AKR1C4

Summary

AKR1C4 (aldo-keto reductase family 1 member C4, HGNC:387) is a protein-coding gene on chromosome 10p15.1, encoding Aldo-keto reductase family 1 member C4 (P17516). 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 bioreduction of chlordecone, a toxic organochlorine pesticide, to chlordecone alcohol in liver. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14.

Source: NCBI Gene 1109 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency (Limited, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 112 total
• Phenotypes (HPO): 5
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001818

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:387
Approved symbol	AKR1C4
Name	aldo-keto reductase family 1 member C4
Location	10p15.1
Locus type	gene with protein product
Status	Approved
Aliases	DD4, HAKRA, C11, 3-alpha-HSD, CDR, MGC22581
Ensembl gene	ENSG00000198610
Ensembl biotype	protein_coding
OMIM	600451
Entrez	1109

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 retained_intron

ENST00000263126, ENST00000380448, ENST00000469875, ENST00000901610, ENST00000901611, ENST00000901612, ENST00000901613, ENST00000901614, ENST00000901615, ENST00000901616, ENST00000901617, ENST00000901618

RefSeq mRNA: 1 — MANE Select: NM_001818 NM_001818

CCDS: CCDS7064

Canonical transcript exons

ENST00000263126 — 9 exons

Exon	Start	End
ENSE00001132431	5196837	5196951
ENSE00003889104	5205757	5205834
ENSE00003889504	5212994	5213159
ENSE00003889838	5218718	5218949
ENSE00003890732	5206275	5206397
ENSE00003890890	5212616	5212725
ENSE00003891315	5216711	5216793
ENSE00003891457	5200181	5200348
ENSE00003893277	5204377	5204493

Expression profiles

Bgee: expression breadth broad, 74 present calls, max score 98.35.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6426 / max 259.5265, expressed in 15 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
103625	0.6426	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.35	gold quality
liver	UBERON:0002107	96.30	gold quality
gall bladder	UBERON:0002110	88.20	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.35	gold quality
islet of Langerhans	UBERON:0000006	63.75	gold quality
duodenum	UBERON:0002114	58.67	gold quality
jejunal mucosa	UBERON:0000399	58.17	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	57.03	gold quality
lower lobe of lung	UBERON:0008949	53.80	silver quality
granulocyte	CL:0000094	53.46	gold quality
nasal cavity epithelium	UBERON:0005384	52.58	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
quadriceps femoris	UBERON:0001377	50.16	gold quality
jejunum	UBERON:0002115	50.02	silver quality
vastus lateralis	UBERON:0001379	49.45	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
thymus	UBERON:0002370	49.12	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
epithelial cell of pancreas	CL:0000083	48.90	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
ileal mucosa	UBERON:0000331	48.68	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	31.30
E-ANND-3	no	2.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF1A, HNF1B, HNF4A, HNF4G, NR0B1, NR1H3

miRNA regulators (miRDB)

22 targeting AKR1C4, 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-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-3160-5P	99.28	69.07	1938
HSA-MIR-520E-5P	99.27	68.90	1513
HSA-MIR-422A	99.18	65.83	550
HSA-MIR-7153-3P	99.00	65.35	608
HSA-MIR-378A-3P	98.43	66.10	548
HSA-MIR-378B	98.43	65.36	573
HSA-MIR-378C	98.43	66.10	548
HSA-MIR-378D	98.43	66.10	548
HSA-MIR-378E	98.43	65.99	551
HSA-MIR-378F	98.43	65.66	554
HSA-MIR-378H	98.43	66.16	545
HSA-MIR-378I	98.43	66.10	548
HSA-MIR-338-3P	98.14	67.38	1137
HSA-MIR-4638-3P	97.90	65.75	905
HSA-MIR-1226-3P	97.51	66.32	1063
HSA-MIR-3619-3P	95.59	65.99	428

Literature-anchored findings (GeneRIF, showing 9)

• Taken together, we conclude that the cell-type-specific expression of DD4 mRNA is regulated by vHNF-1-C. (PMID:12220531)
• the expression level of DD4 mRNA is cooperatively regulated by the amounts of HNF-1 alpha, HNF-4 alpha and HNF-4 gamma. (PMID:12544512)
• Impact of mirtazapine on the activity of a key neurosteroidogenic enzyme, the 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD), and on the levels of neuroactive steroids in relation to clinical response in depression. (PMID:16344854)
• Structure determination of human AKR1C4 and homology modelling of AKR1D1 followed by docking experiments were used to explore active site geometries. (PMID:19013211)
• role of AKR1C4 in the metabolism of testosterone and progesterone via the 5beta-reductase pathway. (PMID:21521174)
• Low progesterone levels and a cystine to serine change at position 145 in AKR1C4 gene are associated with manic/hypomanic irritability in males (PMID:21570127)
• In women only, SNPs in AKR1C4 reduced the likelihood of having exhibited paranoid ideation by circa 60%. (PMID:22356824)
• Studies indicate that mutations in aldo-keto reductase family 1 (AKR1) enzymes AKR1C1 and AKR1C4 are responsible for sexual development dysgenesis and mutations in AKR1D1 are causative in bile-acid deficiency. (PMID:24189185)
• the present study suggests that AKR1C1, AKR1C2, AKR1C3, and AKR1C4 are closely associated with drug resistance to both CDDP and 5FU, and that mefenamic acid, an inhibitor of AKR1C, restores sensitivity through inhibition of drug-resistance in human cancer cells. (PMID:28259989)

