AKR1C3

Summary

AKR1C3 (aldo-keto reductase family 1 member C3, HGNC:386) is a protein-coding gene on chromosome 10p15.1, encoding Aldo-keto reductase family 1 member C3 (P42330). Cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids.

This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ), and the oxidation of 9alpha,11beta-PGF2 to PGD2. It may play an important role in the pathogenesis of allergic diseases such as asthma, and may also have a role in controlling cell growth and/or differentiation. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8644 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 82 total — 2 pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes — 22 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003739

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:386
Approved symbol	AKR1C3
Name	aldo-keto reductase family 1 member C3
Location	10p15.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0119, DDX, HAKRB, PGFS
Ensembl gene	ENSG00000196139
Ensembl biotype	protein_coding
OMIM	603966
Entrez	8644

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 8 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000380554, ENST00000439082, ENST00000470862, ENST00000480697, ENST00000480822, ENST00000602997, ENST00000603312, ENST00000603484, ENST00000605149, ENST00000605322, ENST00000605781, ENST00000879764, ENST00000879765, ENST00000879766, ENST00000879767

RefSeq mRNA: 3 — MANE Select: NM_003739 NM_001253908, NM_001253909, NM_003739

CCDS: CCDS7063, CCDS73062

Canonical transcript exons

ENST00000380554 — 9 exons

Exon	Start	End
ENSE00001896041	5094414	5094528
ENSE00003590941	5107461	5107686
ENSE00003794241	5098802	5098879
ENSE00003794919	5105595	5105677
ENSE00003797688	5102101	5102210
ENSE00003798493	5099327	5099449
ENSE00003798712	5097434	5097550
ENSE00003799033	5096410	5096577
ENSE00003799334	5102485	5102650

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 99.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.7965 / max 4281.9154, expressed in 1395 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
103621	26.6204	1232
103620	11.9555	1265
103614	1.0083	23
103624	0.1267	22
103615	0.0544	15
103616	0.0119	2
103622	0.0113	5
103623	0.0080	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.74	gold quality
pancreatic ductal cell	CL:0002079	99.16	gold quality
gall bladder	UBERON:0002110	99.04	gold quality
duodenum	UBERON:0002114	98.96	gold quality
ileal mucosa	UBERON:0000331	98.73	gold quality
right lobe of liver	UBERON:0001114	98.68	gold quality
nephron tubule	UBERON:0001231	98.60	gold quality
islet of Langerhans	UBERON:0000006	98.23	gold quality
mucosa of transverse colon	UBERON:0004991	97.99	gold quality
skin of hip	UBERON:0001554	97.78	gold quality
adipose tissue	UBERON:0001013	97.72	gold quality
gluteal muscle	UBERON:0002000	97.65	gold quality
liver	UBERON:0002107	97.60	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.56	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.26	gold quality
rectum	UBERON:0001052	97.25	gold quality
descending thoracic aorta	UBERON:0002345	97.25	gold quality
colonic mucosa	UBERON:0000317	97.20	gold quality
nasal cavity mucosa	UBERON:0001826	97.15	gold quality
synovial joint	UBERON:0002217	97.14	gold quality
nasal cavity epithelium	UBERON:0005384	97.13	gold quality
right lung	UBERON:0002167	97.11	gold quality
connective tissue	UBERON:0002384	97.09	gold quality
kidney epithelium	UBERON:0004819	97.00	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.87	gold quality
jejunum	UBERON:0002115	96.82	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.76	gold quality
omental fat pad	UBERON:0010414	96.75	gold quality
peritoneum	UBERON:0002358	96.70	gold quality
adult mammalian kidney	UBERON:0000082	96.64	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-8495	yes	4728.70
E-GEOD-125970	yes	476.85
E-HCAD-4	yes	136.20
E-CURD-114	yes	64.80
E-MTAB-8142	yes	51.91
E-MTAB-5061	yes	20.34
E-CURD-122	yes	17.76
E-HCAD-1	yes	11.63
E-HCAD-31	yes	4.00
E-GEOD-83139	no	3.55
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, KLF15, SP1, SP3

miRNA regulators (miRDB)

13 targeting AKR1C3, 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-4282	99.99	75.36	6408
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-3136-5P	98.53	67.68	793
HSA-MIR-4439	98.53	67.53	793
HSA-MIR-379-5P	97.52	67.81	485
HSA-MIR-3529-5P	97.12	67.06	440
HSA-MIR-4703-3P	96.68	68.61	545
HSA-MIR-184	94.24	64.40	152

Literature-anchored findings (GeneRIF, showing 40)

• Glaucomatous optic nerve head astrocytes express a higher level of 3 alpha-HSD isoform AKR1C3 and its mRNA than normal astrocytes. (PMID:13678667)
• expression and activity of type 5 17beta-hydroxysteroid dehydrogenase and type 3 3alpha-hydroxysteroid dehydrogenase in female subcutaneous tissue and omental adipose tissue and in preadipocytes (PMID:14671194)
• On the basis of crystal structures, a detailed catalytic mechanism of prostaglandin F synthase is proposed and compared to that of AKR1C1 and AKR1C3. (PMID:14979715)
• Overexpression of hPGFS is associated with primary squamous cell carcinoma of the head and neck and tumour cell lines derived from respiratory and digestive organs (PMID:14997212)
• Expression of SRD5A1 (5alphaR1) and SRD5A2 (5alphaR2) is elevated, and expression of AKR1C1 (20alpha-HSO), AKR1C2 (3alpha-HSO3) and AKR1C3 (3alpha-HSO2) is reduced in tumorous as compared to normal breast tissue. (PMID:15212687)
• Single nucleotide polymorphism may play a role in the pathogenesis of lung cancer in this population, particularly among heavily exposed women. (PMID:15284179)
• enzyme distribution differs between normal and hormonal dependent malignancies of the breast and prostate (PMID:15582534)
• Members of the Sp family of transcription factors play an important role in regulating constitutive and stimulated expression of the HSD17B5 gene in H295R cells. (PMID:15814298)
• AKR1C3 protects the mineralocorticoid receptor from activation by deoxycorticosterone in mineralocorticoid target cells of the kidney and colon. (PMID:16337083)
• The expression of AKR1C1 and AKR1C3 in endometrial cancer will govern the ratio of P:E2. (PMID:16338060)
• Based on model structures & inhibition, catalytic mechanism of PGH2 9,11-endoperoxide reductase of PGFS is proposed.Formation of PGF(2alpha) from PGH2 may involve hydride transfer from bound NADPH to PGH2 endoperoxide without specific amino acid residues. (PMID:16475787)
• Type 5 17beta-HSD (AKR1C3) differs significantly from the type 1 enzyme by possessing a spacious and flexible steroid-binding site. (PMID:16480815)
• Elevated expression of AKR1C3 is highly associated with prostate carcinoma (PMID:16601286)
• Glu77Gly AKR1C3 polymorphism is associated with lower testosterone levels in serum. (PMID:16983398)
• report the clinical history, endocrine evaluation and molecular genetics of a prepubertal girl affected by 17beta-HSD3 deficiency, in whom an erroneous diagnosis of androgen insensitivity syndrome was made (PMID:17071532)
• analysis of human type 5 17beta-hydroxysteroid dehydrogenase conformation and binding to inhibitors (PMID:17166832)
• HSD17B5 single nucleotide polymorphisms predicted to have functional effects do not appear to be a risk factor for precocious pubarche in girls from Barcelona, despite these girls being at high risk of developing androgen excess in adulthood (PMID:17583494)
• Carbonyl reductase-1 (CBR1), microsomal prostaglandin E synthase-1 and 2 (mPGES-1, mPGES-2), cytosolic prostaglandin E synthase (cPGES), aldoketoreductase (AKR1C1) and prostaglandin F synthase (AKR1C3) were all expressed in hair follicles. (PMID:17697149)
• Polymorphisms in the HSD17B5 gene are not associated with risk of polycystic ovary syndrome or elevated testosterone levels. (PMID:17940109)
• The maternal methylenetetrahydrofolate reductase A1298C polymorphism was found to be an effect modifier of the maternal intron 4 polymorphism of the AKR1C3 gene and the childhood leukemia risk. (PMID:18339682)
• Among gene transcripts elevated in depressed episodes were prostaglandin D synthetase (PTGDS) and prostaglandin D2 11-ketoreductase (AKR1C3), both involved in hibernation. We hypothesized them to account for some of the rapid cycling symptoms. (PMID:18552976)
• A strong immunoreactivity was detected not only in classically hormone-associated tissues such as prostate and testis but also in non-hormone-associated tissues such as kidney and bladder in humans and rats. (PMID:18574251)
• genetic variation in carcinogen-metabolizing genes, particularly AKR1C3, could be associated with bladder cancer risk. (PMID:18632753)
• Data suggest that adipose tissue AKR1C3 expression may be affected by metabolic disease, and its levels are significantly reduced in response to diet-induced weight loss and correlate with leptin levels. (PMID:18641923)
• The -71G HSD17B5 variant is not a major component of the molecular pathogenetic mechanisms of PCOS, although it might contribute to the severity of hyperandrogenemia in women with PCOS and biochemical hyperandrogenism. (PMID:18692800)
• Higher mRNA levels of enzymes synthesizing and inactivating androgens are found in differentiated adipocytes, consistent with higher androgen-processing rates in these cells. (PMID:18984855)
• 17beta-HSD type 5 was expressed in 56% of breast cancer specimens. decrease in 17beta-HSD type 5 expressions in breast cancer may play a role in the development &/or progression of cancer by modifying the intratumoral levels of estrogens & androgens. (PMID:18996480)
• This is the first study that addresses whether AKR1C3 mediates carcinogen activation within intact living cells following manipulation of AKR1C3 by molecular intervention. (PMID:19162045)
• By western blot analysis, AKR1C3 is present in human liver obtained at autopsy. By western blot analysis, AKR1C3 is barely detectible in human brain obtained at autopsy. (PMID:19273550)
• AKR1C subfamily genes are stress-inducible and might function as survival factors in keratinocytes. (PMID:19320734)
• AKR1C3, through its ability to convert androstenedione to testosterone, is likely responsible for adrenal testosterone production. (PMID:19336506)
• There is no difference in catalytic properties between variants of 17beta-HSD types 7 and 12 and wild-type enzymes, while variants p.Glu77Gly and p.Lys183Arg in 17beta-HSD type 5 showed a slightly decreased activity. (PMID:19460435)
• AKR1C isoforms as a novel target of jasmonates in cancer cells. (PMID:19487289)
• The researchers found an increased risk of breast cancer in women with AKR1C3 who carried 1 or 2 alleles and who used estrogen-progesterone therapy. (PMID:19846565)
• AKR1C3 expression occurs in a Tanner stage dependent-fashion. Pre- and peri-pubertal changes appear to promote expression in Leydig cells. The pediatric cryptorchid testis reveals AKR1C3 expression in Sertoli cells (PMID:19942269)
• AKR1C3 expression increased steroid conversion by MCF-7 cells, leading to a pro-estrogenic state. Expression of AKR1C3 also reduced the anti-proliferative effects of PGD(2) on MCF-7 cells. (PMID:20036328)
• Data indicate that enzymes CYP17A1 and HSD3B1 showed low expression, while AKR1C3 and SRD5A1 were abundantly expressed. (PMID:20086173)
• Expression of AKR1C3 in renal cell carcinoma, papillary urothelial carcinoma, and Wilms tumor is reported. (PMID:20126582)
• A population level survey of AKR1C3 expression in 2,490 individual cases across 19 cancer types using tissue microarrays revealed marked upregulation of AKR1C3 in a subset. (PMID:20145130)
• These findings suggest that AKR1C3 may play important roles in the physiology of endometrial cells (PMID:20661409)

