AKR1C2

Summary

AKR1C2 (aldo-keto reductase family 1 member C2, HGNC:385) is a protein-coding gene on chromosome 10p15.1, encoding Aldo-keto reductase family 1 member C2 (P52895). 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 using NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme binds bile acid with high affinity, and shows minimal 3-alpha-hydroxysteroid dehydrogenase activity. 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 two different isoforms have been found for this gene.

Source: NCBI Gene 1646 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency (Supportive, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 123 total — 4 pathogenic
• Phenotypes (HPO): 5
• Druggable target: yes — 11 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001393392

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:385
Approved symbol	AKR1C2
Name	aldo-keto reductase family 1 member C2
Location	10p15.1
Locus type	gene with protein product
Status	Approved
Aliases	DD, BABP, DD2, HAKRD, MCDR2
Ensembl gene	ENSG00000151632
Ensembl biotype	protein_coding
OMIM	600450
Entrez	1646

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 9 protein_coding, 5 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000380753, ENST00000421196, ENST00000455190, ENST00000460124, ENST00000603073, ENST00000604184, ENST00000604428, ENST00000604439, ENST00000604507, ENST00000604711, ENST00000867374, ENST00000867375, ENST00000867376, ENST00000867377, ENST00000962120

RefSeq mRNA: 5 — MANE Select: NM_001393392 NM_001135241, NM_001321027, NM_001354, NM_001393392, NM_205845

CCDS: CCDS44350, CCDS7062, CCDS81438

Canonical transcript exons

ENST00000380753 — 9 exons

Exon	Start	End
ENSE00001705571	4999200	4999277
ENSE00001895645	4987775	4990038
ENSE00003476336	4995319	4995484
ENSE00003494933	5003752	5003857
ENSE00003514056	4998625	4998747
ENSE00003520820	5001514	5001681
ENSE00003536168	4991831	4991913
ENSE00003598739	4995756	4995865
ENSE00003637927	5000550	5000666

Expression profiles

Bgee: expression breadth ubiquitous, 159 present calls, max score 99.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.3968 / max 3204.5310, expressed in 1006 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
108065	41.4722	1002
108069	0.5097	24
108070	0.3437	17
108068	0.0328	8
108071	0.0205	8
108067	0.0178	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	99.20	gold quality
right lobe of liver	UBERON:0001114	98.27	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.99	gold quality
gall bladder	UBERON:0002110	97.52	gold quality
lower esophagus mucosa	UBERON:0035834	97.49	gold quality
gastrocnemius	UBERON:0001388	96.63	gold quality
muscle of leg	UBERON:0001383	96.31	gold quality
omental fat pad	UBERON:0010414	96.24	gold quality
peritoneum	UBERON:0002358	96.09	gold quality
descending thoracic aorta	UBERON:0002345	96.08	gold quality
ascending aorta	UBERON:0001496	96.04	gold quality
thoracic aorta	UBERON:0001515	95.92	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.85	gold quality
left coronary artery	UBERON:0001626	95.26	gold quality
esophagus mucosa	UBERON:0002469	95.12	gold quality
minor salivary gland	UBERON:0001830	94.89	gold quality
tibial nerve	UBERON:0001323	94.60	gold quality
right atrium auricular region	UBERON:0006631	94.48	gold quality
calcaneal tendon	UBERON:0003701	94.07	gold quality
aorta	UBERON:0000947	94.04	gold quality
cortical plate	UBERON:0005343	93.24	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.21	gold quality
popliteal artery	UBERON:0002250	93.18	gold quality
tibial artery	UBERON:0007610	93.16	gold quality
body of stomach	UBERON:0001161	93.13	gold quality
cardiac atrium	UBERON:0002081	93.11	gold quality
apex of heart	UBERON:0002098	91.92	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.89	gold quality
coronary artery	UBERON:0001621	91.67	gold quality
mucosa of stomach	UBERON:0001199	91.63	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6308	yes	1860.74
E-HCAD-9	yes	778.44
E-GEOD-124472	yes	355.98
E-CURD-114	yes	58.12
E-MTAB-5061	yes	19.62
E-HCAD-1	yes	18.67
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFE2, NFE2L2, NR1H4, TWIST1, TWIST2

miRNA regulators (miRDB)

77 targeting AKR1C2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-190A-5P	99.54	71.45	933
HSA-MIR-190B-5P	99.54	71.40	925
HSA-MIR-6513-5P	99.43	67.81	1071

Literature-anchored findings (GeneRIF, showing 40)