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), AKR1C3 (ENSG00000196139), AKR1B10 (ENSG00000198074), AKR7L (ENSG00000211454), AKR1B15 (ENSG00000227471), AKR1C8 (ENSG00000264006)

Protein

Protein identifiers

Aldo-keto reductase family 1 member C4 — P17516 (reviewed: P17516)

Alternative names: 3-alpha-hydroxysteroid 3-dehydrogenase type I, Chlordecone reductase, Dihydrodiol dehydrogenase 4, HAKRA

All UniProt accessions (1): P17516

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 3alpha/beta-, 17beta- and 20alpha-hydroxysteroids. Required for male sex determination as a component of the ‘backdoor’ androgen biosynthesis pathway that generates 5alpha-dihydrotestosterone (5alpha-DHT) via pregnanes. Acts together with AKR1C2 to convert 5alpha-dihydroprogesterone (5alpha-DHP) to 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP/allopregnanolone), leading to 5alpha-DHT secretion necessary for embryonic gonad differentiation into testis. May regulate the concentrations of circulating neurosteroids. Reduces 5alpha-dihydroprogesterone (5-alpha-DHP) and 5alpha-dihydrodeoxycorticosterone (5-alpha-DHDOC) precursors to 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP/allopregnanolone) and 3alpha,21-dihydroxy-5alpha-pregnane-20-one (3alpha,5alpha-THDOC) neuroactive steroids known to alter neural excitability via allosteric activation of gamma-aminobutyric acid type A receptors (GABAAR). Regulates ligand availability for steroid hormone receptors. Catalyzes the inactivation of 5alpha-DHT and progesterone converting them into 3alpha/beta-androstanediols and (20S)-hydroxypregn-4-en-3-one, respectively. May contribute to the metabolism of adrenal-derived androgens via reduction of 11-keto-5alpha-androstane-3,17-dione (11K-Adione) into 11-ketoandrosterone (11KAST) and of 11-ketodihydrotestosterone (11KDHT) into 11-keto-5alpha-androstane-3alpha/beta,17beta-diol (11K-A3diol). Catalyzes the reduction of estrone into 17beta-estradiol but with low efficiency. In androgen catabolism, may predominantly act as a phase I enzyme by introducing a hydroxyl group prior to conjugation. It can nevertheless participate in the alternative phase II pathway by directly reducing sulfate- or glucuronide-conjugated androgens. Catalyzes the biotransformation of the pesticide chlordecone (kepone) to its corresponding alcohol, leading to increased biliary excretion of the pesticide and concomitant reduction of its neurotoxicity since bile is the major excretory route. 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.

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Expressed in liver. Expressed in fetal and adult testes and adrenal glands.

Post-translational modifications. The N-terminus is blocked.

Disease relevance. 46,XY sex reversal 8 (SRXY8) [MIM:614279] A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. The gene represented in this entry may act as a disease modifier. A splicing mutation resulting in loss of AKR1C4 exon 2 has been found in affected individuals carrying a causative mutation in AKR1C2. These patients manifest a more severe disease phenotype than individuals only carrying mutations in AKR1C2.

Activity regulation. Inhibited by nonsteroidal the anti-inflammatory drugs (NSAID) flufenamic. The oxidation reaction is inhibited by low micromolar concentrations of NADPH.

Pathway. Steroid metabolism.

Polymorphism. The allele with Cys-145/Val-311 shows a three- to five-fold decrease in catalytic efficiency for xenobiotic and steroidal substrates compared to the Ser-145/Leu-311 allele.

Similarity. Belongs to the aldo/keto reductase family.

