulates	PTGS2	“chemical inhibition”
PTGS2	down-regulates	GSK3B
celecoxib	down-regulates	PTGS2	“chemical inhibition”
Pravadoline	down-regulates	PTGS2	“chemical inhibition”
“arachidonic acid”	up-regulates	PTGS2
PTGS2	“up-regulates quantity”	“prostaglandin E2(1-)”	“chemical modification”
SRF	up-regulates	PTGS2
PTGS2	up-regulates	IL4
PTGS2	up-regulates	MYOD1
paracetamol	“down-regulates activity”	PTGS2	“chemical inhibition”
suprofen	“down-regulates activity”	PTGS2	“chemical inhibition”
ketoprofen	“down-regulates activity”	PTGS2	“chemical inhibition”
oxaprozin	“down-regulates activity”	PTGS2	“chemical inhibition”
NfKb-p65/p50	“up-regulates quantity by expression”	PTGS2
IRX1	“up-regulates quantity by expression”	PTGS2	“transcriptional regulation”
N	“up-regulates activity”	PTGS2	“transcriptional regulation”
S	“up-regulates activity”	PTGS2	“transcriptional regulation”
PTGS2	up-regulates	Inflammation
NFATC2	“up-regulates quantity by expression”	PTGS2	“transcriptional regulation”
NFATC1	“up-regulates quantity by expression”	PTGS2	“transcriptional regulation”
NFATC4	“up-regulates quantity by expression”	PTGS2	“transcriptional regulation”
NFATC3	“up-regulates quantity by expression”	PTGS2	“transcriptional regulation”
PTGS2	“down-regulates quantity”	“episterol ester”	“chemical modification”
PTGS2	“up-regulates quantity”	“prostaglandin E2”	binding
AML1-ETO	“up-regulates quantity by expression”	PTGS2	“transcriptional regulation”
indometacin	“down-regulates activity”	PTGS2	“chemical inhibition”

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	7
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

723 predictions. Top by Δscore:

Variant	Effect	Δscore
1:186674758:TTCTC:T	acceptor_gain	1.0000
1:186674760:CTC:C	acceptor_gain	1.0000
1:186674761:TC:T	acceptor_gain	1.0000
1:186674761:TCC:T	acceptor_loss	1.0000
1:186674762:CC:C	acceptor_gain	1.0000
1:186674762:CCTGT:C	acceptor_loss	1.0000
1:186674763:C:A	acceptor_loss	1.0000
1:186674763:C:CC	acceptor_gain	1.0000
1:186674765:G:GC	acceptor_gain	1.0000
1:186674772:C:CT	acceptor_gain	1.0000
1:186674773:G:T	acceptor_gain	1.0000
1:186674774:A:AC	acceptor_gain	1.0000
1:186674774:A:C	acceptor_gain	1.0000
1:186675243:TCTTA:T	donor_loss	1.0000
1:186675244:CTTAC:C	donor_loss	1.0000
1:186675245:TTA:T	donor_loss	1.0000
1:186675246:TA:T	donor_loss	1.0000
1:186675247:A:AC	donor_gain	1.0000
1:186675247:AC:A	donor_gain	1.0000
1:186675248:C:CA	donor_gain	1.0000
1:186675248:CC:C	donor_gain	1.0000
1:186675392:GCAAC:G	acceptor_gain	1.0000
1:186675393:CAAC:C	acceptor_gain	1.0000
1:186675393:CAACC:C	acceptor_gain	1.0000
1:186675395:AC:A	acceptor_gain	1.0000
1:186675395:ACC:A	acceptor_loss	1.0000
1:186675396:CCTG:C	acceptor_gain	1.0000
1:186675397:C:CC	acceptor_gain	1.0000
1:186675399:G:C	acceptor_gain	1.0000
1:186675892:GCTTA:G	donor_loss	1.0000

AlphaMissense

3995 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:186676038:A:G	W373R	0.999
1:186676038:A:T	W373R	0.999
1:186676054:A:C	F367L	0.999
1:186676054:A:T	F367L	0.999
1:186676056:A:G	F367L	0.999
1:186675296:C:G	R453P	0.998
1:186676036:C:A	W373C	0.998
1:186676036:C:G	W373C	0.998
1:186676559:C:G	R293P	0.998
1:186677725:G:T	A188D	0.998
1:186676055:A:G	F367S	0.997
1:186676540:G:C	C299W	0.997
1:186676562:A:G	L292P	0.997
1:186674609:A:G	L520P	0.996
1:186674609:A:T	L520H	0.996
1:186676055:A:C	F367C	0.996
1:186676532:A:G	L302P	0.996
1:186677703:A:C	F195L	0.996
1:186677703:A:T	F195L	0.996
1:186677705:A:G	F195L	0.996
1:186675297:G:T	R453S	0.995
1:186675902:C:T	G418D	0.995
1:186676044:A:C	Y371D	0.995
1:186676070:C:G	R362P	0.995
1:186676138:A:C	S339R	0.995
1:186676138:A:T	S339R	0.995
1:186676140:T:G	S339R	0.995
1:186676142:A:G	L338S	0.995
1:186676566:A:G	W291R	0.995
1:186676566:A:T	W291R	0.995