Cross-species orthologs

18 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:110366	ENSDARG00000004167
danio_rerio	akr1a1a	ENSDARG00000035257
danio_rerio	zgc:110782	ENSDARG00000044544
danio_rerio	zgc:101765	ENSDARG00000054934
danio_rerio	zgc:56622	ENSDARG00000099728
drosophila_melanogaster	CG6083	FBGN0036183
drosophila_melanogaster	CG18547	FBGN0037973
drosophila_melanogaster	CG3397	FBGN0037975
caenorhabditis_elegans		WBGENE00003176
caenorhabditis_elegans		WBGENE00009980
caenorhabditis_elegans		WBGENE00009981
caenorhabditis_elegans		WBGENE00012722
caenorhabditis_elegans		WBGENE00012723
caenorhabditis_elegans		WBGENE00015307
caenorhabditis_elegans		WBGENE00015564
caenorhabditis_elegans		WBGENE00015565
caenorhabditis_elegans		WBGENE00016985
caenorhabditis_elegans		WBGENE00022887

Paralogs (16): AKR7A2 (ENSG00000053371), KCNAB2 (ENSG00000069424), AKR1B1 (ENSG00000085662), AKR1A1 (ENSG00000117448), AKR1D1 (ENSG00000122787), AKR1C2 (ENSG00000151632), AKR7A3 (ENSG00000162482), AKR1E2 (ENSG00000165568), KCNAB1 (ENSG00000169282), KCNAB3 (ENSG00000170049), AKR1C1 (ENSG00000187134), AKR1B10 (ENSG00000198074), AKR1C4 (ENSG00000198610), AKR7L (ENSG00000211454), AKR1B15 (ENSG00000227471), AKR1C8 (ENSG00000264006)

Protein

Protein identifiers

Aldo-keto reductase family 1 member C3 — P42330 (reviewed: P42330)

Alternative names: 17-beta-hydroxysteroid dehydrogenase type 5, 3-alpha-HSD type II, brain, 3-alpha-hydroxysteroid dehydrogenase type 2, Chlordecone reductase homolog HAKRb, Dihydrodiol dehydrogenase 3, Dihydrodiol dehydrogenase type I, HA1753, Prostaglandin F synthase, Testosterone 17-beta-dehydrogenase 5

All UniProt accessions (4): A0A0A0MSS8, P42330, S4R3D5, S4R3Z2

UniProt curated annotations — full annotation on UniProt →

Function. Cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids. Displays broad substrate specificity with distinct positional and stereochemistry, primarily generating 17beta-hydroxysteroids, but also 3alpha- and 20alpha-hydroxysteroids. Produces potent androgens via classical and ‘backdoor’/alternative pathways. In the classical androgen metabolic pathway (biosynthesis of 5alpha-dihydrotestosterone (5alpha-DHT) via testosterone), catalyzes the reduction of delta4-androstenedione to form testosterone. In the ‘backdoor’ androgen metabolic pathway (biosynthesis of 5alpha-dihydrotestosterone (5alpha-DHT) via pregnanes), reduces androsterone to 5alpha-androstane-3alpha,17beta-diol preceding 5alpha-DHT secretion. Reduces 5alpha-DHT to less potent androgen 5alpha-androstane-3alpha,17beta-diol, likely regulating ligand availability for androgen receptors. May contribute to the metabolism of adrenal-derived androgen precursors. Reduces 11-keto-4-androstene-3,17-dione (11KA4) and 11-keto-5alpha-androstane-3,17-dione (11K-Adione) into potent androgens 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT), respectively. In estrogen metabolism, catalyzes the conversion of estrone to potent estrogen 17beta-estradiol. Acts as a prostaglandin (PG) F2alpha synthase. Displays 11-ketoreductase and 9,11-endoperoxide reductase activities and reduces PGD2 to 11beta-PGF2alpha and PGH2 to PGF2alpha. Also displays retinaldehyde reductase activity toward 9-cis-retinal. In vitro can efficiently catalyze bidirectional conversion between ketosteroids and hydroxysteroids using NADPH/NADP(+) or NADH/NAD(+) as cofactors. In vivo however, the reductase activity prevails since the major reducing cofactor NADPH inhibits NAD(+)-dependent oxidase activity. In addition, it is able to reduce in vitro various carbonyl compounds like menadione, phenanthrenequinone and nitrobenzaldehyde.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in many tissues including adrenal gland, brain, kidney, liver, lung, mammary gland, placenta, small intestine, colon, spleen, prostate and testis. High expression in prostate and mammary gland. In the prostate, higher levels in epithelial cells than in stromal cells. In the brain, expressed in medulla, spinal cord, frontotemporal lobes, thalamus, subthalamic nuclei and amygdala. Weaker expression in the hippocampus, substantia nigra and caudate.

Activity regulation. Strongly inhibited by nonsteroidal anti-inflammatory drugs (NSAID) including flufenamic acid and indomethacin. Also inhibited by the flavinoid, rutin, and by selective serotonin inhibitors (SSRIs). The oxidation reaction is inhibited by low micromolar concentrations of NADPH.

Similarity. Belongs to the aldo/keto reductase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P42330-1	1	yes
P42330-2	2

RefSeq proteins (2): NP_001240837, NP_003730* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018170	Aldo/ket_reductase_CS	Conserved_site
IPR020471	AKR	Family
IPR023210	NADP_OxRdtase_dom	Domain
IPR036812	NAD(P)_OxRdtase_dom_sf	Homologous_superfamily
IPR044482	AKR1C	Family

Pfam: PF00248

Enzyme classification (BRENDA):

• EC 1.1.1.188 — prostaglandin-F synthase (BRENDA: 15 organisms, 87 substrates, 86 inhibitors, 90 Km, 7 kcat entries)
• EC 1.1.1.21 — aldose reductase (BRENDA: 36 organisms, 259 substrates, 1272 inhibitors, 280 Km, 134 kcat entries)
• EC 1.1.1.213 — 3alpha-hydroxysteroid 3-dehydrogenase (Re-specific) (BRENDA: 8 organisms, 195 substrates, 114 inhibitors, 85 Km, 65 kcat entries)
• EC 1.1.1.239 — 3alpha(17beta)-hydroxysteroid dehydrogenase (NAD+) (BRENDA: 12 organisms, 141 substrates, 161 inhibitors, 146 Km, 115 kcat entries)
• EC 1.1.1.357 — 3alpha-hydroxysteroid 3-dehydrogenase (BRENDA: 8 organisms, 118 substrates, 31 inhibitors, 151 Km, 108 kcat entries)
• EC 1.1.1.51 — 3(or 17)beta-hydroxysteroid dehydrogenase (BRENDA: 18 organisms, 150 substrates, 207 inhibitors, 72 Km, 42 kcat entries)
• EC 1.1.1.62 — 17beta-estradiol 17-dehydrogenase (BRENDA: 20 organisms, 283 substrates, 790 inhibitors, 95 Km, 44 kcat entries)
• EC 1.1.1.64 — testosterone 17beta-dehydrogenase (NADP+) (BRENDA: 9 organisms, 60 substrates, 221 inhibitors, 29 Km, 1 kcat entries)
• EC 1.3.1.20 — trans-1,2-dihydrobenzene-1,2-diol dehydrogenase (BRENDA: 13 organisms, 160 substrates, 113 inhibitors, 105 Km, 72 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
DL-GLYCERALDEHYDE	0.02–730.2	42
D-XYLOSE	2–1340	21
PROSTAGLANDIN D2	0.003–2	13
PROSTAGLANDIN H2	0.0013–0.033	13
9,10-PHENANTHRENEQUINONE	0.0001–0.002	11
D-GALACTOSE	40–572	11
D-GLUCURONATE	0.152–19.2	11
D-GLUCOSE	47.3–281	10
PROSTAGLANDIN PGD2	0.015–0.18	9
NADPH	0.0032–85	8
4-NITROBENZALDEHYDE	0.0008–0.125	6
NADPH	0.0027–0.067	6
PROSTAGLANDIN PGH2	0.003–0.03	6
BENZALDEHYDE	0.0097–3.3	5
L-XYLOSE	100–1190	5