RefSeq proteins (1): NP_001809* (*=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 1.1.1.357 — 3alpha-hydroxysteroid 3-dehydrogenase (BRENDA: 8 organisms, 118 substrates, 31 inhibitors, 151 Km, 108 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
CHOLIC ACID	0.025–586	10
ANDROSTERONE	0.0005–14	8
NAD+	0.081–1.2	8
5ALPHA-DIHYDROTESTOSTERONE	0.0012–0.071	7
DIHYDROTESTOSTERONE	0.0011–0.016	7
NADP+	0.0002–0.017	7
(S)-INDAN-1-OL	0.146–0.52	5
5BETA-ANDROSTAN-3ALPHA-OL-17-ONE	0.0006–0.0021	5
4-HYDROXYANDROSTENEDIONE	0.0023–0.0336	4
NADPH	0.0001–0.009	4
(R)-TETRALOL	0.16–0.68	3
(S)-TETRALOL	0.11–0.29	3
2-DECALOL	0.16–1.7	3
4-HYDROXYTESTOSTERONE	0.006–0.0269	3
5ALPHA-ANDROSTANE-3ALPHA,17BETA-DIOL	0.0008–0.0031	3

Catalyzed reactions (Rhea), 12 shown:

• chlordecone alcohol + NADP(+) = chlordecone + NADPH + H(+) (RHEA:14401)
• 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)
• androsterone + NADP(+) = 5alpha-androstan-3,17-dione + NADPH + H(+) (RHEA:20377)
• 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)

UniProt features (43 total): helix 17, strand 11, binding site 6, sequence variant 5, chain 1, active site 1, turn 1, site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2FVL	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17516-F1	96.83	0.96

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 (2): 55 (proton donor); 84 (lowers pka of active site tyr)

Ligand- & substrate-binding residues (6): 20–24; 50; 166–167; 190; 216–221; 270–280

Function

Pathways and Gene Ontology

Reactome pathways

13 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-975634	Retinoid metabolism and transport
R-HSA-1430728	Metabolism
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-2187338	Visual phototransduction
R-HSA-556833	Metabolism of lipids
R-HSA-6806667	Metabolism of fat-soluble vitamins
R-HSA-8957322	Metabolism of steroids
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 170 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_C21_STEROID_HORMONE_METABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_KETONE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_BILE_ACID_BIOSYNTHETIC_PROCESS, GOMF_STEROID_DEHYDROGENASE_ACTIVITY_ACTING_ON_THE_CH_OH_GROUP_OF_DONORS_NAD_OR_NADP_AS_ACCEPTOR, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS

GO Biological Process (14): retinoid metabolic process (GO:0001523), prostaglandin metabolic process (GO:0006693), bile acid biosynthetic process (GO:0006699), steroid metabolic process (GO:0008202), androgen metabolic process (GO:0008209), bile acid and bile salt transport (GO:0015721), progesterone metabolic process (GO:0042448), daunorubicin metabolic process (GO:0044597), doxorubicin metabolic process (GO:0044598), cellular response to jasmonic acid stimulus (GO:0071395), alcohol metabolic process (GO:0006066), lipid metabolic process (GO:0006629), monocarboxylic acid metabolic process (GO:0032787), hormone metabolic process (GO:0042445)

GO Molecular Function (19): retinal dehydrogenase (NAD+) activity (GO:0001758), aldose reductase (NADPH) activity (GO:0004032), estradiol 17-beta-dehydrogenase [NAD(P)+] activity (GO:0004303), alcohol dehydrogenase (NADP+) activity (GO:0008106), electron transfer activity (GO:0009055), bile acid transmembrane transporter activity (GO:0015125), oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor (GO:0016655), bile acid binding (GO:0032052), 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), chlordecone reductase activity (GO:0047743), 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 (3): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Synthesis of bile acids and bile salts	3
Metabolism	2
Visual phototransduction	1
Metabolism of fat-soluble vitamins	1
Bile acid and bile salt metabolism	1
Metabolism of steroids	1
Sensory Perception	1
Metabolism of vitamins and cofactors	1
Metabolism of lipids	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	5
ketone metabolic process	3
glycoside metabolic process	2
polyketide metabolic process	2
cellular anatomical structure	2
diterpenoid metabolic process	1
prostanoid metabolic process	1
bile acid metabolic process	1
monocarboxylic acid biosynthetic process	1
lipid metabolic process	1
steroid metabolic process	1
hormone metabolic process	1
lipid transport	1
monocarboxylic acid transport	1
organic hydroxy compound transport	1
C21-steroid hormone metabolic process	1
olefinic compound metabolic process	1
primary alcohol metabolic process	1
tertiary alcohol metabolic process	1
response to jasmonic acid	1
cellular response to hormone stimulus	1
cellular response to fatty acid	1
small molecule metabolic process	1
primary metabolic process	1
carboxylic acid metabolic process	1
metabolic process	1
regulation of hormone levels	1
aldehyde dehydrogenase (NAD+) activity	1
alcohol dehydrogenase (NADP+) activity	1
alcohol dehydrogenase [NAD(P)+] activity	1
molecular_function	1
bile acid and bile salt transport	1
carboxylic acid transmembrane transporter activity	1
lipid transmembrane transporter activity	1
oxidoreductase activity, acting on NAD(P)H	1
monocarboxylic acid binding	1
17-beta-hydroxysteroid dehydrogenase (NAD+) activity	1
17-beta-hydroxysteroid dehydrogenase (NADP+) activity	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen	1
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	1