• human ileal bile acid binding protein binds two molecules of glycocholic acid with low intrinsic affinity but an extraordinarily high degree of positive cooperativity (PMID:11854486)
• The kinetics of 3-alpha-HSD type III indicates an ordered ternary complex mechanism characterized by allopregnanolone formation, with NAD cofactor binding before the steroid substrate and dissociating after release of the steroid product. (PMID:12416991)
• in prostate cells AKR1C2 acts as a 3-ketosteroid reductase to eliminate 5alpha-DHT and prevents activation of the androgen receptor. (PMID:12810547)
• Glaucomatous optic nerve head astrocytes express a higher level of 3alpha-HSD isoform AKR1C2 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)
• Akr1c2 which is up-regulated in esophageal squamous cell carcinoma probably plays an important role in tumor development of esophagus and may be proposed as a potential molecular target treatments. (PMID:15188492)
• 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)
• Tibolone is metabolized by the 3alpha/3beta-hydroxysteroid dehydrogenase activities of the four human isozymes of the aldo-keto reductase 1C subfamily: inversion of stereospecificity with a delta5(10)-3-ketosteroid. (PMID:15383625)
• Loss of AKR1C1 and AKR1C2 in breast cancer results in decreased progesterone catabolism, which, in combination with increased PR expression, may augment progesterone signaling by its nuclear receptors. (PMID:15492289)
• Results suggest that 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 3 might play slightly different roles in zebrafish compared with human although testosterone itself is likely to have similar functions in both organisms. (PMID:16216911)
• human ileal bile acid binding protein has a high degree of selectivity in its interactions with glycocholate and glycochenodeoxycholate brought on by the conformation of its ternary complex (PMID:16411748)
• The regulation of AKR1C2 by antioxidant response element suggests that AKR1C2 detoxifies products of reactive oxidant injury. (PMID:16478829)
• continual intake of arsenic in drinking water might provoke AKR1C2 expression that could in turn induce drug resistance in bladder cancer, and AKR1C2 may have a role in development of bladder cancer (PMID:17203165)
• Wild-type ileal BABP undergoes a slow conformational change after both bile-salt binding sites become occupied, a kinetic step that is missing in mutants that lack positive cooperativity. (PMID:17432832)
• The inhibition of activation of the beta-catenin/TCF-signaling pathway is believed to be one mechanism by which AKR1C2 siRNA exerts a gatekeeper function during hepatocarcinogenesis. (PMID:18251165)
• Results describe cathepsin D and aldo-keto reductase 1C2 and 1B10 dysregulation in Barrett’s esophagus and esophageal adenocarcinoma. (PMID:18396902)
• Incubations of normal human bronchial epithelial cells with individual heavy metals showed that the upregulation of AKR1C1 and AKR1C2 was predominantly caused by lead. (PMID:18654764)
• 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)
• The results show that several naturally occurring single nucleotide polymorphisms in AKR1C2 result in reduced enzyme activities. These variant AKR1C2 alleles may represent one factor involved in the variable degradation of dihydrotestosterone in vivo. (PMID:19258517)
• AKR1C subfamily genes are stress-inducible and might function as survival factors in keratinocytes. (PMID:19320734)
• AKR1C isoforms as a novel target of jasmonates in cancer cells. (PMID:19487289)
• The disulfide bridge does not modify the protein-binding stoichiometry, but has a key role in modulating recognition at both sites, inducing site selectivity for glycocholic and glycochenodeoxycholic acid. (PMID:19754879)
• The researchers found an increased risk of breast cancer in women with AKR1C2 who carried 1 or 2 alleles and who used estrogen-progesterone therapy. (PMID:19846565)
• We investigated associations between single nucleotide polymorphisms in genes HSD3B1, SRD5A1/2, and AKR1C2 and prostate cancer risk (PMID:20056642)
• Overexpression of aldo-keto reductase 1C2 is associated with disease progression in patients with prostatic cancer (PMID:20840669)
• analysis of single nucleotide polymorphisms of AKR1C1 and AKR1C2 (PMID:21217827)
• enhanced metabolism of progesterone by SRD5A1 and the 20alpha-HSD and 3alpha/beta-HSD activities of AKR1C1, AKR1C2 and AKR1C3 (PMID:21232532)
• The folding initiation mechanism of human bile acid-binding protein (BABP) has been examined by (19) F NMR. (PMID:21280124)
• role of AKR1C2 in the metabolism of testosterone and progesterone via the 5beta-reductase pathway. (PMID:21521174)
• Data suggest that interleukin-1beta facilitates progesterone metabolism in cervical fibroblasts by regulating expression of AKR1C1 and AKR1C2. (PMID:22064385)
• Data suggest that modulation of AKR1C2 by glucocorticoids (dexamethasone in this study) locally modifies exposure of adipose cells to endogenous androgens; thus, AKR1C2 activation/inactivation may be involved in regional fat deposition. (PMID:22275760)
• DDH2 expression might be a potential predictor and monitor of cisplatin efficacy in advanced NSCLC patients. (PMID:22534668)
• Significantly higher levels of SRD5A1, AKR1C2, AKR1C3, and HSD17B10 mRNA were however found in bone metastases than in non-malignant and/or malignant prostate tissue (PMID:24244276)
• The V54L mutation significantly decreases the 3alpha-hydroxysteroid dehydrogenase activity of DDH2 for the reduction of dihydrotestosterone. (PMID:24434280)
• In model cell lines of endometrial cancer, AKR1C2 and SRD5A1 have crucial roles in progesterone metabolism. (PMID:25463305)
• The endogenous HMOX1 gene but not the AKR1C2 gene is strongly repressed by Bach1 in HaCaT keratinocytes. (PMID:26244607)
• We identified two powerful genes in the liver cancer metastasis process, AEG-1 and AKR1C2. (PMID:26318406)
• Identify two novel factors, AKR1C2 (positive factor) and NF1 (negative factor), as the AEG-1 downstream players in the process of metastasis in liver cancer. (PMID:26351209)
• Data show that increased levels of AKR1C1/C2 enhanced the sensitivity of esophageal squamous cell carcinoma (ESCC) cells to ethyl-3,4-dihydroxybenzoate (EDHB). (PMID:26934124)
• 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), AKR7A3 (ENSG00000162482), AKR1E2 (ENSG00000165568), KCNAB1 (ENSG00000169282), KCNAB3 (ENSG00000170049), AKR1C1 (ENSG00000187134), AKR1C3 (ENSG00000196139), AKR1B10 (ENSG00000198074), AKR1C4 (ENSG00000198610), AKR7L (ENSG00000211454), AKR1B15 (ENSG00000227471), AKR1C8 (ENSG00000264006)