dbSNP variants (sampled 300 via entrez): RS1000357628 (1:186671890 G>A), RS1000395206 (1:186679521 C>G,T), RS1000781846 (1:186680425 G>A,C), RS1000808915 (1:186672081 A>T), RS1003511546 (1:186681943 C>G), RS1003522722 (1:186682423 C>A), RS1003707668 (1:186674960 C>G), RS1003757875 (1:186675690 G>A,T), RS1004025883 (1:186682042 A>G), RS1004386345 (1:186674713 A>G,T), RS1005230348 (1:186680592 G>A), RS1005305037 (1:186681095 T>C), RS1005397999 (1:186676293 T>C), RS1005464043 (1:186674958 C>A), RS1005909486 (1:186674701 C>A,G)

Disease associations

OMIM: gene MIM:600262 | disease phenotypes: MIM:600807

GenCC curated gene-disease

Mondo (2): cholangiocarcinoma (MONDO:0019087), inherited susceptibility to asthma (MONDO:0010940)

Orphanet (1): Cholangiocarcinoma (Orphanet:70567)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000186_1	Knee osteoarthritis	3.000000e-06
GCST003043_178	Inflammatory bowel disease	2.000000e-07
GCST003044_111	Crohn’s disease	4.000000e-09

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 (4): CHEMBL2094253 (PROTEIN FAMILY), CHEMBL230 (SINGLE PROTEIN), CHEMBL3885623 (PROTEIN FAMILY), CHEMBL4523964 (SELECTIVITY GROUP)

Molecules with ChEMBL bioactivity

192 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,552,351 (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
CHEMBL118	CELECOXIB	4	112,844
CHEMBL25	ASPIRIN	4	694,602
CHEMBL6	INDOMETHACIN	4	156,366
CHEMBL622	ETODOLAC	4	57,872
CHEMBL1008	BEPRIDIL	4	11,776
CHEMBL1009	LEVODOPA	4	103,854
CHEMBL1014	CANDESARTAN CILEXETIL	4	11,194
CHEMBL1020	TOLMETIN	4	60,332
CHEMBL1034	DICLOFENAC SODIUM	4	45,460
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1064	SIMVASTATIN	4	123,163
CHEMBL1071	OXAPROZIN	4	51,044
CHEMBL1077	BROMFENAC	4	12,495
CHEMBL1085	ACETOPHENAZINE	4	5,134
CHEMBL1101	BIPERIDEN	4	11,044
CHEMBL1173055	RUCAPARIB	4	7,009
CHEMBL1198857	VILANTEROL	4	2,552
CHEMBL1200515	DESERPIDINE	4	2,483
CHEMBL1200585	OXYMETHOLONE	4	5,113
CHEMBL1200666	CALCIPOTRIENE	4	21,689
CHEMBL1201124	KETOROLAC TROMETHAMINE	4
CHEMBL1201168	ISOCARBOXAZID	4
CHEMBL1201213	ISOETHARINE	4
CHEMBL1201250	BENZQUINAMIDE	4
CHEMBL1201303	PYRVINIUM	4
CHEMBL1201304	INDOCYANINE GREEN ACID FORM	4
CHEMBL1201794	RIBOFLAVIN 5’-PHOSPHATE	4
CHEMBL1206690	PARECOXIB	4
CHEMBL122	ROFECOXIB	4
CHEMBL1224	ACRIVASTINE	4

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

PharmGKB clinical annotations

6 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs12042763	Efficacy	3	aspirin	Prostatic Neoplasms
rs20417	Efficacy	3	aspirin	Coronary Artery Disease
rs20417	Efficacy	3	rofecoxib
rs20417	Efficacy	3	ibuprofen
rs4648287	Toxicity	3	atenolol	Hypertension
rs5275	Efficacy	3	capecitabine;oxaliplatin	Colorectal Neoplasms

PharmGKB variants

13 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs5272	PTGS2		0.00	0
rs5273	PTGS2		0.00	0
rs5275	PTGS2	3	2.75	1	capecitabine;oxaliplatin
rs20417	PTGS2	3	2.50	3	rofecoxib;ibuprofen;aspirin
rs689466	PTGS2		0.00	0
rs3218622	PTGS2		0.00	0
rs3218625	PTGS2		0.00	0
rs4648276	PTGS2		0.00	0
rs4648287	PTGS2	3	1.50	1	atenolol
rs12042763	PTGS2	3	2.50	1	aspirin
rs4648310	PTGS2		0.00	0
rs2745557	PTGS2		0.00	0
rs5277	PTGS2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Cyclooxygenase

Most potent curated ligand interactions (44 total), top 25:

Ligand	Action	Affinity	Parameter
NS-398	Inhibition	8.72	pIC50
GW406381	Inhibition	8.52	pIC50
benzquinamide	Inhibition	8.32	pIC50
SC-236	Inhibition	8.3	pIC50
valdecoxib	Inhibition	8.3	pIC50
flurbiprofen	Inhibition	8.0	pIC50
(S)-ARN2508	Inhibition	7.92	pIC50
diclofenac	Inhibition	7.7	pIC50
meclofenamic acid	Inhibition	7.4	pIC50
SC-58125	Inhibition	7.39	pIC50
peptide 30 [PMID: 27019010]	Inhibition	7.22	pIC50
tigemocoxib	Inhibition	7.2	pIC50
carprofen	Inhibition	6.99	pIC50
compound 3 [Uddin et al., 2020]	Inhibition	6.7	pIC50
compound 12a [PMID: 29031075]	Inhibition	6.64	pIC50
HR1405-01	Inhibition	6.52	pIC50
celecoxib	Inhibition	6.52	pIC50
rofecoxib	Inhibition	6.5	pIC50
lumiracoxib	Inhibition	6.49	pKi
compound 9 [Kumar et al., 2019]	Inhibition	6.44	pIC50
SWE101	Inhibition	6.38	pIC50
meloxicam	Inhibition	6.31	pIC50
nimesulide	Inhibition	6.22	pIC50
ketoprofen	Inhibition	6.16	pIC50
resveratrol	Inhibition	6.12	pIC50

Binding affinities (BindingDB)