Catalyzed reactions (Rhea), 12 shown:

• prostaglandin F2alpha + NADP(+) = prostaglandin D2 + NADPH + H(+) (RHEA:10140)
• testosterone + NAD(+) = androst-4-ene-3,17-dione + NADH + H(+) (RHEA:14929)
• testosterone + NADP(+) = androst-4-ene-3,17-dione + NADPH + H(+) (RHEA:14981)
• 5alpha-androstane-3beta,17beta-diol + NADP(+) = 17beta-hydroxy-5alpha-androstan-3-one + NADPH + H(+) (RHEA:16297)
• 17beta-estradiol + NAD(+) = estrone + NADH + H(+) (RHEA:24612)
• 17beta-estradiol + NADP(+) = estrone + NADPH + H(+) (RHEA:24616)
• a 3alpha-hydroxysteroid + NADP(+) = a 3-oxosteroid + NADPH + H(+) (RHEA:34783)
• 5alpha-androstane-3alpha,17beta-diol + NAD(+) = 17beta-hydroxy-5alpha-androstan-3-one + NADH + H(+) (RHEA:42004)
• (20S)-hydroxypregn-4-en-3-one + NAD(+) = progesterone + NADH + H(+) (RHEA:42108)
• (20S)-hydroxypregn-4-en-3-one + NADP(+) = progesterone + NADPH + H(+) (RHEA:42112)
• 5alpha-androstane-3alpha,17beta-diol + NADP(+) = 17beta-hydroxy-5alpha-androstan-3-one + NADPH + H(+) (RHEA:42116)
• 5alpha-androstane-3alpha,17beta-diol + NAD(+) = androsterone + NADH + H(+) (RHEA:42124)

UniProt features (66 total): helix 20, binding site 11, strand 11, sequence conflict 7, sequence variant 6, site 4, mutagenesis site 3, chain 1, active site 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

67 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1S1P	X-RAY DIFFRACTION	1.2
1ZQ5	X-RAY DIFFRACTION	1.3
6F78	X-RAY DIFFRACTION	1.3
2FGB	X-RAY DIFFRACTION	1.35
8BBS	X-RAY DIFFRACTION	1.4
9JRP	X-RAY DIFFRACTION	1.49
4WDT	X-RAY DIFFRACTION	1.5
4XVE	X-RAY DIFFRACTION	1.55
4WRH	X-RAY DIFFRACTION	1.6
9JT5	X-RAY DIFFRACTION	1.62
4WDX	X-RAY DIFFRACTION	1.64
9JT4	X-RAY DIFFRACTION	1.64
3UGR	X-RAY DIFFRACTION	1.65
9JRU	X-RAY DIFFRACTION	1.67
3UWE	X-RAY DIFFRACTION	1.68
1RY0	X-RAY DIFFRACTION	1.69
1RY8	X-RAY DIFFRACTION	1.69
1S2A	X-RAY DIFFRACTION	1.7
4DZ5	X-RAY DIFFRACTION	1.7
4WDU	X-RAY DIFFRACTION	1.7
6GXK	X-RAY DIFFRACTION	1.7
7C7F	X-RAY DIFFRACTION	1.7
8RRJ	X-RAY DIFFRACTION	1.7
3UG8	X-RAY DIFFRACTION	1.73
9JT6	X-RAY DIFFRACTION	1.74
9FFD	X-RAY DIFFRACTION	1.75
3R8G	X-RAY DIFFRACTION	1.8
1S2C	X-RAY DIFFRACTION	1.8
4DBW	X-RAY DIFFRACTION	1.8
4DBS	X-RAY DIFFRACTION	1.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42330-F1	96.55	0.93

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 (5): 55 (proton donor); 54 (important for substrate specificity); 84 (lowers pka of active site tyr); 227 (involved in ligand recognition and product release); 306 (involved in ligand recognition and product release)

Ligand- & substrate-binding residues (11): 216–222; 270–272; 276–280; 23–24; 50; 55; 117; 128; 129; 166–167; 190

Mutagenesis-validated functional residues (3):

Position	Phenotype
75	no effect on 17beta-hsd activity.
226	decreases in the retinaldehyde reductase activity. 3-fold decrease in the kcat value, whereas the km value does not vary
226	decrease in the retinaldehyde reductase activity. exhibits changes in both km and kcat values.

Function

Pathways and Gene Ontology

Reactome pathways

20 pathways

ID	Pathway
R-HSA-193368	Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
R-HSA-193775	Synthesis of bile acids and bile salts via 24-hydroxycholesterol
R-HSA-193807	Synthesis of bile acids and bile salts via 27-hydroxycholesterol
R-HSA-2162123	Synthesis of Prostaglandins (PG) and Thromboxanes (TX)
R-HSA-5365859	RA biosynthesis pathway
R-HSA-975634	Retinoid metabolism and transport
R-HSA-1430728	Metabolism
R-HSA-162582	Signal Transduction
R-HSA-192105	Synthesis of bile acids and bile salts
R-HSA-194068	Bile acid and bile salt metabolism
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-2142753	Arachidonate metabolism
R-HSA-2187338	Visual phototransduction
R-HSA-5362517	Signaling by Retinoic Acid
R-HSA-556833	Metabolism of lipids
R-HSA-6806667	Metabolism of fat-soluble vitamins
R-HSA-8957322	Metabolism of steroids
R-HSA-8978868	Fatty acid metabolism
R-HSA-9006931	Signaling by Nuclear Receptors
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 422 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, MODULE_93, LI_CISPLATIN_RESISTANCE_DN, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, MODULE_52, GOBP_EPITHELIUM_DEVELOPMENT, JI_RESPONSE_TO_FSH_UP, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS, GOBP_RESPONSE_TO_CORTICOSTEROID, GOZGIT_ESR1_TARGETS_DN, GOBP_CELLULAR_RESPONSE_TO_PROSTAGLANDIN_STIMULUS, GOBP_C21_STEROID_HORMONE_METABOLIC_PROCESS

GO Biological Process (34): retinoid metabolic process (GO:0001523), prostaglandin metabolic process (GO:0006693), G protein-coupled receptor signaling pathway (GO:0007186), response to nutrient (GO:0007584), steroid metabolic process (GO:0008202), positive regulation of cell population proliferation (GO:0008284), male gonad development (GO:0008584), cellular response to starvation (GO:0009267), farnesol catabolic process (GO:0016488), keratinocyte differentiation (GO:0030216), progesterone metabolic process (GO:0042448), retinal metabolic process (GO:0042574), macromolecule metabolic process (GO:0043170), daunorubicin metabolic process (GO:0044597), doxorubicin metabolic process (GO:0044598), prostanoid biosynthetic process (GO:0046457), regulation of retinoic acid receptor signaling pathway (GO:0048385), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), testosterone biosynthetic process (GO:0061370), renal absorption (GO:0070293), cellular response to calcium ion (GO:0071277), cellular response to prostaglandin stimulus (GO:0071379), cellular response to corticosteroid stimulus (GO:0071384), cellular response to jasmonic acid stimulus (GO:0071395), cellular response to prostaglandin D stimulus (GO:0071799), negative regulation of retinoic acid biosynthetic process (GO:1900053), regulation of testosterone biosynthetic process (GO:2000224), positive regulation of endothelial cell apoptotic process (GO:2000353), positive regulation of reactive oxygen species metabolic process (GO:2000379), alcohol metabolic process (GO:0006066), lipid metabolic process (GO:0006629), monocarboxylic acid metabolic process (GO:0032787), hormone metabolic process (GO:0042445), retinol metabolic process (GO:0042572)

GO Molecular Function (25): retinal dehydrogenase (NAD+) activity (GO:0001758), aldose reductase (NADPH) activity (GO:0004032), estradiol 17-beta-dehydrogenase [NAD(P)+] activity (GO:0004303), all-trans-retinol dehydrogenase (NAD+) activity (GO:0004745), alcohol dehydrogenase (NADP+) activity (GO:0008106), oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor (GO:0016655), bile acid binding (GO:0032052), prostaglandin H2 endoperoxidase reductase activity (GO:0036130), prostaglandin D2 11-ketoreductase activity (GO:0036131), obsolete geranylgeranyl reductase activity (GO:0045550), ketoreductase activity (GO:0045703), prostaglandin F synthase activity (GO:0047017), 15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity (GO:0047020), androsterone dehydrogenase [NAD(P)+] activity (GO:0047023), 5-alpha-androstane-3-beta,17-beta-diol dehydrogenase (NADP+) activity (GO:0047024), testosterone dehydrogenase (NAD+) activity (GO:0047035), androstan-3-alpha,17-beta-diol dehydrogenase (NAD+) activity (GO:0047044), testosterone dehydrogenase (NADP+) activity (GO:0047045), ketosteroid monooxygenase activity (GO:0047086), Delta4-3-oxosteroid 5beta-reductase activity (GO:0047787), all-trans-retinol dehydrogenase (NADP+) activity (GO:0052650), 3-alpha-hydroxysteroid 3-dehydrogenase [NAD(P)+] activity (GO:0140169), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), obsolete testosterone dehydrogenase [NAD(P)+] activity (GO:0030283)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Synthesis of bile acids and bile salts	3
Metabolism	2
Metabolism of lipids	2
Arachidonate metabolism	1
Signaling by Retinoic Acid	1
Visual phototransduction	1
Metabolism of fat-soluble vitamins	1
Bile acid and bile salt metabolism	1
Metabolism of steroids	1
Fatty acid metabolism	1
Sensory Perception	1
Signaling by Nuclear Receptors	1
Metabolism of vitamins and cofactors	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
steroid dehydrogenase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	4
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	4
ketone metabolic process	3
prostanoid metabolic process	2
olefinic compound metabolic process	2
glycoside metabolic process	2
polyketide metabolic process	2
prostaglandin metabolic process	2
cellular anatomical structure	2
diterpenoid metabolic process	1
G protein-coupled receptor activity	1
signal transduction	1
response to nutrient levels	1
response to chemical	1
lipid metabolic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
gonad development	1
development of primary male sexual characteristics	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
polyprenol catabolic process	1
sesquiterpenoid catabolic process	1
farnesol metabolic process	1
primary alcohol catabolic process	1
epidermal cell differentiation	1
skin development	1
C21-steroid hormone metabolic process	1
retinoid metabolic process	1
aldehyde metabolic process	1
metabolic process	1
primary alcohol metabolic process	1
tertiary alcohol metabolic process	1
unsaturated fatty acid biosynthetic process	1
icosanoid biosynthetic process	1
retinoic acid receptor signaling pathway	1
regulation of intracellular signal transduction	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1