Protein

Protein identifiers

Aldo-keto reductase family 1 member C2 — P52895 (reviewed: P52895)

Alternative names: Chlordecone reductase homolog HAKRD, Dihydrodiol dehydrogenase 2, Dihydrodiol dehydrogenase/bile acid-binding protein, Type III 3-alpha-hydroxysteroid dehydrogenase

All UniProt accessions (3): P52895, B4DK69, S4R3P0

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-hydroxysteroids, but also 3beta-, 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 AKR1C4 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. 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. In neurosteroid biosynthesis, may preferentially reduce 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. Can form 17beta-hydroxysteroids such as testosterone and estradiol albeit with lower efficiency when compared to AKR1C3. 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-A3alphadiol). May also play a role in prostaglandin (PG) metabolism by reducing PGD2 to 11beta-PGF2. Also able to metabolize xenobiotics (S)-indan-1-ol and trans-1,2-dihydrobenzene-1,2-diols. 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.

Subcellular location. Cytoplasm. Cytosol.

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

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 disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by bile acids such as lithocholic acid with an IC(50) of 0.07 uM, ursodeoxycholic acid with an IC(50) of 0.08 uM and chenodeoxycholic acid with an IC(50) of 0.13 uM. Inhibited by anti-inflammatory drugs such as flufenamic acid with an IC(50) of 0.9 uM, indomethacin with an IC(50) of 75 uM and ibuprofen with an IC(50) of 6.9 uM. Inhibited by aromatic synthetic compounds such as hexestrol with an IC(50) of 2.8 uM, 1,10-phenanthroline with an IC(50) of 2100 uM and 1,7-phenanthroline with an IC(50) of 1500 uM. Not affected by fluoxetine, paroxetine, sertraline, norfluoxetine, carbamazepine, clozapine, flurbiprofen, or bromosulfophthalein. The oxidation reaction is inhibited by low micromolar concentrations of NADPH. Inhibited by anti-anxiety drugs benzodiazepines.

Pathway. Steroid metabolism.

Similarity. Belongs to the aldo/keto reductase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P52895-1	1	yes
P52895-2	2

RefSeq proteins (5): NP_001128713, NP_001307956, NP_001345, NP_001380321, NP_995317 (=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 1.1.1.213 — 3alpha-hydroxysteroid 3-dehydrogenase (Re-specific) (BRENDA: 8 organisms, 195 substrates, 114 inhibitors, 85 Km, 65 kcat entries)
• EC 1.1.1.357 — 3alpha-hydroxysteroid 3-dehydrogenase (BRENDA: 8 organisms, 118 substrates, 31 inhibitors, 151 Km, 108 kcat entries)
• EC 1.1.1.50 — 3alpha-hydroxysteroid 3-dehydrogenase (Si-specific) (BRENDA: 17 organisms, 293 substrates, 102 inhibitors, 177 Km, 105 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)

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

Substrate	Km (mM)	Measurements
CAMPHORQUINONE	0.1–26	24
ANDROSTERONE	0.0001–0.21	16
D-XYLOSE	0.8–213	15
5ALPHA-DIHYDROTESTOSTERONE	0.0001–0.071	12
NAD+	0.0031–0.87	11
CHOLIC ACID	0.025–586	10
ANDROSTERONE	0.0004–0.1	9
ANDROSTERONE	0.0005–14	8
NAD+	0.081–1.2	8
TRANS-BENZENE DIHYDRODIOL	0.017–2.6	8
5ALPHA-DIHYDROTESTOSTERONE	0.0012–0.071	7
DIHYDROTESTOSTERONE	0.0011–0.016	7
NADP+	0.0002–0.017	7
NADH	0.004–0.4	7
17BETA-HYDROXY-5ALPHA-ANDROSTAN-3-ONE	0.0012–0.726	6

Catalyzed reactions (Rhea), 12 shown:

• testosterone + NADP(+) = androst-4-ene-3,17-dione + NADPH + H(+) (RHEA:14981)
• (S)-indan-1-ol + NAD(+) = indan-1-one + NADH + H(+) (RHEA:16317)
• (S)-indan-1-ol + NADP(+) = indan-1-one + NADPH + H(+) (RHEA:16321)
• (1R,2R)-1,2-dihydrobenzene-1,2-diol + NADP(+) = catechol + NADPH + H(+) (RHEA:16729)
• 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 (81 total): binding site 27, helix 16, strand 12, sequence conflict 10, sequence variant 6, mutagenesis site 4, splice variant 2, chain 1, active site 1, site 1, turn 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
4XO6	X-RAY DIFFRACTION	1.2
1J96	X-RAY DIFFRACTION	1.25
4JTR	X-RAY DIFFRACTION	1.3
4JQA	X-RAY DIFFRACTION	1.45
4JQ4	X-RAY DIFFRACTION	1.52
4JQ1	X-RAY DIFFRACTION	1.6
4JTQ	X-RAY DIFFRACTION	1.6
4JQ2	X-RAY DIFFRACTION	1.75
4JQ3	X-RAY DIFFRACTION	1.75
4XO7	X-RAY DIFFRACTION	1.75
2IPJ	X-RAY DIFFRACTION	1.8
1XJB	X-RAY DIFFRACTION	1.9
2HDJ	X-RAY DIFFRACTION	2
4L1X	X-RAY DIFFRACTION	2
4L1W	X-RAY DIFFRACTION	2.2
1IHI	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52895-F1	96.82	0.97