264 measured of 370 human assays (538 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-[3-[[2-[4-(5-chloro-3-pyridinyl)phenyl]-2-cyclopentylacetyl]amino]-2-methylphenyl]-2-methylpropanoic acid	IC50	0.188 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
dexamethasone (tetramethyl-rhodamine conjugated )	EC50	0.2 nM
3-nitrooxypropyl 2-[1-(4-methoxyphenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]acetate	IC50	2 nM	US-9162979: 1,5-Diary1-2-alkylpyrrole-3-substituted nitro esters, selective COX-2 inhibitors and nitric oxide donors
4-(Benzo[d][1,3]dioxol-5-yl)-2-(2-(4-phenylpiperazin-1-yl)-2-oxoethyl)-6-phenylpyridazin-3(2H)-one (13)	KD	3.3 nM
4-(Benzo[d][1,3]dioxol-5-yl)-2-(2-(4-(4-fluorophenyl)piperazin-1-yl)-2-oxoethyl)-6-phenylpyrid-azin-3(2H)-one (14)	KD	3.3 nM
3-(3-{[(2R)-2-cyclopentyl-2-{4-[6-methyl-5-(trifluoromethyl)pyridin-3-yl]phenyl}acetyl]amino}-2-methylphenyl)pentanoic acid, Single Enantiomer	IC50	6.57 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
3-[3-({cyclopentyl[3-fluoro-4-(5-isobutylpyridin-3-yl)phenyl]acetyl}amino)-2-methylphenyl]pentanoic acid, single enantiomer	IC50	6.82 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
3-nitrooxypropyl 2-[1-(3-fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]acetate	IC50	7 nM	US-9162979: 1,5-Diary1-2-alkylpyrrole-3-substituted nitro esters, selective COX-2 inhibitors and nitric oxide donors
(−) {3-[(Cyclopentyl{4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetyl)amino]-2-methylphenoxy}acetic acid	IC50	9.85 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(−) 3-{3-[(cyclobutyl{3-fluoro-4-[6-methyl-5-(trifluoromethyl)pyridin-3-yl]phenyl}acetyl)amino]-2-methylphenyl}propanoic acid, Single Enantiomer	IC50	10.1 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
3-[3-({(2R)-2-cyclopentyl-2-[4-(5-isobutylpyridin-3-yl)phenyl]acetyl}amino)-2-methylphenyl]pentanoic acid, Single Enantiomer	IC50	10.4 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
3-[3-({cyclopentyl[4-(5-ethylpyridin-3-yl)-3-fluorophenyl]acetyl}amino)-2-methylphenyl]pentanoic acid, Single Enantiomer	IC50	10.5 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(3R/S)-3-[3-({(2R/S)-2-[4-(5-Chloropyridin-3-yl)phenyl]-2-cyclopentylacetyl}amino)-2-methylphenyl]pentanoic acid	IC50	11.2 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
3-[3-[[2-[4-(5-chloro-3-pyridinyl)-3-fluorophenyl]-2-cyclobutylacetyl]amino]-2-methylphenyl]butanoic acid	IC50	11.7 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
3-[3-[[2-cyclobutyl-2-[3-fluoro-4-[5-(trifluoromethyl)-3-pyridinyl]phenyl]acetyl]amino]-2-methylphenyl]butanoic acid	IC50	12.6 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(3R/S)-3-[3-({(2R/S)-2-Cyclopentyl-2-[4-(5-ethylpyridin-3-yl)phenyl]acetyl}amino)-2-methylphenyl]pentanoic acid	IC50	12.9 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(3R/S)-3-[3-({(2R/S)-2-[4-(5-Chloro-6-methylpyridin-3-yl)phenyl]-2-cyclopentylacetyl}amino)-2-methylphenyl]butanoic acid	IC50	13 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
3-[3-[[2-[4-(5-chloro-6-methyl-3-pyridinyl)phenyl]-2-cyclobutylacetyl]amino]-2-methylphenyl]butanoic acid	IC50	13.5 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
3-(3-{[(2R)-2-cyclopentyl-2-{4-[6-methyl-5-(trifluoromethyl)pyridin-3-yl]phenyl}acetyl]amino}-2-methylphenyl)propanoic acid	IC50	13.5 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
2-[2-[1-(4-fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]ethoxy]ethyl nitrate	IC50	14 nM	US-9162979: 1,5-Diary1-2-alkylpyrrole-3-substituted nitro esters, selective COX-2 inhibitors and nitric oxide donors
2-[1-(3-fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]-N-(3-hydroxypropyl)acetamide	IC50	14 nM	US-9162979: 1,5-Diary1-2-alkylpyrrole-3-substituted nitro esters, selective COX-2 inhibitors and nitric oxide donors
2-[3-[[2-[4-(5-chloro-3-pyridinyl)phenyl]-2-cyclopentylacetyl]amino]-2-methylphenoxy]acetic acid	IC50	14 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
4-(Benzo[d][1,3]dioxol-5-yl)-2-(2-(3,4-dimethoxyphenethylamine)-2-oxoethyl)-6-phenyl-pyridazin-3(2H)-one (11)	KD	14 nM
3-[3-({cyclobutyl[3-fluoro-4-(5-isobutylpyridin-3-yl)phenyl]acetyl}amino)-2-methylphenyl]propanoic acid, Single Enantiomer	IC50	14.1 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(−) 3-{3-[(Cyclopentyl{3-fluoro-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetyl)amino]-2-methylphenyl}propanoic acid	IC50	14.2 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(R/S) {3-[(Cyclopentyl{4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetyl)amino]-2-methylphenoxy}acetic acid	IC50	14.3 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
3-[3-[[2-[4-(5-chloro-3-pyridinyl)phenyl]-2-cyclopentylacetyl]amino]-6-methoxy-2-methylphenyl]propanoic acid	IC50	14.3 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(R/S) 3-{3-[(Cyclopentyl{4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetyl)amino]-2-methylphenyl}propanoic acid	IC50	14.5 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
3-[2-[2-methyl-5-(4-methylsulfonylphenyl)-1-phenylpyrrol-3-yl]ethoxy]propyl nitrate	IC50	15 nM	US-9162979: 1,5-Diary1-2-alkylpyrrole-3-substituted nitro esters, selective COX-2 inhibitors and nitric oxide donors
3-(3-{[(2R)-2-cyclopentyl-2-{4-[5-(2-methylpropyl)pyridin-3-yl]phenyl}acetyl]amino}-2-methylphenyl)propanoic acid	IC50	15 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(−) (R) 3-[3-({4-(5-Chloro-6-methylpyridin-3-yl)phenylacetyl}amino)-2-methylphenyl]propanoic acid	IC50	15.6 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(R/S) 3-{3-[(Cyclopentyl{3-fluoro-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetyl)amino]-2-methylphenyl}propanoic acid	IC50	15.9 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(3R/S)-3-[3-({(2R/S)-2-[4-(5-Chloro-6-methylpyridin-3-yl)-3-fluorophenyl]-2-cyclopentylacetyl}amino)-2-methylphenyl]butanoic acid	IC50	15.9 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
3-[3-({(2R)-2-cyclopentyl-2-[4-(5-isopropoxypyridin-3-yl)phenyl]acetyl}amino)-2-methylphenyl]pentanoic acid, Single Enantiomer	IC50	16.7 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
2-[2-[2-methyl-5-(4-methylsulfonylphenyl)-1-phenylpyrrol-3-yl]ethoxy]ethyl nitrate	IC50	17 nM	US-9162979: 1,5-Diary1-2-alkylpyrrole-3-substituted nitro esters, selective COX-2 inhibitors and nitric oxide donors
(−) 3-[3-({4-(5-Chloropyridin-3-yl)-3-fluorophenylacetyl}amino)-2-methylphenyl]propanoic acid	IC50	17.6 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
3-(3-{[(2R)-2-cyclopentyl-2-{4-[5-(2,2,2-trifluoroethyl)pyridin-3-yl]phenyl}acetyl]amino}-2-methylphenyl)pentanoic acid, Single Enantiomer	IC50	17.7 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
2-nitrooxyethyl 2-[1-(3-fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]acetate	IC50	19 nM	US-9162979: 1,5-Diary1-2-alkylpyrrole-3-substituted nitro esters, selective COX-2 inhibitors and nitric oxide donors
(R/S) 3-{3-[(Cyclopentyl{3-methyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetyl)amino]-2-methylphenyl}propanoic acid	IC50	19.2 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(−) 3-{3-[(cyclopentyl{3-fluoro-4-[6-methyl-5-(trifluoromethyl)pyridin-3-yl]phenyl}acetyl)amino]-2-methylphenyl}propanoic acid, Single Enantiomer	IC50	19.3 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(−) 3-[3-({cyclopentyl[3-fluoro-4-(5-isobutyl-6-methylpyridin-3-yl)phenyl]acetyl}amino)-2-methylphenyl]propanoic acid, Single Enantiomer	IC50	20 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(3R/S)-3-(3-{[(2R/S)-2-Cyclopentyl-2-{4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetyl]amino}-2-methylphenyl)butanoic acid	IC50	20.3 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(−) (R) 3-{3-[(Cyclopentyl{4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetyl)amino]-2-methylphenyl}propanoic acid	IC50	20.4 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
3-[3-({(2R)-2-cyclopentyl-2-[4-(5-ethylpyridin-3-yl)phenyl]acetyl}amino)-2-methylphenyl]pentanoic acid, Single Enantiomer	IC50	20.8 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(R/S) 3-[3-({4-(5-Chloro-6-methylpyridin-3-yl)phenylacetyl}amino)-2-methylphenyl]propanoic acid	IC50	22 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(3R/S)-3-[3-({(2R/S)-2-Cyclopentyl-2-[4-(5-ethylpyridin-3-yl)phenyl]acetyl}amino)-2-methylphenyl]butanoic acid	IC50	22 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
3-hydroxypropyl 2-[1-(3-fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]acetate	IC50	23 nM	US-9162979: 1,5-Diary1-2-alkylpyrrole-3-substituted nitro esters, selective COX-2 inhibitors and nitric oxide donors
3-[3-({(2R)-2-[4-(5-chloro-6-methylpyridin-3-yl)phenyl]-2-cyclopentylacetyl}amino)-6-fluoro-2-methylphenyl]propanoic acid	IC50	23.7 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
N-[3-({(2R)-2-[4-(5-chloro-6-methylpyridin-3-yl)phenyl]-2-cyclopentylacetyl}amino)-2-methylphenyl]-N-methylglycine	IC50	23.9 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
(−) N-{3-[(cyclopentyl{3-fluoro-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetyl)amino]-2-methylphenyl}-N-methylglycine, Single Enantiomer	IC50	24.2 nM	US-10172814: Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof

ChEMBL bioactivities

5553 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	IC50	0.02	nM	CHEMBL499069
10.70	IC50	0.02	nM	CHEMBL501208
10.70	IC50	0.02	nM	CHEMBL525247
10.16	IC50	0.06998	nM	CHEMBL502555
10.15	IC50	0.07	nM	CHEMBL502555
10.10	IC50	0.08	nM	CHEMBL143776
10.05	IC50	0.09	nM	CHEMBL524543
10.05	IC50	0.09	nM	CHEMBL500936
10.05	IC50	0.08995	nM	CHEMBL524543
10.05	IC50	0.08995	nM	CHEMBL500936
10.05	IC50	0.09	nM	THIOSEMICARBAZIDE
9.92	IC50	0.12	nM	CHEMBL140167
9.85	IC50	0.14	nM	CHEMBL499349
9.85	IC50	0.14	nM	INDOMETHACIN
9.77	IC50	0.17	nM	CHEMBL525021
9.77	IC50	0.1698	nM	CHEMBL525021
9.74	IC50	0.18	nM	CHEMBL500943
9.74	IC50	0.1799	nM	CHEMBL500943
9.73	IC50	0.188	nM	CHEMBL4582020
9.72	Kd	0.19	nM	CHEMBL1957450
9.70	IC50	0.2	nM	CHEMBL1958349
9.60	IC50	0.25	nM	CHEMBL551829
9.55	IC50	0.28	nM	CHEMBL525250
9.55	IC50	0.2799	nM	CHEMBL525250
9.55	IC50	0.28	nM	CHEMBL551148
9.52	IC50	0.3	nM	CHEMBL271173
9.52	IC50	0.3	nM	CHEMBL423296
9.44	IC50	0.36	nM	CHEMBL502285
9.44	IC50	0.3597	nM	CHEMBL502285
9.43	IC50	0.37	nM	CHEMBL502554
9.43	IC50	0.3698	nM	CHEMBL502554
9.40	IC50	0.4	nM	CHEMBL270293
9.36	IC50	0.44	nM	CHEMBL186632
9.35	IC50	0.45	nM	CHEMBL282093
9.33	Ki	0.47	nM	CELECOXIB
9.30	IC50	0.5	nM	CHEMBL561891
9.30	IC50	0.5	nM	CHEMBL108201
9.28	IC50	0.52	nM	CELECOXIB
9.27	IC50	0.54	nM	CHEMBL500674
9.27	IC50	0.5395	nM	CHEMBL500674
9.22	IC50	0.6	nM	CHEMBL499070
9.22	IC50	0.5998	nM	CHEMBL499070
9.10	IC50	0.8	nM	CHEMBL500675
9.10	IC50	0.7998	nM	CHEMBL500675
9.00	IC50	1	nM	CHEMBL327384
9.00	IC50	1	nM	CHEMBL88717
9.00	IC50	1	nM	CHEMBL432945
9.00	IC50	1	nM	CHEMBL313387
9.00	IC50	1	nM	CHEMBL5089355
9.00	IC50	1	nM	CHEMBL5200454