Protein interactions and networks

STRING

1152 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AKR1C4	DHRS9	Q9BPW9	945
AKR1C4	DHDH	Q9UQ10	925
AKR1C4	HSD3B2	P26439	677
AKR1C4	SRD5A3	Q9H8P0	638
AKR1C4	SRD5A1	P18405	623
AKR1C4	SRD5A2	P31213	587
AKR1C4	HSD17B6	O14756	579
AKR1C4	UBR5	O95071	576
AKR1C4	HSD3B7	Q9H2F3	565
AKR1C4	AKR7A2	O43488	544
AKR1C4	CBR1	P16152	522
AKR1C4	HSD17B1	P14061	520
AKR1C4	HSD17B3	P37058	514
AKR1C4	HSD3B1	P14060	507
AKR1C4	DHRS11	Q6UWP2	471

IntAct

13 interactions, top by confidence:

A	B	Type	Score
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
AKR1C4	PLXDC2	psi-mi:“MI:0915”(physical association)	0.590
TMEM59	B4GALT5	psi-mi:“MI:0914”(association)	0.530
AKR1C2	IPO8	psi-mi:“MI:0914”(association)	0.350
AKR1C2	BRD4	psi-mi:“MI:0914”(association)	0.350
BMP4	A2ML1	psi-mi:“MI:0914”(association)	0.350
HOXB6	ANKHD1-EIF4EBP3	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (15): AKR1C4 (Affinity Capture-MS), AKR1C4 (Affinity Capture-MS), PLXDC2 (Affinity Capture-MS), AKR1C4 (Affinity Capture-MS), AKR1C4 (Affinity Capture-MS), PLXDC2 (Affinity Capture-MS), AKR1C4 (Affinity Capture-MS), AKR1C4 (Affinity Capture-MS), PLXDC2 (Affinity Capture-MS), AKR1C4 (Affinity Capture-MS), AKR1C3 (Affinity Capture-MS), AKR1C4 (Affinity Capture-MS), AKR1C1 (Cross-Linking-MS (XL-MS)), AKR1C2 (Cross-Linking-MS (XL-MS)), AKR1C4 (Affinity Capture-Luminescence)

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

4 interactions.

A	Effect	B	Mechanism
HNF1B	“up-regulates quantity by expression”	AKR1C4	“transcriptional regulation”
HNF1A	“up-regulates quantity by expression”	AKR1C4	“transcriptional regulation”
HNF4G	“up-regulates quantity by expression”	AKR1C4	“transcriptional regulation”
HNF4A	“up-regulates quantity by expression”	AKR1C4	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	37
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

1746 predictions. Top by Δscore:

Variant	Effect	Δscore
10:5200345:AAAG:A	donor_loss	1.0000
10:5200346:AAG:A	donor_loss	1.0000
10:5200347:AGGT:A	donor_loss	1.0000
10:5200349:G:GA	donor_loss	1.0000
10:5200350:T:A	donor_loss	1.0000
10:5206271:CCAGG:C	acceptor_loss	1.0000
10:5206272:CAGGT:C	acceptor_loss	1.0000
10:5206273:A:AG	acceptor_gain	1.0000
10:5206273:A:C	acceptor_loss	1.0000
10:5206274:G:A	acceptor_loss	1.0000
10:5206274:G:GG	acceptor_gain	1.0000
10:5206274:GGTC:G	acceptor_gain	1.0000
10:5206394:CCAGG:C	donor_loss	1.0000
10:5206395:CAGGT:C	donor_loss	1.0000
10:5206396:AGG:A	donor_loss	1.0000
10:5206398:G:GA	donor_loss	1.0000
10:5206398:G:GG	donor_gain	1.0000
10:5206399:T:G	donor_loss	1.0000
10:5212603:T:A	acceptor_gain	1.0000
10:5212742:G:GT	donor_gain	1.0000
10:5216794:G:GG	donor_gain	1.0000
10:5197312:TTG:T	donor_gain	0.9900
10:5197448:A:AG	donor_gain	0.9900
10:5200175:CTTCA:C	acceptor_loss	0.9900
10:5200176:TTCA:T	acceptor_loss	0.9900
10:5200177:TCAGG:T	acceptor_loss	0.9900
10:5200178:CAG:C	acceptor_loss	0.9900
10:5200179:AGGTT:A	acceptor_loss	0.9900
10:5200180:G:GT	acceptor_loss	0.9900
10:5206273:AG:A	acceptor_gain	0.9900