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 (27): 190; 217; 217; 219; 221; 221; 222; 222; 270; 270; 24; 271 …

Mutagenesis-validated functional residues (4):

Position	Phenotype
24	partially switches the stereospecificity of the reductase activity from 17beta to 17alpha. acquires the capacity to meta
54	17-fold reduction in 3alpha hydroxysteroid dehydrogenase activity toward 5alpha-dht. 4.4-fold increase in 20alpha hydrox
301	decreases 3-alpha-hydroxysteroid reductase activity about 50-fold.
304	decreases 3-alpha-hydroxysteroid reductase activity about 500-fold.

Function

Pathways and Gene Ontology

Reactome pathways

8 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-1430728	Metabolism
R-HSA-192105	Synthesis of bile acids and bile salts
R-HSA-194068	Bile acid and bile salt metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-8957322	Metabolism of steroids

MSigDB gene sets: 200 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, MODULE_93, GOBP_DIGESTION, MODULE_92, GOBP_EPITHELIUM_DEVELOPMENT, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS, GOBP_CELLULAR_RESPONSE_TO_PROSTAGLANDIN_STIMULUS, GOBP_C21_STEROID_HORMONE_METABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, ADDYA_ERYTHROID_DIFFERENTIATION_BY_HEMIN, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_KETONE_METABOLIC_PROCESS

GO Biological Process (16): prostaglandin metabolic process (GO:0006693), G protein-coupled receptor signaling pathway (GO:0007186), digestion (GO:0007586), steroid metabolic process (GO:0008202), positive regulation of cell population proliferation (GO:0008284), epithelial cell differentiation (GO:0030855), progesterone metabolic process (GO:0042448), daunorubicin metabolic process (GO:0044597), doxorubicin metabolic process (GO:0044598), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cellular response to jasmonic acid stimulus (GO:0071395), cellular response to prostaglandin D stimulus (GO:0071799), alcohol metabolic process (GO:0006066), lipid metabolic process (GO:0006629), monocarboxylic acid metabolic process (GO:0032787), hormone metabolic process (GO:0042445)

GO Molecular Function (13): aldose reductase (NADPH) activity (GO:0004032), estradiol 17-beta-dehydrogenase [NAD(P)+] activity (GO:0004303), oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor (GO:0016655), carboxylic acid binding (GO:0031406), bile acid binding (GO:0032052), androsterone dehydrogenase [NAD(P)+] activity (GO:0047023), androstan-3-alpha,17-beta-diol dehydrogenase (NAD+) activity (GO:0047044), ketosteroid monooxygenase activity (GO:0047086), trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity (GO:0047115), indanol dehydrogenase activity (GO:0047718), 3-alpha-hydroxysteroid 3-dehydrogenase [NAD(P)+] activity (GO:0140169), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Synthesis of bile acids and bile salts	3
Bile acid and bile salt metabolism	1
Metabolism of steroids	1
Metabolism	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	4
ketone metabolic process	3
glycoside metabolic process	2
polyketide metabolic process	2
cellular anatomical structure	2
prostanoid metabolic process	1
G protein-coupled receptor activity	1
signal transduction	1
multicellular organismal process	1
lipid metabolic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cell differentiation	1
epithelium development	1
C21-steroid hormone metabolic process	1
olefinic compound metabolic process	1
primary alcohol metabolic process	1
tertiary alcohol metabolic process	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
response to jasmonic acid	1
cellular response to hormone stimulus	1
cellular response to fatty acid	1
cellular response to prostaglandin stimulus	1
response to prostaglandin D	1
cellular response to alcohol	1
cellular response to ketone	1
small molecule metabolic process	1
primary metabolic process	1
carboxylic acid metabolic process	1
metabolic process	1
regulation of hormone levels	1
alcohol dehydrogenase (NADP+) activity	1
oxidoreductase activity, acting on NAD(P)H	1
anion binding	1
organic acid binding	1
monocarboxylic acid binding	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

Protein interactions and networks

STRING

1448 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AKR1C2	DHRS9	Q9BPW9	930
AKR1C2	DHDH	Q9UQ10	907
AKR1C2	SRD5A1	P18405	779
AKR1C2	HSD17B3	P37058	742
AKR1C2	CYP17A1	P05093	664
AKR1C2	SRD5A2	P31213	647
AKR1C2	HSD17B6	O14756	613
AKR1C2	ATAD1	Q8NBU5	609
AKR1C2	SRD5A3	Q9H8P0	606
AKR1C2	HSD3B2	P26439	567
AKR1C2	DHFR	P00374	556
AKR1C2	HSD3B1	P14060	533
AKR1C2	CBR1	P16152	523
AKR1C2	DHODH	Q02127	519
AKR1C2	HSD17B1	P14061	496

IntAct

17 interactions, top by confidence:

A	B	Type	Score
AKR1C2	AKR1C4	psi-mi:“MI:0914”(association)	0.640
AKR1C2	AKR1C3	psi-mi:“MI:0914”(association)	0.530
TMEM59	B4GALT5	psi-mi:“MI:0914”(association)	0.530
AKR1C2	IPO8	psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
INPPL1	ACTN4	psi-mi:“MI:0914”(association)	0.350
SRRT	A2ML1	psi-mi:“MI:0914”(association)	0.350
GOT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
PRXL2A	A2ML1	psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350
PINK1	A2ML1	psi-mi:“MI:0914”(association)	0.350
AKR1C2	BRD4	psi-mi:“MI:0914”(association)	0.350
HOXB6	ANKHD1-EIF4EBP3	psi-mi:“MI:0914”(association)	0.350
LGALS9	CYB5A	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350
AKR1C2	LAMTOR5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (76): IPO8 (Affinity Capture-MS), AKR1C4 (Affinity Capture-MS), AKR1C3 (Affinity Capture-MS), AKR1C1 (Affinity Capture-MS), ZFP1 (Affinity Capture-MS), AKR1C2 (Co-fractionation), AKR1C2 (Co-fractionation), AKR1C2 (Co-fractionation), AKR1C2 (Co-fractionation), AKR1C2 (Co-fractionation), C11orf54 (Co-fractionation), MIF (Co-fractionation), AKR1C1 (Affinity Capture-MS), AKR1C4 (Affinity Capture-MS), ZFP1 (Affinity Capture-MS)

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

3 interactions.

A	Effect	B	Mechanism
hexestrol	down-regulates	AKR1C2	“chemical inhibition”
TWIST2	“up-regulates quantity by expression”	AKR1C2	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	AKR1C2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of canonical NF-kappaB signal transduction	5	18.2×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	48
Likely benign	12
Benign	51

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
30064	NM_001393392.1(AKR1C2):c.235A>G (p.Ile79Val)	Pathogenic
30065	NM_001393392.1(AKR1C2):c.270T>G (p.His90Gln)	Pathogenic
30066	NM_001393392.1(AKR1C2):c.899A>C (p.Asn300Thr)	Pathogenic
30067	NM_001393392.1(AKR1C2):c.666T>G (p.His222Gln)	Pathogenic

SpliceAI

1160 predictions. Top by Δscore:

Variant	Effect	Δscore
10:4991829:A:AC	donor_gain	1.0000
10:4991830:C:CC	donor_gain	1.0000
10:4995314:CTCA:C	donor_loss	1.0000
10:4995315:TCACC:T	donor_loss	1.0000
10:4995317:ACC:A	donor_loss	1.0000
10:4995318:C:A	donor_loss	1.0000
10:4995480:CCACC:C	acceptor_gain	1.0000
10:4995481:CACC:C	acceptor_gain	1.0000
10:4995481:CACCC:C	acceptor_gain	1.0000
10:4995483:CC:C	acceptor_gain	1.0000
10:4995483:CCCTG:C	acceptor_loss	1.0000
10:4995484:CC:C	acceptor_gain	1.0000
10:4995484:CCTGG:C	acceptor_loss	1.0000
10:4995485:C:A	acceptor_loss	1.0000
10:4995485:C:CC	acceptor_gain	1.0000
10:4995485:C:T	acceptor_gain	1.0000
10:4995486:T:A	acceptor_loss	1.0000
10:4995738:T:TA	donor_gain	1.0000
10:4998620:CTCA:C	donor_loss	1.0000
10:4998621:TCA:T	donor_loss	1.0000
10:4998623:A:AC	donor_gain	1.0000
10:4998623:AC:A	donor_gain	1.0000
10:4998624:C:CG	donor_gain	1.0000
10:4998624:CC:C	donor_gain	1.0000
10:4998624:CCT:C	donor_gain	1.0000
10:4998624:CCTG:C	donor_gain	1.0000
10:4998624:CCTGG:C	donor_gain	1.0000
10:4998743:ATGGC:A	acceptor_gain	1.0000
10:4998744:TGGC:T	acceptor_gain	1.0000
10:4998745:GGC:G	acceptor_gain	1.0000

AlphaMissense

2116 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:5001514:C:A	K84N	0.994
10:5001514:C:G	K84N	0.994
10:4999203:C:A	W148C	0.991
10:4999203:C:G	W148C	0.991
10:4999205:A:G	W148R	0.989
10:4999205:A:T	W148R	0.989
10:5001526:G:C	F80L	0.988
10:5001526:G:T	F80L	0.988
10:5001528:A:G	F80L	0.988
10:5001616:A:C	D50E	0.986
10:5001616:A:T	D50E	0.986
10:4998694:G:C	N167K	0.985
10:4998694:G:T	N167K	0.985
10:5000581:A:G	L113P	0.985
10:4998691:G:C	F168L	0.982
10:4998691:G:T	F168L	0.982
10:4998693:A:G	F168L	0.982
10:5001617:T:A	D50V	0.982
10:5001515:T:G	K84T	0.981
10:4995352:G:C	S271R	0.979
10:4995352:G:T	S271R	0.979
10:4995354:T:G	S271R	0.979
10:5000635:A:T	V95D	0.979
10:5000575:A:G	L115P	0.978
10:5001617:T:G	D50A	0.978
10:4990011:A:C	F319L	0.977
10:4990011:A:T	F319L	0.977
10:4990013:A:G	F319L	0.977
10:4991897:A:G	L288S	0.977
10:4998699:A:G	S166P	0.977

dbSNP variants (sampled 300 via entrez): RS10618 (10:4998686 T>A,C), RS10643636 (10:4994269 C>CAA,CAACT,CAAT,CAATA,CAATG,CAATT,CAATTTA), RS10692238 (10:5014194 A>ATC), RS10710137 (10:5019098 TG>T), RS10795218 (10:5011223 C>G,T), RS10795220 (10:5012502 C>A,G), RS10795221 (10:5012510 A>C,T), RS10904383 (10:4989685 C>T), RS10904384 (10:4991111 G>A,C), RS10904385 (10:4992680 T>A,C,G), RS10904386 (10:4992984 C>A,G,T), RS10904387 (10:4993054 C>T), RS10904388 (10:5006914 C>A,G,T), RS10904389 (10:5008224 G>A,C,T), RS10904390 (10:5008805 G>A)