Protein interactions and networks

STRING

1672 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AKR1C3	DHRS9	Q9BPW9	926
AKR1C3	DHDH	Q9UQ10	899
AKR1C3	SRD5A1	P18405	863
AKR1C3	HSD17B3	P37058	858
AKR1C3	HSD17B2	P37059	816
AKR1C3	HSD3B2	P26439	815
AKR1C3	CYP17A1	P05093	804
AKR1C3	HSD17B6	O14756	786
AKR1C3	HSD17B1	P14061	729
AKR1C3	PTGFR	P43088	729
AKR1C3	DHRS11	Q6UWP2	727
AKR1C3	HSD3B1	P14060	714
AKR1C3	PTGES	O14684	705
AKR1C3	SRD5A2	P31213	702
AKR1C3	CBR1	P16152	673

IntAct

25 interactions, top by confidence:

A	B	Type	Score
MORF4L1	SIN3B	psi-mi:“MI:0914”(association)	0.730
AKR1C2	AKR1C4	psi-mi:“MI:0914”(association)	0.640
AKR1C3	AKR1C4	psi-mi:“MI:0914”(association)	0.620
AKR1C4	AKR1C3	psi-mi:“MI:0915”(physical association)	0.620
AKR1C2	AKR1C3	psi-mi:“MI:0914”(association)	0.530
AKR1C3	AKR1D1	psi-mi:“MI:0914”(association)	0.530
MAGEA11	AKR1C3	psi-mi:“MI:0915”(physical association)	0.370
AKR1C2	IPO8	psi-mi:“MI:0914”(association)	0.350
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
SRRT	A2ML1	psi-mi:“MI:0914”(association)	0.350
ATF2	PLOD2	psi-mi:“MI:0914”(association)	0.350
ATF3	ILVBL	psi-mi:“MI:0914”(association)	0.350
CEBPA	MYO1C	psi-mi:“MI:0914”(association)	0.350
CEBPD	PTGES	psi-mi:“MI:0914”(association)	0.350
ERBB2	DNM1L	psi-mi:“MI:0914”(association)	0.350
FOS	ILVBL	psi-mi:“MI:0914”(association)	0.350
MYC	AP3B1	psi-mi:“MI:0914”(association)	0.350
STAT3	IDH3B	psi-mi:“MI:0914”(association)	0.350
HUNK	AKR1C3	psi-mi:“MI:0915”(physical association)	0.000
AKR1C3	RIF1	psi-mi:“MI:0915”(physical association)	0.000
AKR1C3	ZHX1	psi-mi:“MI:0915”(physical association)	0.000
AKR1C3	UBE2W	psi-mi:“MI:0915”(physical association)	0.000
AKR1C3	ACIN1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (68): AKR1C3 (Affinity Capture-MS), AKR1C4 (Affinity Capture-MS), AKR1C1 (Affinity Capture-MS), AKR1D1 (Affinity Capture-MS), AKR1C3 (Two-hybrid), AKR1C3 (Affinity Capture-Western), AKR1C3 (Reconstituted Complex), AKR1C1 (Affinity Capture-MS), AKR1C4 (Affinity Capture-MS), AKR1C3 (Affinity Capture-MS), AKR1D1 (Affinity Capture-MS), AKR1C3 (Proximity Label-MS), AKR1C3 (Affinity Capture-MS), AKR1C3 (Synthetic Lethality), UBE2W (Two-hybrid)

ESM2 similar proteins: A6QP05, B0BNF8, B2GV72, O00764, O14756, O35331, O54753, O54909, O75452, O75828, O88451, P16152, P17516, P42330, P46597, P47727, P47844, P48758, P50170, P52895, P55006, P80508, Q04828, Q1XAA8, Q28960, Q3SZD7, Q3SZM9, Q3T001, Q3U0B3, Q3ZBV9, Q5R7C9, Q5RCU5, Q5REQ0, Q6SKR2, Q6UWP2, Q6W8P9, Q71R50, Q8C436, Q8HZJ0, Q8K183

Diamond homologs: A0A1D5XGW0, A0A1X9QHJ0, A0A2P1GIY9, A0A9E7S518, A0A9E7S5B9, B4F9A4, B9VRJ2, C9JRZ8, D3ZF77, E7C196, H9JTG9, M9PF61, O08782, O32210, O34678, O49133, O60218, O70473, O80944, P02532, P05980, P07943, P0DKI7, P0DXG9, P0DXH7, P14065, P14550, P15121, P15122, P16116, P17264, P17516, P21300, P23457, P23901, P26690, P28475, P31867, P42330, P45376

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AR	“down-regulates quantity by repression”	AKR1C3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	61
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1077184	Single allele	Pathogenic
1330170	GRCh37/hg19 10p15.3-15.1(chr10:60501-5238964)x1	Pathogenic

SpliceAI

808 predictions. Top by Δscore:

Variant	Effect	Δscore
10:5096573:CAAAG:C	donor_loss	1.0000
10:5096574:AAAGG:A	donor_loss	1.0000
10:5096575:AAGGT:A	donor_loss	1.0000
10:5096576:AGG:A	donor_loss	1.0000
10:5096578:G:GA	donor_loss	1.0000
10:5096579:T:A	donor_loss	1.0000
10:5097432:A:AG	acceptor_gain	1.0000
10:5097433:G:GA	acceptor_gain	1.0000
10:5097433:GCT:G	acceptor_gain	1.0000
10:5097433:GCTTT:G	acceptor_gain	1.0000
10:5097506:GAC:G	donor_gain	1.0000
10:5097546:TAAAG:T	donor_loss	1.0000
10:5097547:AAAG:A	donor_loss	1.0000
10:5097548:AAGG:A	donor_loss	1.0000
10:5097551:G:GA	donor_loss	1.0000
10:5097552:T:A	donor_loss	1.0000
10:5099323:A:AG	acceptor_gain	1.0000
10:5099325:A:AG	acceptor_gain	1.0000
10:5099325:A:AT	acceptor_loss	1.0000
10:5099325:AG:A	acceptor_gain	1.0000
10:5099326:G:GT	acceptor_gain	1.0000
10:5099326:GG:G	acceptor_gain	1.0000
10:5099326:GGC:G	acceptor_gain	1.0000
10:5099326:GGCC:G	acceptor_gain	1.0000
10:5099326:GGCCA:G	acceptor_gain	1.0000
10:5099445:ACCAG:A	donor_gain	1.0000
10:5099446:CCAG:C	donor_gain	1.0000
10:5099447:CAG:C	donor_gain	1.0000
10:5099448:AG:A	donor_gain	1.0000
10:5099448:AGGTG:A	donor_loss	1.0000

AlphaMissense

2123 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:5098876:G:C	W148C	0.990
10:5098876:G:T	W148C	0.990
10:5098874:T:A	W148R	0.988
10:5098874:T:C	W148R	0.988
10:5096563:T:C	F80L	0.987
10:5096565:C:A	F80L	0.987
10:5096565:C:G	F80L	0.987
10:5096577:G:C	K84N	0.987
10:5096577:G:T	K84N	0.987
10:5099381:T:C	F168L	0.983
10:5099383:C:A	F168L	0.983
10:5099383:C:G	F168L	0.983
10:5105611:T:C	L288S	0.983
10:5097519:T:C	L113P	0.980
10:5102592:G:C	R263P	0.980
10:5102577:G:C	R258P	0.979
10:5096461:T:C	F46L	0.978
10:5096463:C:A	F46L	0.978
10:5096463:C:G	F46L	0.978
10:5099375:T:C	S166P	0.978
10:5099363:T:C	S162P	0.977
10:5102615:A:C	S271R	0.977
10:5102617:C:A	S271R	0.977
10:5102617:C:G	S271R	0.977
10:5096475:T:A	D50E	0.976
10:5096475:T:G	D50E	0.976
10:5096447:C:A	A41E	0.973
10:5096576:A:C	K84T	0.973
10:5097525:T:C	L115P	0.969
10:5099370:G:A	G164E	0.968

dbSNP variants (sampled 300 via entrez): RS1000231105 (10:5052165 C>G), RS1000272588 (10:5093110 A>C), RS1000304598 (10:5046917 G>T), RS1000317134 (10:5060443 G>A), RS1000347162 (10:5056056 C>T), RS1000402638 (10:5097907 T>C,G), RS1000449365 (10:5056324 T>A), RS1000531978 (10:5078779 C>T), RS1000544125 (10:5073428 G>A), RS1000664961 (10:5087531 C>T), RS1000672876 (10:5047086 G>A), RS1000908564 (10:5059499 G>C,T), RS1000983637 (10:5073725 C>G), RS1001100180 (10:5067561 A>C), RS1001218767 (10:5078606 G>A)