PubChem BioAssay actives

2601 with measured affinity, of 6100 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[3-(4-methoxyphenyl)-1H-indol-2-yl]benzenesulfonamide	362870: Inhibition of COX2	ic50	<0.0001	uM
3-(4-methoxyphenyl)-2-(4-methylsulfonylphenyl)-1H-indole	362870: Inhibition of COX2	ic50	<0.0001	uM
3-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-1H-indole	362870: Inhibition of COX2	ic50	<0.0001	uM
4-[3-(4-(111C)methoxyphenyl)-1H-indol-2-yl]benzenesulfonamide	1896014: Inhibition of COX2 (unknown origin)	ic50	<0.0001	uM
3-(4-methylphenyl)-2-(4-methylsulfonylphenyl)-1H-indole	362870: Inhibition of COX2	ic50	0.0001	uM
4-(3-phenyl-1H-indol-2-yl)benzenesulfonamide	362870: Inhibition of COX2	ic50	0.0001	uM
4-[3-(4-methylphenyl)-1H-indol-2-yl]benzenesulfonamide	362870: Inhibition of COX2	ic50	0.0001	uM
4-(5-chloro-3-phenyl-1H-indol-2-yl)benzenesulfonamide	362870: Inhibition of COX2	ic50	0.0001	uM
3-(3,4-dimethylphenyl)-2-(4-methylsulfonylphenyl)-1H-indole	362870: Inhibition of COX2	ic50	0.0002	uM
N-[(4-fluorophenyl)methyl]-4-(4-methylsulfonylphenyl)-6-(trifluoromethyl)pyrimidin-2-amine	432545: Inhibition of human COX2 expressed in african green monkey COS cells assessed as inhibition of arachidonic acid-stimulated PGE2 production treated 1 hr before arachidonic acid challenge by enzyme immunoassay	ic50	0.0003	uM
4-[2-(4-ethoxyphenyl)pyrazolo[1,5-b]pyridazin-3-yl]benzenesulfonamide	241308: Inhibition of human cyclooxygenase-2 expressed in COS cells	ic50	0.0004	uM
5-chloro-2-(4-methylsulfonylphenyl)-3-phenyl-1H-indole	362870: Inhibition of COX2	ic50	0.0004	uM
1-methoxy-4-[2-(4-methylsulfonylphenyl)cyclopenten-1-yl]benzene	162346: In vitro inhibition of prostaglandin G/H synthase 2 (COX-2).	ic50	0.0005	uM
2-(4-methylsulfonylphenyl)-3-phenyl-1H-indole	362870: Inhibition of COX2	ic50	0.0006	uM
4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0010	uM
[3-[[4-(1-benzothiophen-3-yl)-1,3-thiazol-2-yl]methyl]-5-methoxy-2-methylindol-1-yl]-(4-chlorophenyl)methanone	162658: Inhibitory concentration against human recombinant Prostaglandin G/H synthase 2 cloned and expressed in baculovirus (Sf9)	ic50	0.0010	uM
4-[5-[4-(trifluoromethyl)phenyl]spiro[2.4]hept-5-en-6-yl]benzenesulfonamide	162653: Inhibitory activity against prostaglandin G/H synthase 2 (COX-2).	ic50	0.0010	uM
6-(4-chlorophenyl)-5-(4-methylsulfonylphenyl)spiro[2.4]hept-5-ene	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0010	uM
4-[6-(4-chlorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0010	uM
4-[5-(4-methoxyphenyl)spiro[2.4]hept-5-en-6-yl]benzenesulfonamide	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0010	uM
5-[[1-[(2S)-2-hydroxy-3-(5-hydroxy-4-oxo-2-phenylchromen-7-yl)oxypropyl]indol-3-yl]methylidene]-1,3-diazinane-2,4,6-trione	1810792: Inhibition of human COX-2 using arachidonic acid as substrate preincubated for 10 mins followed by substrate addition and measured after 2 mins by EIA	ic50	0.0010	uM
4-(111C)methoxy-6-(4-methylsulfonylphenyl)-N-(thiophen-2-ylmethyl)pyrimidin-2-amine	1896014: Inhibition of COX2 (unknown origin)	ic50	0.0010	uM
phenyl 5-methyl-3-(4-methylphenyl)pyrazole-1-sulfonate	1752430: Inhibition of human recombinant COX-2 assessed as production of PGE2 using arachidonic acid as a substrate preincubated for 60 mins followed by substrate addition and measured after 2 mins by ELISA analysis	ic50	0.0011	uM
[4-[3-(4-methylsulfonylphenyl)-5-oxo-2H-furan-4-yl]phenyl] acetate	162503: In vitro inhibitory concentration of compound required to inhibit Prostaglandin G/H synthase 2 enzyme was determined	ic50	0.0013	uM
6-(3-bromo-4-methoxyphenyl)-5-(4-methylsulfonylphenyl)spiro[2.4]hept-5-ene	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0013	uM
(3E)-1-(2,6-dichlorophenyl)-3-[(4-oxochromen-3-yl)methylidene]indol-2-one	1177989: Inhibition of human recombinant COX-2 assessed as decrease in prostaglandin production using arachidonic acid as substrate incubated with enzyme for 10 mins prior to substrate challenge by enzyme immunoassay	ic50	0.0013	uM
4-[3-(3,4-dimethylphenyl)-1H-indol-2-yl]benzenesulfonamide	362870: Inhibition of COX2	ic50	0.0015	uM
4-[6-(3-chloro-4-fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0015	uM
5-(4-methylphenyl)-6-(4-methylsulfonylphenyl)spiro[2.4]hept-5-ene	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0015	uM
[3-[3-(4-methylsulfonylphenyl)-5-oxo-2H-furan-4-yl]phenyl] acetate	162503: In vitro inhibitory concentration of compound required to inhibit Prostaglandin G/H synthase 2 enzyme was determined	ic50	0.0017	uM
4-[4-fluoro-5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide	162507: In vitro inhibitory concentration required to block human recombinant prostaglandin G/H synthase 2 (COX-2)	ic50	0.0017	uM
4-[4-(18F)fluoro-5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide	1896014: Inhibition of COX2 (unknown origin)	ic50	0.0017	uM
4-phenyl-3-[4-(2H-tetrazol-5-yl)phenyl]-2H-furan-5-one	270014: Inhibition of COX2	ic50	0.0018	uM
5-[4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]phenyl]-2H-tetrazole	270014: Inhibition of COX2	ic50	0.0019	uM
4-[2-(3-chloro-4-fluorophenyl)-4,5-difluorophenyl]benzenesulfonamide	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0020	uM
4-[2-(3,4-dichlorophenyl)cyclopenten-1-yl]benzenesulfonamide	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0020	uM
4-[4,5-difluoro-2-(4-fluoro-3-methylphenyl)phenyl]benzenesulfonamide	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0020	uM
4-[6-(3-bromo-4-methoxyphenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0020	uM
4-[2-(4-methoxyphenyl)cyclopenten-1-yl]benzenesulfonamide	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0020	uM
6-(4-methylsulfonylphenyl)-5-[4-(trifluoromethyl)phenyl]spiro[2.4]hept-5-ene	162653: Inhibitory activity against prostaglandin G/H synthase 2 (COX-2).	ic50	0.0020	uM
4-[6-(3-fluoro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0020	uM