Disease associations

OMIM: gene MIM:600450 | disease phenotypes: MIM:614279

GenCC curated gene-disease

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

Mondo (2): 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency (MONDO:0013664), CIC-rearranged sarcoma (MONDO:0956989)

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

HPO phenotypes

5 total (5 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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST003425_4	Longevity	2.000000e-07
GCST008163_103	Height	7.000000e-06
GCST012228_397	Waist-hip index	2.000000e-11
GCST012228_398	Waist-hip index	1.000000e-08
GCST012229_132	Hip index	6.000000e-12
GCST012229_133	Hip index	3.000000e-10
GCST012230_73	Waist-to-hip ratio adjusted for BMI	6.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
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): CHEMBL5847 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

11 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 702,350 (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
CHEMBL12	DIAZEPAM	4	92,281
CHEMBL154	NAPROXEN	4	136,434
CHEMBL175	DEXIBUPROFEN	4	12,118
CHEMBL295124	BERBERINE	4	26,682
CHEMBL509	MECLOFENAMIC ACID	4	45,809
CHEMBL563	FLURBIPROFEN	4	71,809
CHEMBL6	INDOMETHACIN	4	156,366
CHEMBL686	MEFENAMIC ACID	4	61,835
CHEMBL717	MEDROXYPROGESTERONE ACETATE	4	51,452
CHEMBL23588	FLUFENAMIC ACID	2	34,797
CHEMBL23832	FENAMIC ACID	1	12,767

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

Binding affinities (BindingDB)

22 measured of 36 human assays (36 total across all organisms); most potent 22 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
2-(phenylamino)benzoic acid	IC50	440 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
(6alpha)-17-(Acetyloxy)-6-methylpreg-4-ene-3,20-dione	IC50	700 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid	IC50	980 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
3-(2,4-dinitroanilino)benzoic acid	KI	2660 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
4-phenylamino benzoic acid	IC50	3000 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
DIAZEPAM	IC50	5600 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
2-(2-Hydroxyphenyl)-4H-chromen-4-one (3d)	IC50	6200 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
3-[N-(4-methoxyphenyl)amino]benzoic acid	IC50	11000 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
3-phenylamino benzoic acid	IC50	13000 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
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
3-[N-(4-methylphenyl)amino]benzoic acid	IC50	56000 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
2-[(1R,2R)-3-oxo-2-[(Z)-pent-2-enyl]cyclopentyl]acetic acid	KI	106000 nM	US-9271961: Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof

ChEMBL bioactivities

269 potent at pChembl≥5 of 497 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.82	Ki	1.5	nM	CHEMBL1275725
7.85	Ki	14	nM	CHEMBL1277647
7.84	IC50	14.5	nM	CHEMBL2323507
7.77	Ki	17	nM	CHEMBL1275704
7.68	Ki	21	nM	CHEMBL1275703
7.58	Ki	26	nM	CHEMBL1277741
7.54	Ki	29	nM	CHEMBL1277648
7.45	IC50	35.73	nM	CHEMBL2323474
7.27	IC50	53.5	nM	CHEMBL2323522
7.24	IC50	57	nM	CHEMBL178687
7.20	Ki	63	nM	CHEMBL1275723
7.16	Ki	70	nM	CHEMBL449129
7.09	IC50	81	nM	CHEMBL2323481
7.09	Ki	82	nM	CHEMBL447448
7.06	Ki	87	nM	CHEMBL387536
6.89	IC50	130	nM	CHEMBL194686
6.85	IC50	140	nM	CHEMBL6151784
6.82	IC50	150	nM	CHEMBL22815
6.82	IC50	150	nM	CHEMBL3623738
6.80	IC50	160	nM	CHEMBL5436838
6.78	Ki	168	nM	CHEMBL1275724
6.77	IC50	170	nM	CHEMBL6144459
6.72	IC50	190	nM	CHEMBL2043313
6.72	IC50	190	nM	CHEMBL2043318
6.70	IC50	200	nM	CHEMBL5401700
6.66	IC50	220	nM	CHEMBL2043310
6.66	Ki	220	nM	MEFENAMIC ACID
6.64	IC50	230	nM	CHEMBL5398882
6.62	IC50	240	nM	CHEMBL5426283
6.62	IC50	240	nM	CHEMBL5419252
6.62	IC50	240	nM	CHEMBL5405863
6.57	IC50	270	nM	CHEMBL2043319
6.57	IC50	270	nM	CHEMBL3623735
6.55	IC50	280	nM	CHEMBL1574420
6.55	IC50	280	nM	CHEMBL2043314
6.55	IC50	280	nM	CHEMBL5422601
6.55	IC50	280	nM	CHEMBL6162926
6.54	IC50	290	nM	CHEMBL2043320
6.54	IC50	290	nM	CHEMBL193971
6.54	IC50	290	nM	CHEMBL6169938
6.52	IC50	300	nM	CHEMBL5419326
6.51	IC50	310	nM	CHEMBL5406588
6.47	IC50	340	nM	CHEMBL5439918
6.46	IC50	350	nM	CHEMBL5414784
6.43	IC50	370	nM	FLUFENAMIC ACID
6.43	IC50	370	nM	CHEMBL5396002
6.42	IC50	380	nM	CHEMBL23479
6.41	IC50	390	nM	CHEMBL5410510
6.40	IC50	400	nM	CHEMBL2043302
6.40	IC50	400	nM	CHEMBL5425327