AlphaMissense

2124 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:5200334:T:C	F80L	0.979
10:5200336:C:A	F80L	0.979
10:5200336:C:G	F80L	0.979
10:5205829:T:A	W148R	0.979
10:5205829:T:C	W148R	0.979
10:5200348:G:C	K84N	0.978
10:5200348:G:T	K84N	0.978
10:5205831:G:C	W148C	0.973
10:5205831:G:T	W148C	0.973
10:5213124:A:C	S271R	0.970
10:5213126:C:A	S271R	0.970
10:5213126:C:G	S271R	0.970
10:5200232:T:C	F46L	0.969
10:5200234:C:A	F46L	0.969
10:5200234:C:G	F46L	0.969
10:5200246:T:A	D50E	0.968
10:5200246:T:G	D50E	0.968
10:5213101:G:C	R263P	0.968
10:5204380:T:A	W86R	0.963
10:5204380:T:C	W86R	0.963
10:5204462:T:C	L113P	0.963
10:5216727:T:C	L288S	0.962
10:5206329:T:C	F168L	0.961
10:5206331:C:A	F168L	0.961
10:5206331:C:G	F168L	0.961
10:5218743:T:C	F319L	0.960
10:5218745:T:A	F319L	0.960
10:5218745:T:G	F319L	0.960
10:5200218:C:A	A41E	0.959
10:5200245:A:T	D50V	0.959

dbSNP variants (sampled 300 via entrez): RS1000011130 (10:5195192 C>T), RS1000210221 (10:5205105 C>T), RS1000286930 (10:5199883 C>T), RS1000338697 (10:5199730 C>T), RS1000854992 (10:5219382 A>G), RS1000907437 (10:5219167 T>G), RS1001027595 (10:5208866 A>G), RS1001483972 (10:5209790 C>T), RS1001640788 (10:5215141 A>G), RS1001887240 (10:5199450 C>T), RS1002371846 (10:5213705 T>C), RS1002476314 (10:5218890 G>A,C), RS1002783244 (10:5208813 C>A,T), RS1002951058 (10:5197991 C>A,T), RS1003133681 (10:5203327 A>G)

Disease associations

OMIM: gene MIM:600451 | disease phenotypes: MIM:614279

GenCC curated gene-disease

Disease	Classification	Inheritance
46,XY disorder of sex development due to testicular 17,20-desmolase deficiency	Limited	Autosomal recessive

Mondo (2): hypotensive disorder (MONDO:0005468), 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency (MONDO:0013664)

Orphanet (1): 46,XY difference of sex development due to testicular 17,20-desmolase deficiency (Orphanet:443087)

HPO phenotypes

5 total (6 of 5 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000037	Male pseudohermaphroditism
HP:0000062	Ambiguous genitalia
HP:0012245	Sex reversal
HP:0002615	Hypotension

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST002216_19	Triglycerides	2.000000e-12
GCST004237_42	Triglyceride levels	1.000000e-14
GCST008156_80	Hip circumference adjusted for BMI	6.000000e-06
GCST009364_45	Triglyceride levels x long total sleep time interaction (2df test)	3.000000e-11
GCST010083_44	Hemoglobin levels	1.000000e-11
GCST010173_117	Triglyceride levels	2.000000e-12
GCST010241_4	Apolipoprotein A1 levels	1.000000e-19
GCST010244_273	Triglyceride levels	3.000000e-16
GCST012491_1	Menarche (age at onset)	3.000000e-09
GCST90000025_391	Appendicular lean mass	4.000000e-12
GCST90002383_478	Hematocrit	5.000000e-11
GCST90002384_181	Hemoglobin	5.000000e-11
GCST90011900_48	Serum alkaline phosphatase levels	5.000000e-13
GCST90013406_228	Liver enzyme levels (alkaline phosphatase)	2.000000e-21

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004509	hemoglobin measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004703	age at menarche
EFO:0004980	appendicular lean mass
EFO:0004348	hematocrit
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007022	Hypotension	C14.907.514
C564109	Male Pseudohermaphroditism due to Deficiency of Testicular 17,20-Desmolase (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4999 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 228,175 (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
CHEMBL563	FLURBIPROFEN	4	71,809
CHEMBL6	INDOMETHACIN	4	156,366

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11253043	Metabolism/PK	3	exemestane
rs17134592	Metabolism/PK	3	naltrexone
rs3829125	Metabolism/PK	3	naltrexone

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11253043	AKR1C4	3	0.00	1	exemestane
rs17134592	AKR1C4	3	0.00	1	naltrexone
rs3829125	AKR1C4	3	0.00	1	naltrexone