Disease associations

OMIM: gene MIM:603966 | disease phenotypes: MIM:618652

GenCC curated gene-disease

Mondo (3): hypotensive disorder (MONDO:0005468), neurooculocardiogenitourinary syndrome (MONDO:0032850), prostate cancer (MONDO:0008315)

Orphanet (2): Neurooculocardiogenitourinary syndrome (Orphanet:684305), Familial prostate cancer (Orphanet:1331)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0002615	Hypotension

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009008_4	Epithelial ovarian cancer	5.000000e-07
GCST011981_10	Homeostasis model assessment of insulin resistance	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004501	HOMA-IR

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007022	Hypotension	C14.907.514
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4681 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

22 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,385,028 (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
CHEMBL1034	DICLOFENAC SODIUM	4	45,460
CHEMBL12	DIAZEPAM	4	92,281
CHEMBL1200963	BIMATOPROST	4	11,007
CHEMBL1481	GLIMEPIRIDE	4	33,335
CHEMBL154	NAPROXEN	4	136,434
CHEMBL175	DEXIBUPROFEN	4	12,118
CHEMBL295124	BERBERINE	4	26,682
CHEMBL427216	GLICLAZIDE	4	22,353
CHEMBL509	MECLOFENAMIC ACID	4	45,809
CHEMBL521	IBUPROFEN	4	228,490
CHEMBL563	FLURBIPROFEN	4	71,809
CHEMBL6	INDOMETHACIN	4	156,366
CHEMBL686	MEFENAMIC ACID	4	61,835
CHEMBL717	MEDROXYPROGESTERONE ACETATE	4	51,452
CHEMBL2017974	BUPARLISIB	3	6,568
CHEMBL2103840	DINACICLIB	3	2,257
CHEMBL121626	TOLFENAMIC ACID	2	20,424
CHEMBL2107254	CLOXAZOLAM	2	2,356
CHEMBL23588	FLUFENAMIC ACID	2	34,797
CHEMBL267476	LINOLEIC ACID	2	323,195
CHEMBL23832	FENAMIC ACID	1
CHEMBL4513510	ASP-9521	1

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1937840	Efficacy	3	docetaxel;doxorubicin	Breast Neoplasms
rs1937840	Other	3	doxorubicin	Breast Neoplasms
rs62621365	Metabolism/PK	3	exemestane

PharmGKB variants

7 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12529	AKR1C3		0.00	0
rs1937840	AKR1C3	3	3.00	2	doxorubicin;docetaxel;doxorubicin
rs62621365	AKR1C3	3	0.00	1	exemestane
rs4987102	AKR1C3		0.00	0
rs35575889	AKR1C3		0.00	0
rs34186955	AKR1C3		0.00	0
rs28943579	AKR1C3		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Prostaglandin synthases

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
tolfenamic acid	Inhibition	8.1	pKi
RJG-2051	Inhibition	7.46	pIC50
compound 1 [Lolli et al., 2019]	Inhibition	6.52	pIC50

Binding affinities (BindingDB)

199 measured of 213 human assays (213 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-[methyl-[(8S,9S,13S,14S)-13-methyl-17-(6-methylpyridazin-4-yl)-6,7,8,9,11,12,14,15-octahydrocyclopenta[a]phenanthrene-3-carbonyl]amino]propanoic acid	IC50	0.5 nM	US-9487554: Estra-1,3,5(10),16-tetraene-3-carboxamide derivatives, processes for their preparation, pharmaceutical preparations comprising them and their use for preparing medicaments
[8-(3-bromophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	0.5 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(5-bromo-2-methylphenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	0.5 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2-chloro-5-fluorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	0.5 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2,5-dichlorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	0.6 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2,3-dihydro-1-benzofuran-7-ylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	0.6 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2-bromophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	0.7 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
sodium 5-({8-[(3,5-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}carbonyl)-1,2,3-triazol-1-ide	IC50	0.7 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
(3R)-3-[[(8S,9S,13S,14S)-17-(5-fluoro-3-pyridinyl)-13-methyl-6,7,8,9,11,12,14,15-octahydrocyclopenta[a]phenanthrene-3-carbonyl]amino]butanoic acid	IC50	0.8 nM	US-9487554: Estra-1,3,5(10),16-tetraene-3-carboxamide derivatives, processes for their preparation, pharmaceutical preparations comprising them and their use for preparing medicaments
[8-(2-chloro-6-methylphenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	0.8 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2,3-dichlorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	0.8 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2-chloro-3-fluorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	0.8 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(3,5-dichlorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	0.9 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(3-chloro-2-fluorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	0.9 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
2H-triazol-4-yl-[8-[3-(trifluoromethyl)phenyl]sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone	IC50	0.9 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2-nitrophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	0.9 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2-chloro-4-fluorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	0.9 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(1,3-benzodioxol-5-ylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	0.9 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
2H-triazol-4-yl-[8-[2-(trifluoromethyl)phenyl]sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone	IC50	1 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(3,5-dimethylphenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(3-methoxyphenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2-methoxy-4-methylphenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(5-chlorothiophen-2-yl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.1 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2,5-difluorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.1 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2,5-dimethylphenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.1 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(3-chloro-2-methylphenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.1 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
2H-triazol-4-yl-[8-[2-(trifluoromethoxy)phenyl]sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone	IC50	1.1 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(3,4-dichlorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.1 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(4-fluoro-2-methoxyphenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.1 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
sodium 5-({8-[(3-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}carbonyl)-1,2,3-triazol-1-ide	IC50	1.1 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
(3S)-3-[[(8S,9S,13S,14S)-17-(5-fluoro-3-pyridinyl)-13-methyl-6,7,8,9,11,12,14,15-octahydrocyclopenta[a]phenanthrene-3-carbonyl]amino]butanoic acid	IC50	1.2 nM	US-9487554: Estra-1,3,5(10),16-tetraene-3-carboxamide derivatives, processes for their preparation, pharmaceutical preparations comprising them and their use for preparing medicaments
[8-(3-fluorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.2 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(3-chlorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(triazolidin-4-yl)methanone	IC50	1.2 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(3-chloro-4-fluorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.2 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(4-ethylphenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.2 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(1,3-dihydro-2,1,3-benzothiadiazol-4-ylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.2 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2,1,3-benzothiadiazol-5-ylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.2 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
3-[[(8S,9S,13S,14S)-17-(5-fluoro-3-pyridinyl)-13-methyl-6,7,8,9,11,12,14,15-octahydrocyclopenta[a]phenanthrene-3-carbonyl]-methylamino]propanoic acid	IC50	1.3 nM	US-9487554: Estra-1,3,5(10),16-tetraene-3-carboxamide derivatives, processes for their preparation, pharmaceutical preparations comprising them and their use for preparing medicaments
[8-[3-(pentafluoro-lambda6-sulfanyl)phenyl]sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(triazolidin-4-yl)methanone	IC50	1.3 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
(8-naphthalen-1-ylsulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-(2H-triazol-4-yl)methanone	IC50	1.3 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2-methoxyphenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.3 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
2-chloro-6-[[3-(2H-triazole-4-carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]sulfonyl]benzonitrile	IC50	1.3 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
4-[[[(8S,9S,13S,14S)-17-(5-fluoro-3-pyridinyl)-13-methyl-6,7,8,9,11,12,14,15-octahydrocyclopenta[a]phenanthrene-3-carbonyl]amino]methyl]oxane-4-carboxylic acid	IC50	1.4 nM	US-9487554: Estra-1,3,5(10),16-tetraene-3-carboxamide derivatives, processes for their preparation, pharmaceutical preparations comprising them and their use for preparing medicaments
2-[[(8S,9S,13S,14S)-13-methyl-17-(6-methylpyridazin-4-yl)-6,7,8,9,11,12,14,15-octahydrocyclopenta[a]phenanthren-3-yl]oxy]acetic acid	IC50	1.4 nM	US-9512169: 3-substituted estra-1,3,5(10),16-tetraene derivatives, methods for the production thereof, pharmaceutical preparations containing same, and use thereof for the production of medicaments
[8-(3,5-difluorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.4 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2-chlorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(triazolidin-4-yl)methanone	IC50	1.4 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(3-methylphenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.4 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
2H-triazol-4-yl-[8-(2,4,6-trimethylphenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone	IC50	1.4 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
2H-triazol-4-yl-[8-(2,4,6-trichlorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone	IC50	1.4 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones
[8-(2-fluorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone	IC50	1.5 nM	US-10167293: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-ylmethanones