PubChem BioAssay actives

210 with measured affinity, of 762 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
3-fluoro-2-hydroxy-5-phenylbenzoic acid	536803: Inhibition of human AKR1C2 dehydrogenase activity by fluorometric assay	ki	0.0015	uM
5-(4-butylphenyl)-3-chloro-2-hydroxybenzoic acid	536803: Inhibition of human AKR1C2 dehydrogenase activity by fluorometric assay	ki	0.0140	uM
3-chloro-2-hydroxy-5-(3-methylphenyl)benzoic acid	536803: Inhibition of human AKR1C2 dehydrogenase activity by fluorometric assay	ki	0.0170	uM
3-chloro-2-hydroxy-5-phenylbenzoic acid	536803: Inhibition of human AKR1C2 dehydrogenase activity by fluorometric assay	ki	0.0210	uM
3-chloro-2-hydroxy-5-[4-(trifluoromethoxy)phenyl]benzoic acid	536803: Inhibition of human AKR1C2 dehydrogenase activity by fluorometric assay	ki	0.0260	uM
3-chloro-2-hydroxy-5-[4-(2-methylpropyl)phenyl]benzoic acid	536803: Inhibition of human AKR1C2 dehydrogenase activity by fluorometric assay	ki	0.0290	uM
3-chloro-2-hydroxy-5-(4-methylphenyl)benzoic acid	536803: Inhibition of human AKR1C2 dehydrogenase activity by fluorometric assay	ki	0.0630	uM
3,5-dichloro-2-hydroxybenzoic acid	1798661: Assay of Enzyme Activity from Article 10.1021/jm8003575: “Selectivity determinants of inhibitor binding to human 20alpha-hydroxysteroid dehydrogenase: crystal structure of the enzyme in ternary complex with coenzyme and the potent inhibitor 3,5-dichlorosalicylic acid.”	ki	0.0700	uM
3,5-Dibromosalicylic acid	350173: Inhibition of human recombinant type 3 3-alpha-HSD expressed in Escherichia coli JM109	ki	0.0820	uM
3-bromo-2-hydroxy-5-phenylbenzoic acid	350173: Inhibition of human recombinant type 3 3-alpha-HSD expressed in Escherichia coli JM109	ki	0.0870	uM
2-[3-fluoro-4-[2-(trifluoromethyl)phenyl]phenyl]propanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.1300	uM
2-[4-(pentafluoro-lambda6-sulfanyl)anilino]benzoic acid	1251281: Inhibition of recombinant AKR1C2 (unknown origin) using S-tetralol as substrate	ic50	0.1500	uM
2-(3-chloroanilino)benzoic acid	666395: Inhibition of recombinant AKR1C2 assessed as NADP+ dependent oxidation of S-tetralol by fluorescence assay	ic50	0.1500	uM
1-(3-fluoro-4-quinolin-3-ylphenyl)cyclopropane-1-carboxylic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.1600	uM
3-chloro-2-hydroxy-5-(2-phenylethynyl)benzoic acid	536803: Inhibition of human AKR1C2 dehydrogenase activity by fluorometric assay	ki	0.1680	uM
4-methoxy-2-(3-nitroanilino)benzoic acid	666395: Inhibition of recombinant AKR1C2 assessed as NADP+ dependent oxidation of S-tetralol by fluorescence assay	ic50	0.1900	uM
4-methoxy-2-(4-nitroanilino)benzoic acid	666395: Inhibition of recombinant AKR1C2 assessed as NADP+ dependent oxidation of S-tetralol by fluorescence assay	ic50	0.1900	uM
2-[4-(3,4-dichlorophenyl)-3-methylphenyl]propanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.2000	uM
Mefenamic Acid	703562: Inhibition of human recombinant AKR1C2 assessed as 1-acenaphthenol oxidation by spectrophotometry	ki	0.2200	uM
4-methoxy-2-[3-(trifluoromethyl)anilino]benzoic acid	666395: Inhibition of recombinant AKR1C2 assessed as NADP+ dependent oxidation of S-tetralol by fluorescence assay	ic50	0.2200	uM
2-(3-fluoro-4-quinolin-6-ylphenyl)propanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.2300	uM
2-[4-(6-methoxynaphthalen-2-yl)-3-(trifluoromethyl)phenyl]butanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.2400	uM
2-[4-(2-chlorophenyl)-3-methoxyphenyl]propanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.2400	uM
2-[4-(4-tert-butylphenyl)-3-fluorophenyl]propanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.2400	uM
2-[3-(pentafluoro-lambda6-sulfanyl)anilino]benzoic acid	1251281: Inhibition of recombinant AKR1C2 (unknown origin) using S-tetralol as substrate	ic50	0.2700	uM
2-(4-acetylanilino)-4-methoxybenzoic acid	666395: Inhibition of recombinant AKR1C2 assessed as NADP+ dependent oxidation of S-tetralol by fluorescence assay	ic50	0.2700	uM
2-[4-(3,4-dichlorophenyl)-3-(trifluoromethyl)phenyl]butanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.2800	uM
2-(4-nitroanilino)benzoic acid	666395: Inhibition of recombinant AKR1C2 assessed as NADP+ dependent oxidation of S-tetralol by fluorescence assay	ic50	0.2800	uM
2-(3-chloroanilino)-4-methoxybenzoic acid	666395: Inhibition of recombinant AKR1C2 assessed as NADP+ dependent oxidation of S-tetralol by fluorescence assay	ic50	0.2800	uM
2-(4-chloroanilino)-4-methoxybenzoic acid	666395: Inhibition of recombinant AKR1C2 assessed as NADP+ dependent oxidation of S-tetralol by fluorescence assay	ic50	0.2900	uM
2-[3-fluoro-4-[4-(trifluoromethyl)phenyl]phenyl]propanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.2900	uM