Binding affinities (BindingDB)

11 measured of 22 human assays (22 total across all organisms); most potent 11 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-[1-(4-chlorobenzoyl)-5-methoxy-3-methylindol-2-yl]propanoic acid	IC50	17.7 nM	US-9346803: Indomethacin analogs for the treatment of castrate-resistant prostate cancer
3-[1-(4-chlorobenzoyl)-3-ethyl-5-methoxyindol-2-yl]propanoic acid	IC50	30.7 nM	US-9346803: Indomethacin analogs for the treatment of castrate-resistant prostate cancer
3,5-dichloro-2-hydroxybenzoic acid	KI	58 nM
9-(4-chlorobenzoyl)-6-methoxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid	IC50	76.2 nM	US-9346803: Indomethacin analogs for the treatment of castrate-resistant prostate cancer
3-[1-(4-chlorobenzoyl)-5-methoxy-3-methylindol-2-yl]-N-methylsulfonylpropanamide	IC50	100 nM	US-9346803: Indomethacin analogs for the treatment of castrate-resistant prostate cancer
2-[1-[4-(chloromethyl)benzoyl]-5-methoxy-2-methylindol-3-yl]acetic acid	IC50	100 nM	US-9346803: Indomethacin analogs for the treatment of castrate-resistant prostate cancer
4-acetyl-2-(2-carboxyanilino)benzoic acid	IC50	27700 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
3-[N-(4-chlorophenyl)amino]benzoic acid	IC50	30200 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
3-[N-(4-acetylphenyl)amino]benzoic acid	IC50	38600 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
2-(5-methoxy-2-nitroanilino)benzoic acid	IC50	42700 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
2-[2-nitro-5-(trifluoromethyl)anilino]benzoic acid	IC50	50000 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof

ChEMBL bioactivities

68 potent at pChembl≥5 of 122 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.30	IC50	49.75	nM	CHEMBL2323472
7.05	IC50	90	nM	CHEMBL6171622
6.66	IC50	220	nM	CHEMBL6175015
6.62	IC50	240	nM	CHEMBL6150439
6.52	IC50	300	nM	CHEMBL6165313
6.51	IC50	310	nM	CHEMBL6165285
6.50	IC50	320	nM	CHEMBL6144459
6.48	IC50	330	nM	CHEMBL6176177
6.46	IC50	350	nM	CHEMBL4089817
6.44	IC50	360	nM	CHEMBL5203670
6.43	IC50	370	nM	CHEMBL6151784
6.39	IC50	410	nM	CHEMBL6152267
6.37	IC50	430	nM	CHEMBL6164956
6.35	IC50	450	nM	CHEMBL6176901
6.32	IC50	480	nM	CHEMBL6175880
6.30	IC50	500	nM	CHEMBL6175545
6.29	IC50	510	nM	CHEMBL6162926
6.26	IC50	550	nM	CHEMBL6169938
6.20	IC50	630	nM	CHEMBL6169281
6.16	IC50	700	nM	CHEMBL6162896
6.12	IC50	750	nM	CHEMBL5179823
6.10	IC50	800	nM	CHEMBL6170977
6.09	IC50	820	nM	CHEMBL4081954
6.08	IC50	830	nM	CHEMBL6133488
5.96	IC50	1090	nM	CHEMBL6171081
5.95	IC50	1130	nM	CHEMBL6160647
5.93	IC50	1170	nM	CHEMBL6159600
5.91	IC50	1240	nM	CHEMBL5412756
5.90	IC50	1270	nM	CHEMBL5436517
5.85	IC50	1400	nM	CHEMBL5179823
5.85	IC50	1400	nM	CHEMBL6166683
5.84	IC50	1460	nM	CHEMBL6168606
5.82	IC50	1500	nM	CHEMBL6169489
5.81	IC50	1560	nM	CHEMBL5398973
5.78	IC50	1650	nM	CHEMBL6175007
5.75	IC50	1780	nM	CHEMBL6134466
5.71	IC50	1950	nM	CHEMBL2323508
5.66	IC50	2210	nM	CHEMBL6148869
5.64	IC50	2300	nM	CAFFEIC ACID PHENETHYL ESTER
5.62	IC50	2400	nM	CHEMBL5432550
5.54	IC50	2910	nM	CHEMBL6174401
5.53	IC50	2980	nM	FLURBIPROFEN
5.50	IC50	3150	nM	CHEMBL2323522
5.48	IC50	3290	nM	CHEMBL6165242
5.48	IC50	3290	nM	CHEMBL6144544
5.46	IC50	3510	nM	CHEMBL2323507
5.40	IC50	3950	nM	CHEMBL5422070
5.39	IC50	4040	nM	OCTYL_GALLATE
5.33	IC50	4670	nM	CHEMBL5421222
5.27	IC50	5340	nM	CHEMBL4758386