4-[2-(1,3-benzodioxol-5-yl)cyclopenten-1-yl]benzenesulfonamide	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0020	uM
4-[2-[3-chloro-4-(dimethylamino)phenyl]cyclopenten-1-yl]benzenesulfonamide	160434: Inhibition of human Prostaglandin G/H synthase 2	ic50	0.0020	uM
1-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(4-methylsulfonylphenyl)benzene	1532167: Inhibition of recombinant human COX-2 expressed in Baculovirus infected sf9 cells using arachidonic acid as substrate preincubated for 10 mins followed by substrate addition measured after 10 mins by ELISA	ic50	0.0020	uM
3-(4-methylsulfonylphenyl)-2-phenylpyrazolo[1,5-b]pyridazine	241308: Inhibition of human cyclooxygenase-2 expressed in COS cells	ic50	0.0020	uM
3-[1-[(4-chlorophenyl)methyl]-3-(3,3-dimethylbutanoyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid	160848: The compound was tested for inhibitory activity against Prostaglandin G/H synthase in human polymorphonuclear leukocytes[PMNS]	ic50	0.0020	uM
4-(5-fluoro-3-phenyl-1H-indol-2-yl)benzenesulfonamide	362870: Inhibition of COX2	ic50	0.0020	uM
(7E)-5-methyl-3-(5-nitrothiophen-2-yl)-7-[(5-nitrothiophen-2-yl)methylidene]-2-phenyl-3,3a,4,6-tetrahydropyrazolo[4,3-c]pyridine	1939574: Inhibition of COX-2 (unknown origin) using arachidonic acid as substrate incubated for 1 min by absorbance based analysis	ic50	0.0020	uM
2-[4-[4-(trifluoromethyl)phenyl]triazol-1-yl]ethyl 4-methylsulfonylbenzoate	1939590: Inhibition of human COX-2 using arachidonic acid as substrate incubated for 30 secs by ELISA	ic50	0.0020	uM
(7E)-3-(5-bromothiophen-2-yl)-7-[(5-bromothiophen-2-yl)methylidene]-5-methyl-2-phenyl-3,3a,4,6-tetrahydropyrazolo[4,3-c]pyridine	1939574: Inhibition of COX-2 (unknown origin) using arachidonic acid as substrate incubated for 1 min by absorbance based analysis	ic50	0.0020	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Dinoprostone	increases activity, increases reaction, increases expression, decreases activity, affects chemical synthesis (+11 more)	58
Lipopolysaccharides	increases secretion, increases expression, increases reaction, decreases reaction, increases activity (+6 more)	57
Resveratrol	decreases reaction, affects binding, increases reaction, increases expression, decreases expression (+7 more)	51
Tetradecanoylphorbol Acetate	affects reaction, increases reaction, affects cotreatment, decreases chemical synthesis, increases expression (+4 more)	34
N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide	affects reaction, increases expression, increases abundance, increases chemical synthesis, affects response to substance (+11 more)	33
Celecoxib	decreases activity, decreases expression, affects binding, increases chemical synthesis, increases reaction (+7 more)	32
Particulate Matter	increases secretion, affects expression, decreases reaction, increases expression, increases abundance (+4 more)	31
Acetylcysteine	increases abundance, decreases reaction, increases expression, affects cotreatment, decreases expression (+2 more)	28
Quercetin	affects cotreatment, increases expression, decreases chemical synthesis, decreases expression, increases reaction (+5 more)	27
SB 203580	affects cotreatment, increases reaction, decreases reaction, increases expression, decreases expression (+4 more)	26
Curcumin	decreases expression, increases expression, decreases reaction, affects cotreatment, decreases activity (+2 more)	22
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	increases chemical synthesis, affects localization, affects binding, increases reaction, decreases reaction (+2 more)	20
Tetrachlorodibenzodioxin	decreases reaction, increases expression, increases reaction, affects reaction, decreases expression (+3 more)	20
sodium arsenite	increases reaction, affects response to substance, decreases expression, decreases reaction, increases expression (+1 more)	19
Indomethacin	decreases activity, affects cotreatment, decreases reaction, increases expression, affects binding (+3 more)	19
bisphenol A	decreases reaction, increases expression, increases reaction, affects response to substance, affects reaction (+4 more)	17
Dexamethasone	increases secretion, affects cotreatment, decreases expression, decreases reaction, increases expression (+2 more)	17
U 0126	increases reaction, increases activity, affects reaction, affects cotreatment, decreases activity (+2 more)	16
Aspirin	increases expression, decreases activity, decreases expression, decreases reaction, increases activity (+4 more)	16
nimesulide	decreases expression, affects cotreatment, decreases reaction, decreases activity, decreases abundance (+6 more)	15
Vehicle Emissions	increases abundance, increases expression, affects cotreatment, decreases expression, increases secretion (+4 more)	15
Estradiol	affects cotreatment, decreases reaction, increases expression, increases reaction, affects expression (+2 more)	13
pyrazolanthrone	increases expression, increases chemical synthesis, increases reaction, decreases reaction	12
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	increases expression, affects cotreatment, increases reaction, decreases expression, decreases reaction	11
Arsenic Trioxide	decreases expression, decreases reaction, affects cotreatment, affects localization, increases expression (+2 more)	11
3-(4-methylphenylsulfonyl)-2-propenenitrile	decreases reaction, increases expression, increases abundance	10
Cisplatin	decreases expression, increases response to substance, decreases response to substance, increases expression, affects cotreatment (+3 more)	10
Flurbiprofen	increases chemical synthesis, increases reaction, decreases activity, increases activity, decreases reaction (+1 more)	10
Tobacco Smoke Pollution	increases abundance, decreases reaction, increases expression	10
Arachidonic Acid	affects binding, increases expression, increases reaction, increases response to substance, increases metabolic processing (+6 more)	10