ChEMBL bioactivities

1269 potent at pChembl≥5 of 1370 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.47	IC50	0.34	nM	CHEMBL2413849
9.30	IC50	0.5	nM	CHEMBL4110932
9.30	IC50	0.5	nM	CHEMBL5823188
9.30	IC50	0.5	nM	CHEMBL5821749
9.30	IC50	0.5	nM	CHEMBL5830459
9.22	IC50	0.6	nM	CHEMBL6057463
9.22	IC50	0.6	nM	CHEMBL5780480
9.15	IC50	0.7	nM	CHEMBL5937799
9.15	IC50	0.7	nM	CHEMBL5861450
9.10	IC50	0.8	nM	CHEMBL4113242
9.10	IC50	0.8	nM	CHEMBL6018327
9.10	IC50	0.8	nM	CHEMBL6047517
9.10	IC50	0.8	nM	CHEMBL5936044
9.05	IC50	0.9	nM	CHEMBL5802431
9.05	IC50	0.9	nM	CHEMBL5929250
9.05	IC50	0.9	nM	CHEMBL5831697
9.05	IC50	0.9	nM	CHEMBL6062917
9.05	IC50	0.9	nM	CHEMBL5953328
9.05	IC50	0.9	nM	CHEMBL5784368
9.00	IC50	1	nM	CHEMBL5928563
9.00	IC50	1	nM	CHEMBL5984967
9.00	IC50	1	nM	CHEMBL5799029
9.00	IC50	1	nM	CHEMBL5770395
8.96	IC50	1.1	nM	CHEMBL5758553
8.96	IC50	1.1	nM	CHEMBL5768217
8.96	IC50	1.1	nM	CHEMBL5953684
8.96	IC50	1.1	nM	CHEMBL5870645
8.96	IC50	1.1	nM	CHEMBL5987454
8.96	IC50	1.1	nM	CHEMBL6049557
8.96	IC50	1.1	nM	CHEMBL5827959
8.96	IC50	1.1	nM	CHEMBL5915814
8.92	IC50	1.2	nM	CHEMBL3914633
8.92	IC50	1.2	nM	CHEMBL5915814
8.92	IC50	1.2	nM	CHEMBL6062231
8.92	IC50	1.2	nM	CHEMBL5877194
8.92	IC50	1.2	nM	CHEMBL5984813
8.92	IC50	1.2	nM	CHEMBL5992358
8.92	IC50	1.2	nM	CHEMBL5963454
8.89	IC50	1.3	nM	CHEMBL4108488
8.89	IC50	1.3	nM	CHEMBL5964045
8.89	IC50	1.3	nM	CHEMBL5956106
8.89	IC50	1.3	nM	CHEMBL5899327
8.89	IC50	1.3	nM	CHEMBL5740798
8.85	IC50	1.4	nM	CHEMBL4110197
8.85	IC50	1.4	nM	CHEMBL4108488
8.85	IC50	1.4	nM	CHEMBL5861450
8.85	IC50	1.4	nM	CHEMBL6043065
8.85	IC50	1.4	nM	CHEMBL5861563
8.85	IC50	1.4	nM	CHEMBL5828348
8.85	IC50	1.4	nM	CHEMBL5830090