PubChem BioAssay actives

26 with measured affinity, of 283 total; 25 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
N-[3-(4-fluorophenyl)propyl]-7-hydroxy-2-oxochromene-3-carboxamide	1465666: Inhibition of recombinant human AKR1C4 using S-tetralol as substrate	ic50	0.3500	uM
7-[2-[(6-oxo-4-propyl-1H-pyrimidin-2-yl)sulfanyl]acetyl]-1,3,4,5-tetrahydro-1-benzazepin-2-one	1874812: Inhibition of human recombinant AKR1C4 transfected in Escherichia coli BL21 (DE3) pLysS competent cells assessed as inhibition of NADP+ dependent oxidation of S-tetralol using S-tetralol as substrate incubated for 10 mins by fluorescence microplate reader assay	ic50	0.3600	uM
5-[[(6-ethoxy-3,4-dihydro-2H-chromene-3-carbonyl)-methylamino]methyl]-2-methylfuran-3-carboxylic acid	1874812: Inhibition of human recombinant AKR1C4 transfected in Escherichia coli BL21 (DE3) pLysS competent cells assessed as inhibition of NADP+ dependent oxidation of S-tetralol using S-tetralol as substrate incubated for 10 mins by fluorescence microplate reader assay	ic50	0.7500	uM
7-hydroxy-N-[3-(4-hydroxyphenyl)propyl]-2-oxochromene-3-carboxamide	1465666: Inhibition of recombinant human AKR1C4 using S-tetralol as substrate	ic50	0.8200	uM
3-[4-(3,5-dichlorophenyl)-3-(trifluoromethyl)phenyl]pentan-2-one	1997378: Inhibition of human recombinant AKR1C4 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	1.2400	uM
2-[4-(3,5-dimethoxyphenyl)-3-(trifluoromethyl)phenyl]butanoic acid	1997378: Inhibition of human recombinant AKR1C4 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	1.2700	uM
2-[4-(3-methoxyphenyl)-3-(trifluoromethyl)phenyl]propanoic acid	1997378: Inhibition of human recombinant AKR1C4 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	1.5600	uM
3-[1-(4-chlorobenzoyl)-3-ethyl-5-methoxyindol-2-yl]propanoic acid	729254: Inhibition of human recombinant AKR1C4-mediated NADP+-dependent oxidation of S-(+)-1,2,3,4-tetrahydro-1-naphthol	ic50	1.9500	uM
2-phenylethyl (E)-3-(3,4-dihydroxyphenyl)prop-2-enoate	664543: Inhibition of human recombinant GST-tagged AKR1C4 expressed in Escherichia coli using S-tetralol as substrate by fluorometry	ic50	2.3000	uM
(E)-3-[3-[(4-methylphenyl)methylcarbamoyl]-5-(4-phenylphenyl)phenyl]prop-2-enoic acid	1997740: Inhibition of recombinant AKR1C4 (unknown origin) dehydrogenase activity by measuring NADH formation by spectrophotometry	ic50	2.4000	uM
Flurbiprofen	1997378: Inhibition of human recombinant AKR1C4 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	2.9800	uM
9-(4-chlorobenzoyl)-6-methoxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid	729254: Inhibition of human recombinant AKR1C4-mediated NADP+-dependent oxidation of S-(+)-1,2,3,4-tetrahydro-1-naphthol	ic50	3.1500	uM
3-[1-(4-chlorobenzoyl)-5-methoxy-3-methylindol-2-yl]propanoic acid	729254: Inhibition of human recombinant AKR1C4-mediated NADP+-dependent oxidation of S-(+)-1,2,3,4-tetrahydro-1-naphthol	ic50	3.5100	uM
1-[3-fluoro-4-(3-fluoro-4-methylphenyl)phenyl]cyclopropane-1-carboxylic acid	1997378: Inhibition of human recombinant AKR1C4 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	3.9500	uM
octyl 3,4,5-trihydroxybenzoate	1674119: Inhibition of N-terminal His-tagged human AKR1C4 expressed in Escherichia coli BL21 (Condon Plus) competent cells using 9,10 -Phenanthrenequinone as substrate in presence of NADPH by fluorescence method	ic50	4.0400	uM
2-[4-(3-fluoro-4-methylphenyl)-3-(trifluoromethyl)phenyl]butanoic acid	1997378: Inhibition of human recombinant AKR1C4 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	4.6700	uM
3-[(4,5-dinitronaphthalen-1-yl)amino]benzoic acid	1674088: Inhibition of human AKR1C4 using S-tetralol as substrate in presence of NADP by fluorescence method	ic50	5.3400	uM
3-[2-nitro-4-(trifluoromethyl)anilino]benzoic acid	666398: Inhibition of recombinant AKR1C4 assessed as NADP+ dependent oxidation of S-tetralol by fluorescence assay	ic50	5.5000	uM