ChEMBL screening assays

1548 unique, capped per target: 1478 binding, 35 functional, 34 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2038420	Binding	Inhibition of cyclooxygenase-mediated PGE2 production in human HT-29 cells at 1 uM after 25 hrs by LC-MS/MS analysis	Radiosynthesis of a ¹⁸F-labeled 2,3-diarylsubstituted indole via McMurry coupling for functional characterization of cyclooxygenase-2 (COX-2) in vitro and in vivo. — Bioorg Med Chem
CHEMBL4273610	ADMET	Modulation of COX1/2-mediated PGF2a level in human M1 macrophages derived from LPS/IFNgamma-polarized human monocyte derived macrophages at 3 uM preincubated for 15 mins followed by Escherichia coli (O6:K2:H1) challenge for 90 mins by LC-MS	Discovery of a benzenesulfonamide-based dual inhibitor of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase that favorably modulates lipid mediator biosynthesis in inflammation. — Eur J Med Chem
CHEMBL660374	Functional	Half-maximal inhibition of the COX activity was measured by the direct analysis of the consumed O2 using isolated sheep seminal vesicles	New indene-derivatives with anti-proliferative properties. — Bioorg Med Chem Lett

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1H3	Abcam A-549 PTGS2 KO	Cancer cell line	Male
CVCL_B2CQ	Abcam HeLa PTGS2 KO	Cancer cell line	Female
CVCL_D7YV	Ubigene A-549 PTGS2 KO	Cancer cell line	Male
CVCL_E0M6	Ubigene HeLa PTGS2 KO	Cancer cell line	Female
CVCL_KT48	HeLa SilenciX COX2	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