PubChem BioAssay actives

963 with measured affinity, of 1511 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-(2-hydroxy-2-methylpropyl)piperidin-1-yl]-(5-methyl-1H-indol-2-yl)methanone	764524: Inhibition of human 17beta-HSD5 expressed in HEK293 cells using androstenedione as substrate assessed as testosterone synthesis after 4 hrs	ic50	0.0003	uM
3-[[(8S,9S,13S,14S)-17-(5-fluoro-3-pyridinyl)-13-methyl-6,7,8,9,11,12,14,15-octahydrocyclopenta[a]phenanthrene-3-carbonyl]-methylamino]propanoic acid	1997735: Inhibition of AKR1C3 (unknown origin)	ic50	0.0018	uM
[4-(2-hydroxy-2-methylpropyl)piperidin-1-yl]-(1H-indol-2-yl)methanone	764524: Inhibition of human 17beta-HSD5 expressed in HEK293 cells using androstenedione as substrate assessed as testosterone synthesis after 4 hrs	ic50	0.0021	uM
2-[4-(3-fluoro-4-methylphenyl)-3-(trifluoromethyl)phenyl]butanoic acid	1997375: Inhibition of human recombinant AKR1C3 transfected in Escherichia coli BL21 (DE3) pLysS competent cells using S-tetralol as substrate assessed as inhibition of NADP+ dependent substrate oxidation incubated for 10 mins by fluorescence microplate reader assay	ic50	0.0029	uM
(8R,9S,13S,14S,17R)-3’,3’,13-trimethylspiro[7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17,6’-oxane]-2’-one	417690: Inhibition of human 17beta-HSD5 expressed in HEK293 cells assessed as enzyme-mediated transformation of [14C]-4-androstene-3,17-dione in to [14C]-testosterone after 18 hrs	ic50	0.0029	uM
N-(2-chlorophenyl)-2-[(3,5-dimethyl-1,2-oxazol-4-yl)methoxy]benzamide	2002778: Inhibition of C-terminal His tagged AKR1C3 (unknown origin) expressed in Escherichia coli incubated for 10 mins by fluorometric analysis	ic50	0.0030	uM
[4-(2,4-dichlorophenyl)piperazin-1-yl]-morpholin-4-ylmethanone	1064706: Inhibition of AKR1C3 (unknown origin) expressed in human HCT116 cells assessed as formation of PR-104H from PR-104A preincubated for 2 hrs	ic50	0.0030	uM
(8R,9S,13S,14S,17R)-5’,5’,13-trimethyl-6’-oxospiro[7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17,2’-oxane]-3-carboxamide	360690: Inhibition of human 17beta HSD5 in HEK cells	ic50	0.0032	uM
(13S,17R)-5’,5’,13-trimethyl-6’-oxospiro[7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17,2’-oxane]-3-carboxamide	1797610: Scintillation Proximity Assay (SPA) from Article 10.1074/jbc.m606784200: “Structure-based inhibitor design for an enzyme that binds different steroids: a potent inhibitor for human type 5 17beta-hydroxysteroid dehydrogenase.”	ic50	0.0032	uM
1-[4-(3,5-dichlorophenyl)-3-fluorophenyl]cyclopropane-1-carboxylic acid	1997375: Inhibition of human recombinant AKR1C3 transfected in Escherichia coli BL21 (DE3) pLysS competent cells using S-tetralol as substrate assessed as inhibition of NADP+ dependent substrate oxidation incubated for 10 mins by fluorescence microplate reader assay	ic50	0.0038	uM
3-[4-(3,5-dichlorophenyl)-3-(trifluoromethyl)phenyl]pentan-2-one	1997375: Inhibition of human recombinant AKR1C3 transfected in Escherichia coli BL21 (DE3) pLysS competent cells using S-tetralol as substrate assessed as inhibition of NADP+ dependent substrate oxidation incubated for 10 mins by fluorescence microplate reader assay	ic50	0.0038	uM
[4-(2-hydroxyethyl)piperidin-1-yl]-(1H-indol-2-yl)methanone	764524: Inhibition of human 17beta-HSD5 expressed in HEK293 cells using androstenedione as substrate assessed as testosterone synthesis after 4 hrs	ic50	0.0045	uM
3-[(6-bromo-3,4-dihydro-1H-isoquinolin-2-yl)sulfonyl]benzoic acid	1328857: Inhibition of human recombinant His-tagged AKR1C3 expressed in Escherichia coli BL21 (DE3) cells using 8-Acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-aza-benzo[de]anthracen-10-one as substrate after 1 hr in presence of NADPH by fluorescence assay	ic50	0.0060	uM
(8R,9S,13S,14S,17R)-3’,13-dimethylspiro[7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17,6’-oxane]-2’-one	417690: Inhibition of human 17beta-HSD5 expressed in HEK293 cells assessed as enzyme-mediated transformation of [14C]-4-androstene-3,17-dione in to [14C]-testosterone after 18 hrs	ic50	0.0061	uM
2-(3-chloro-2-methylanilino)benzoic acid	664572: Inhibition of human AKR1C3 using S-(+)-1,2,3,4-tetrahydro-1-naphthol as substrate	ki	0.0080	uM
3-[(3-methyl-3,4-dihydro-1H-isoquinolin-2-yl)sulfonyl]benzoic acid	1328857: Inhibition of human recombinant His-tagged AKR1C3 expressed in Escherichia coli BL21 (DE3) cells using 8-Acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-aza-benzo[de]anthracen-10-one as substrate after 1 hr in presence of NADPH by fluorescence assay	ic50	0.0085	uM
3-[(6-chloro-3,4-dihydro-1H-isoquinolin-2-yl)sulfonyl]benzoic acid	1328857: Inhibition of human recombinant His-tagged AKR1C3 expressed in Escherichia coli BL21 (DE3) cells using 8-Acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-aza-benzo[de]anthracen-10-one as substrate after 1 hr in presence of NADPH by fluorescence assay	ic50	0.0087	uM
2-[(3,5-dimethyl-1,2-oxazol-4-yl)methoxy]-N-(2-methoxyphenyl)benzamide	2002778: Inhibition of C-terminal His tagged AKR1C3 (unknown origin) expressed in Escherichia coli incubated for 10 mins by fluorometric analysis	ic50	0.0089	uM
3-[(5-nitro-3,4-dihydro-1H-isoquinolin-2-yl)sulfonyl]benzoic acid	1328857: Inhibition of human recombinant His-tagged AKR1C3 expressed in Escherichia coli BL21 (DE3) cells using 8-Acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-aza-benzo[de]anthracen-10-one as substrate after 1 hr in presence of NADPH by fluorescence assay	ic50	0.0089	uM
amino (13S,17R)-3-(2-methoxyethoxy)-5’,5’,13-trimethyl-6’-oxospiro[7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17,2’-oxane]-2-carboxylate	1797610: Scintillation Proximity Assay (SPA) from Article 10.1074/jbc.m606784200: “Structure-based inhibitor design for an enzyme that binds different steroids: a potent inhibitor for human type 5 17beta-hydroxysteroid dehydrogenase.”	ic50	0.0095	uM
[(8R,9S,13S,14S,17R)-3-(2-methoxyethoxy)-5’,5’,13-trimethyl-6’-oxospiro[7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17,2’-oxane]-2-yl] carbamate	360690: Inhibition of human 17beta HSD5 in HEK cells	ic50	0.0095	uM
2-[3-(2H-tetrazol-5-yl)phenyl]sulfonyl-3,4-dihydro-1H-isoquinoline	703400: Inhibition of human recombinant N-terminal His6-tagged AKR1C3 expressed in Escherichia coli BL21(DE3) cells using 8-Acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-aza-benzo[de]anthracen-10-one as substrate after 1 hr by fluorimetric analysis	ic50	0.0095	uM
[4-(2-hydroxy-2-methylpropyl)piperidin-1-yl]-(5-methoxy-1H-indol-2-yl)methanone	1997736: Inhibition of human AKR1C3	ic50	0.0100	uM
(8R,9S,13S,14S,17S)-13-methylspiro[7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17,6’-oxane]-2’-one	417690: Inhibition of human 17beta-HSD5 expressed in HEK293 cells assessed as enzyme-mediated transformation of [14C]-4-androstene-3,17-dione in to [14C]-testosterone after 18 hrs	ic50	0.0100	uM
[4-(4-iodophenyl)piperazin-1-yl]-morpholin-4-ylmethanone	1064706: Inhibition of AKR1C3 (unknown origin) expressed in human HCT116 cells assessed as formation of PR-104H from PR-104A preincubated for 2 hrs	ic50	0.0100	uM
1-[4-[3,5-bis(trifluoromethyl)phenyl]-3-fluorophenyl]cyclopropane-1-carboxylic acid	1997375: Inhibition of human recombinant AKR1C3 transfected in Escherichia coli BL21 (DE3) pLysS competent cells using S-tetralol as substrate assessed as inhibition of NADP+ dependent substrate oxidation incubated for 10 mins by fluorescence microplate reader assay	ic50	0.0107	uM
1-[4-(2-methylpiperidin-1-yl)sulfonylphenyl]pyrrolidin-2-one	729950: Inhibition of recombinant AKR1C3 (unknown origin) overexpressed in human HCT116 cells assessed as inhibition of aerobic reduction of dinitrobenzamide PR-104A to its hydroxylamine metabolite by LC-MS/MS assay	ic50	0.0110	uM
3-[(5-bromo-3,4-dihydro-1H-isoquinolin-2-yl)sulfonyl]benzoic acid	1328857: Inhibition of human recombinant His-tagged AKR1C3 expressed in Escherichia coli BL21 (DE3) cells using 8-Acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-aza-benzo[de]anthracen-10-one as substrate after 1 hr in presence of NADPH by fluorescence assay	ic50	0.0110	uM
3-[(5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)sulfonyl]benzoic acid	1328857: Inhibition of human recombinant His-tagged AKR1C3 expressed in Escherichia coli BL21 (DE3) cells using 8-Acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-aza-benzo[de]anthracen-10-one as substrate after 1 hr in presence of NADPH by fluorescence assay	ic50	0.0110	uM
2-[(3,5-dimethyl-1,2-oxazol-4-yl)methoxy]-5-methoxy-N-phenylbenzamide	2002778: Inhibition of C-terminal His tagged AKR1C3 (unknown origin) expressed in Escherichia coli incubated for 10 mins by fluorometric analysis	ic50	0.0115	uM
[4-(2-hydroxypropyl)piperidin-1-yl]-(1H-indol-2-yl)methanone	764524: Inhibition of human 17beta-HSD5 expressed in HEK293 cells using androstenedione as substrate assessed as testosterone synthesis after 4 hrs	ic50	0.0120	uM
3-[(7-bromo-3,4-dihydro-1H-isoquinolin-2-yl)sulfonyl]benzoic acid	1328857: Inhibition of human recombinant His-tagged AKR1C3 expressed in Escherichia coli BL21 (DE3) cells using 8-Acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-aza-benzo[de]anthracen-10-one as substrate after 1 hr in presence of NADPH by fluorescence assay	ic50	0.0120	uM
[4-(4-bromophenyl)piperazin-1-yl]-morpholin-4-ylmethanone	1064706: Inhibition of AKR1C3 (unknown origin) expressed in human HCT116 cells assessed as formation of PR-104H from PR-104A preincubated for 2 hrs	ic50	0.0120	uM
3-(1,2,3,4-tetrahydronaphthalen-2-ylsulfonyl)benzoic acid	1328857: Inhibition of human recombinant His-tagged AKR1C3 expressed in Escherichia coli BL21 (DE3) cells using 8-Acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-aza-benzo[de]anthracen-10-one as substrate after 1 hr in presence of NADPH by fluorescence assay	ic50	0.0129	uM
3-[(7-methyl-3,4-dihydro-1H-isoquinolin-2-yl)sulfonyl]benzoic acid	1328857: Inhibition of human recombinant His-tagged AKR1C3 expressed in Escherichia coli BL21 (DE3) cells using 8-Acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-aza-benzo[de]anthracen-10-one as substrate after 1 hr in presence of NADPH by fluorescence assay	ic50	0.0129	uM
3-(3,4-dihydro-1H-isoquinolin-2-ylsulfonyl)-N-methylbenzamide	703395: Inhibition of AKR1C3 overexpressed in human HCT116 cells assessed as inhibition of PR-104A conversion to hydroxylamine after 2 hrs by spectrophotometric analysis	ic50	0.0130	uM
[3-(3,4-dihydro-1H-isoquinolin-2-ylsulfonyl)phenyl]-morpholin-4-ylmethanone	703395: Inhibition of AKR1C3 overexpressed in human HCT116 cells assessed as inhibition of PR-104A conversion to hydroxylamine after 2 hrs by spectrophotometric analysis	ic50	0.0130	uM
(8R,9S,13S,14S,17R)-3-(2-methoxyethoxy)-5’,5’,13-trimethyl-6’-oxospiro[7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17,2’-oxane]-2-carbonitrile	360690: Inhibition of human 17beta HSD5 in HEK cells	ic50	0.0130	uM
3-(3,4-dihydro-1H-isoquinolin-2-ylsulfonyl)benzoic acid	703400: Inhibition of human recombinant N-terminal His6-tagged AKR1C3 expressed in Escherichia coli BL21(DE3) cells using 8-Acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-aza-benzo[de]anthracen-10-one as substrate after 1 hr by fluorimetric analysis	ic50	0.0130	uM
1-[1-(1H-indole-2-carbonyl)piperidin-4-yl]propan-2-one	764524: Inhibition of human 17beta-HSD5 expressed in HEK293 cells using androstenedione as substrate assessed as testosterone synthesis after 4 hrs	ic50	0.0130	uM
[4-(4-chloro-2-methylphenyl)piperazin-1-yl]-morpholin-4-ylmethanone	1064706: Inhibition of AKR1C3 (unknown origin) expressed in human HCT116 cells assessed as formation of PR-104H from PR-104A preincubated for 2 hrs	ic50	0.0130	uM
[4-[4-chloro-2-(hydroxymethyl)phenyl]piperazin-1-yl]-morpholin-4-ylmethanone	1064706: Inhibition of AKR1C3 (unknown origin) expressed in human HCT116 cells assessed as formation of PR-104H from PR-104A preincubated for 2 hrs	ic50	0.0130	uM
(13S,17R)-3-(2-methoxyethoxy)-5’,5’,13-trimethyl-6’-oxospiro[7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17,2’-oxane]-2-carbonitrile	1797610: Scintillation Proximity Assay (SPA) from Article 10.1074/jbc.m606784200: “Structure-based inhibitor design for an enzyme that binds different steroids: a potent inhibitor for human type 5 17beta-hydroxysteroid dehydrogenase.”	ic50	0.0130	uM
2-[4-(3,4-difluorophenyl)-3-methylphenyl]propanoic acid	1997375: Inhibition of human recombinant AKR1C3 transfected in Escherichia coli BL21 (DE3) pLysS competent cells using S-tetralol as substrate assessed as inhibition of NADP+ dependent substrate oxidation incubated for 10 mins by fluorescence microplate reader assay	ic50	0.0133	uM
2-[4-[3,5-bis(trifluoromethyl)phenyl]-3-methoxyphenyl]propanoic acid	1997375: Inhibition of human recombinant AKR1C3 transfected in Escherichia coli BL21 (DE3) pLysS competent cells using S-tetralol as substrate assessed as inhibition of NADP+ dependent substrate oxidation incubated for 10 mins by fluorescence microplate reader assay	ic50	0.0135	uM
3-(3,4-dihydro-1H-isoquinolin-2-ylsulfonyl)-N,N-dimethylbenzamide	703395: Inhibition of AKR1C3 overexpressed in human HCT116 cells assessed as inhibition of PR-104A conversion to hydroxylamine after 2 hrs by spectrophotometric analysis	ic50	0.0140	uM
3-[(7-iodo-3,4-dihydro-1H-isoquinolin-2-yl)sulfonyl]benzoic acid	1328857: Inhibition of human recombinant His-tagged AKR1C3 expressed in Escherichia coli BL21 (DE3) cells using 8-Acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-aza-benzo[de]anthracen-10-one as substrate after 1 hr in presence of NADPH by fluorescence assay	ic50	0.0140	uM
3-[(5-iodo-3,4-dihydro-1H-isoquinolin-2-yl)sulfonyl]benzoic acid	1328857: Inhibition of human recombinant His-tagged AKR1C3 expressed in Escherichia coli BL21 (DE3) cells using 8-Acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-aza-benzo[de]anthracen-10-one as substrate after 1 hr in presence of NADPH by fluorescence assay	ic50	0.0140	uM
1-[3-fluoro-4-(3-fluoro-4-methylphenyl)phenyl]cyclopropane-1-carboxylic acid	1997375: Inhibition of human recombinant AKR1C3 transfected in Escherichia coli BL21 (DE3) pLysS competent cells using S-tetralol as substrate assessed as inhibition of NADP+ dependent substrate oxidation incubated for 10 mins by fluorescence microplate reader assay	ic50	0.0143	uM
1-[4-(3-methylpiperidin-1-yl)sulfonylphenyl]pyrrolidin-2-one	729950: Inhibition of recombinant AKR1C3 (unknown origin) overexpressed in human HCT116 cells assessed as inhibition of aerobic reduction of dinitrobenzamide PR-104A to its hydroxylamine metabolite by LC-MS/MS assay	ic50	0.0150	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, increases reaction, increases response to substance, increases stability	13
Valproic Acid	increases expression, affects expression, decreases methylation, affects cotreatment	10
Benzo(a)pyrene	increases expression, increases reaction, decreases expression, affects cotreatment, decreases reaction	7
Tobacco Smoke Pollution	affects expression, increases expression	7
9,10-phenanthrenequinone	affects activity, decreases reaction, increases expression, increases metabolic processing, increases reduction (+1 more)	6
Cadmium	increases abundance, increases expression	6
Daunorubicin	decreases activity, increases response to substance, decreases response to substance, increases metabolic processing, increases abundance (+2 more)	6
Arsenic Trioxide	decreases response to substance, affects binding, decreases reaction, increases expression	5
Estradiol	affects cotreatment, increases expression, decreases expression, increases chemical synthesis, increases metabolic processing (+1 more)	5
Indomethacin	increases expression, decreases reaction, increases metabolic processing, increases reduction, decreases activity (+2 more)	5
Particulate Matter	increases abundance, increases expression, affects cotreatment, affects expression, increases reaction	5
daunorubicinol	increases chemical synthesis, increases abundance, increases metabolic processing, increases reduction, decreases reaction	4
Flufenamic Acid	affects binding, affects response to substance, decreases reaction, increases metabolic processing, decreases activity	4
Progesterone	increases chemical synthesis, increases reduction, decreases expression, increases expression, increases metabolic processing	4
Medroxyprogesterone Acetate	affects cotreatment, decreases reaction, increases reduction, increases abundance, increases metabolic processing (+1 more)	4
Cadmium Chloride	increases abundance, increases expression	4
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	3
Androstenedione	increases metabolic processing, increases chemical synthesis, increases reduction, decreases reaction	3
Arsenic	increases expression, increases reaction, increases response to substance, increases stability, increases abundance	3
Vehicle Emissions	affects expression, increases reaction, affects cotreatment, increases expression, increases abundance	3
20-alpha-Dihydroprogesterone	increases reduction, increases chemical synthesis, increases metabolic processing	3
Doxorubicin	affects reduction, increases metabolic processing, decreases expression	3
Meclofenamic Acid	decreases activity	3
NADP	increases oxidation, increases reduction, decreases reaction, increases reaction, affects activity (+1 more)	3
Testosterone	increases abundance, increases chemical synthesis, increases metabolic processing, increases reduction	3
Tretinoin	affects binding, decreases activity, decreases reaction, increases metabolic processing, increases abundance (+2 more)	3
Prostaglandin D2	decreases chemical synthesis, decreases response to substance, decreases metabolic processing, increases metabolic processing, increases reduction (+3 more)	3
beta-Naphthoflavone	increases expression	3
cloxazolam	decreases activity	2
bisphenol A	affects expression, increases methylation	2