(E)-3-[3-(4-chlorophenyl)-5-[(4-methylphenyl)methylcarbamoyl]phenyl]prop-2-enoic acid	1997740: Inhibition of recombinant AKR1C4 (unknown origin) dehydrogenase activity by measuring NADH formation by spectrophotometry	ic50	6.0000	uM
(E)-3-[3-[(4-methylphenyl)methylcarbamoyl]-5-naphthalen-2-ylphenyl]prop-2-enoic acid	1997740: Inhibition of recombinant AKR1C4 (unknown origin) dehydrogenase activity by measuring NADH formation by spectrophotometry	ic50	6.1000	uM
(E)-3-[3-(4-bromophenyl)-5-[(4-methylphenyl)methylcarbamoyl]phenyl]prop-2-enoic acid	1997740: Inhibition of recombinant AKR1C4 (unknown origin) dehydrogenase activity by measuring NADH formation by spectrophotometry	ic50	6.5000	uM
(E)-3-[3-(4-fluorophenyl)-5-[(4-methylphenyl)methylcarbamoyl]phenyl]prop-2-enoic acid	1997740: Inhibition of recombinant AKR1C4 (unknown origin) dehydrogenase activity by measuring NADH formation by spectrophotometry	ic50	8.0000	uM
3-[(4-nitronaphthalen-1-yl)amino]benzoic acid	658487: Inhibition of recombinant AKR1C4 assessed as enzyme catalyzed oxidation of S-tetralol by fluorimetric assay	ic50	8.1700	uM
3-[[7-(2H-tetrazol-5-yl)-3,4-dihydro-1H-isoquinolin-2-yl]sulfonyl]benzoic acid	703399: Inhibition of human recombinant N-terminal His6-tagged AKR1C4 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	9.8100	uM
(E)-3-[3-(4-methylphenyl)-5-[(4-methylphenyl)methylcarbamoyl]phenyl]prop-2-enoic acid	1997740: Inhibition of recombinant AKR1C4 (unknown origin) dehydrogenase activity by measuring NADH formation by spectrophotometry	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Progesterone	affects abundance, affects metabolic processing, increases reduction, decreases abundance	3
Dihydrotestosterone	decreases reaction, increases metabolic processing, increases reduction	3
Aflatoxin B1	affects expression, decreases expression	3
9,10-phenanthrenequinone	increases reduction, affects activity	2
Acetaminophen	decreases expression, affects cotreatment	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Chenodeoxycholic Acid	decreases expression, affects cotreatment	2
Diazepam	decreases activity	2
Flufenamic Acid	decreases activity, decreases reaction, increases metabolic processing	2
Chlordecone	increases reduction	2
NADP	affects activity, affects cotreatment, increases oxidation, increases reduction, decreases reaction	2
Valproic Acid	decreases methylation, affects cotreatment, increases expression	2
Cyclosporine	decreases expression, affects cotreatment	2
Medroxyprogesterone Acetate	affects cotreatment, affects response to substance, decreases activity	2
Phenolphthalein	decreases activity	2
methyleugenol	decreases expression	1
cloxazolam	decreases activity	1
propionaldehyde	decreases expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, decreases expression	1
bisphenol A	affects expression	1
sodium arsenate	increases abundance, increases expression	1
tetrahydrodeoxycorticosterone	affects oxidation	1
cresolphthalein	decreases activity	1
1-indanol	increases oxidation	1
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone	increases metabolic processing	1
octyl gallate	decreases activity	1
benzo(a)pyrene 7,8-dihydrodiol	affects activity, affects cotreatment, increases oxidation	1
sodium arsenite	decreases expression	1
3’,3’’,5’,5’’-tetrabromophenolphthalein	decreases activity	1
butyraldehyde	decreases expression	1

ChEMBL screening assays

32 unique, capped per target: 29 binding, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2025088	Binding	Inhibition of recombinant AKR1C4 assessed as enzyme catalyzed oxidation of S-tetralol by fluorimetric assay	Crystal structures of AKR1C3 containing an N-(aryl)amino-benzoate inhibitor and a bifunctional AKR1C3 inhibitor and androgen receptor antagonist. Therapeutic leads for castrate resistant prostate cancer. — Bioorg Med Chem Lett
CHEMBL3541802	ADMET	Activity of human recombinant AKR1C4 expressed in HEK293 cells assessed as (1R,2S,5S)-N-((2S,3R)-4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-ca	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