ChEMBL screening assays

204 unique, capped per target: 197 binding, 7 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004012	Binding	Inhibition of human 17beta HSD5 mediated conversion of testosterone to delta-4-androstene-3,17-dione	Structure-based inhibitor design for an enzyme that binds different steroids: a potent inhibitor for human type 5 17beta-hydroxysteroid dehydrogenase. — J Biol Chem
CHEMBL3527795	ADMET	Drug metabolism in human recombinant AKR1C2 expressing HEK293 cells treated with 20 uM boceprevir assessed as 100 uM flufenamic acid-mediated inhibition of AKR1C3-mediated metabolite formation after 120 mins in presence of NADPH by LC-MS/MS	Characterization of human liver enzymes involved in the biotransformation of boceprevir, a hepatitis C virus protease inhibitor. — Drug Metab Dispos

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00115726	PHASE4	COMPLETED	Trial Assessing the Effect of Preoperative Furosemide on Intraoperative Blood Pressure
NCT00173706	PHASE4	UNKNOWN	Evaluation of the Effects of L-Carnitine Injection in Patients Undergoing Hemodialysis
NCT00694343	PHASE4	COMPLETED	Efficacy of Voluven® for the Prevention of Hypotension During Spinal Anesthesia for Cesarean Section
NCT00777166	PHASE4	COMPLETED	Cardiac Effects of Oxytocin Administrated During Cesarean Section, Signs of Myocardial Ischemia
NCT00781157	PHASE4	COMPLETED	Phenylephrine for Spinal Induced Hypotension
NCT00846651	PHASE4	COMPLETED	Spinal Anesthesia Induced Hypotension During Cesarean Section
NCT00922844	PHASE4	TERMINATED	The Effect of Sevoflurane Versus Isoflurane on Vasopressor Need
NCT00991627	PHASE4	COMPLETED	Different Approaches to Maternal Hypotension During Cesarean Section
NCT00996190	PHASE4	COMPLETED	Best Regimen for Phenylephrine Administration During Cesarean Section
NCT01067391	PHASE4	COMPLETED	Effect of Tadalafil (Cialis) on the Cardiovascular System of Spinal Cord Injury (SCI) Males
NCT01414842	PHASE4	COMPLETED	HFR A-equilibrium on Cardiovascular Stability
NCT01415284	PHASE4	UNKNOWN	ED50 Determination of Hydroxyethylstarch for Treatment of Hypotension During Cesarean Section Under Spinal Anesthesia
NCT01418118	PHASE4	COMPLETED	Assessment of the Effects of Pressors on Graft Blood Flow After Free Tissue Transfer Surgery
NCT01481740	PHASE4	COMPLETED	Preventing Hypotension in Parturients With an Elevated Body Mass Index (BMI)
NCT01549223	PHASE4	COMPLETED	Oxytocin And Uterotonic Agent Use For Cesarean Delivery
NCT02004834	PHASE4	ACTIVE_NOT_RECRUITING	Levobupivacaine and Lidocaine for Paravertebral Block Causes Greater Hemodynamic Oscillations Than Levobupivacaine
NCT02135146	PHASE4	COMPLETED	Evaluating Fluid Strategies in Thoracic Surgery Patients Utilizing a Goal Directed Approach
NCT02323399	PHASE4	RECRUITING	Study to Determine the Pharmacokinetics and Pharmacodynamic Effects of Phenylephrine on BP Via IV
NCT02393196	PHASE4	UNKNOWN	Colloid Preload Versus Colloid Coload During Cesarean Deliveries
NCT02477501	PHASE4	COMPLETED	Ephedrine vs. Nor Epinephrine Infusion in Preventing Hypotension After Spinal Anesthesia for Cesarean Section
NCT02737813	PHASE4	COMPLETED	Cardiac Output Changes During Hyperbaric and Isobaric Bupivacaine in Patients Undergoing Cesarean Section
NCT02771158	PHASE4	WITHDRAWN	Midodrine During Recovery From Septic Shock
NCT02802683	PHASE4	COMPLETED	Hemodynamic Impact of Hyperbaric Versus Isobaric for Spinal Anesthesia During Cesarean Delivery
NCT02854787	PHASE4	COMPLETED	Intravenous Bolus of Phenylephrine vs. Norepinephrine in Preventing Hypotension After Spinal Anesthesia
NCT02913768	PHASE4	COMPLETED	Reduction in Spinal-induced Hypotension With Ondansetron in Parturients Undergoing Caesarean Section
NCT02969239	PHASE4	UNKNOWN	Norepinephrine and Phenylephrine for Maternal Cardiac Output During Spinal Anesthesia for Elective Cesarean Delivery
NCT03595319	PHASE4	UNKNOWN	Median Sevoflurane Concentration for Hypotension Between Young and Elderlypatients: Adaptive Clinical Trial
NCT03602014	PHASE4	COMPLETED	Dose Response to the Norepinephrine Precursor Droxidopa in Hypotensive Individuals With Spinal Cord Injury
NCT03664037	PHASE4	COMPLETED	Dexamethasone Blunts the Hypotensive Effect of Spinal Anesthesia in Geriatric Patients Undergoing Lower Limb Orthopedic Surgeries
NCT03704909	PHASE4	COMPLETED	Manging Post Spinal Hypotension During Elective Cesarean Section
NCT03706755	PHASE4	COMPLETED	Comparison of Two Doses of Norepinephrine in Preventing Hypotension After Spinal Anesthesia
NCT03973411	PHASE4	UNKNOWN	Ondansetron in the Prevention of Hypotension in Patients Undergoing Spinal Anesthesia
NCT04529005	PHASE4	COMPLETED	Angiotensin II in the Perioperative Management of Hypotension in Kidney Transplant Recipients
NCT04575675	PHASE4	COMPLETED	Dapagliflozin on Hypotensive Heart Failure Patients After Sacubitril/Valsartan Therapy
NCT04701190	PHASE4	COMPLETED	Different Noradrenaline Protocols in Post Spinal Hypotension in CS
NCT04705896	PHASE4	RECRUITING	Albumin To Enhance Recovery After Acute Kidney Injury
NCT04789330	PHASE4	COMPLETED	Norepinephrine vs Phenylephrine During General Anesthesia
NCT04908592	PHASE4	COMPLETED	Efficacy of Dexamethasone in Attenuation of Postinduction Hypotension in Geriatric Patients Undergoing General Anesthesia
NCT05166330	PHASE4	UNKNOWN	Two Ratios of Propofol-ketamine Admixture for Rapid-sequence Induction Anesthesia for Emergency Laparotomy
NCT05248932	PHASE4	COMPLETED	Norepinephrine to Prevent Hypotension in Ceasrean Delivery