2-[4-(3,4-dichlorophenyl)-3-(trifluoromethyl)phenyl]propanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.3000	uM
2-[4-(4-formylphenyl)-3-(trifluoromethyl)phenyl]propanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.3100	uM
2-[4-(4-nitrophenyl)-3-(trifluoromethyl)phenyl]butanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.3400	uM
2-(3-fluoro-4-naphthalen-1-ylphenyl)propanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.3500	uM
2-[4-(1,3-benzodioxol-5-yl)-3-(trifluoromethyl)phenyl]butanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.3700	uM
2-[3-(trifluoromethyl)anilino]benzoic acid	577841: Inhibition of AKR1C2 by fluorimetric method	ic50	0.3700	uM
2-(3-methylanilino)benzoic acid	666395: Inhibition of recombinant AKR1C2 assessed as NADP+ dependent oxidation of S-tetralol by fluorescence assay	ic50	0.3800	uM
2-[3-fluoro-4-(3-nitrophenyl)phenyl]propanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.3900	uM
2-(4-acetylanilino)benzoic acid	666395: Inhibition of recombinant AKR1C2 assessed as NADP+ dependent oxidation of S-tetralol by fluorescence assay	ic50	0.4000	uM
2-[4-(4-methylphenyl)-3-(trifluoromethyl)phenyl]propanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.4000	uM
2-[3-methoxy-4-[4-(trifluoromethyl)phenyl]phenyl]propanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.4000	uM
2-(4-chloroanilino)benzoic acid	666395: Inhibition of recombinant AKR1C2 assessed as NADP+ dependent oxidation of S-tetralol by fluorescence assay	ic50	0.4100	uM
2-[4-(3,4-difluorophenyl)-3-methylphenyl]propanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.4400	uM
2-anilinobenzoic acid	577841: Inhibition of AKR1C2 by fluorimetric method	ic50	0.4400	uM
2-[4-(4-nitrophenyl)-3-(trifluoromethyl)phenyl]propanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.4500	uM
2-[4-(2-chloro-4-pyridinyl)-3-(trifluoromethyl)phenyl]butanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.4500	uM
2-[4-(2-methylquinolin-6-yl)-3-(trifluoromethyl)phenyl]butanoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.4500	uM
4-[4-(1-carboxypropyl)-2-(trifluoromethyl)phenyl]benzoic acid	1997374: Inhibition of human recombinant AKR1C2 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	0.4700	uM
5-(4-tert-butylphenyl)-3-chloro-2-hydroxybenzoic acid	536803: Inhibition of human AKR1C2 dehydrogenase activity by fluorometric assay	ki	0.4700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	9
Benzo(a)pyrene	affects methylation, increases activity, increases reaction, increases expression, affects response to substance (+1 more)	8
Tobacco Smoke Pollution	affects expression, increases expression	8
sodium arsenite	decreases expression, increases expression	7
9,10-phenanthrenequinone	increases metabolic processing, increases reduction, affects activity	4
Arsenic Trioxide	decreases response to substance, affects binding, decreases reaction, increases expression	4
Cisplatin	decreases response to substance, affects cotreatment, increases expression, decreases expression	4
Dihydrotestosterone	increases reduction, decreases reaction, decreases activity, increases metabolic processing	4
captax	increases activity, increases expression	3
bisphenol A	decreases expression, decreases methylation, affects expression	3
trichostatin A	affects cotreatment, increases expression	3
cinnamaldehyde	increases activity, increases expression, increases reaction	3
4-phenylenediamine	increases expression, increases activity	3
Cadmium	increases abundance, increases expression	3
Dinitrochlorobenzene	increases expression, increases activity	3
Flufenamic Acid	decreases reaction, increases metabolic processing, decreases activity	3
Hydrogen Peroxide	affects expression, increases abundance, increases expression	3
Indomethacin	decreases activity	3
Lithocholic Acid	affects binding, decreases activity	3
Meclofenamic Acid	decreases activity	3
NADP	affects activity, affects cotreatment, increases oxidation, increases reduction, decreases reaction (+1 more)	3
Progesterone	increases reduction	3
Ursodeoxycholic Acid	increases reduction, decreases activity, affects cotreatment, decreases reaction	3
Cyclosporine	increases expression	3
Cadmium Chloride	affects expression, increases abundance, increases expression	3
tert-Butylhydroperoxide	increases expression	3
Particulate Matter	increases abundance, increases expression, affects cotreatment	3
bisphenol F	decreases expression, increases expression	2
citral	increases activity, increases expression	2
lead acetate	increases expression	2

ChEMBL screening assays

80 unique, capped per target: 62 binding, 18 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1285651	Binding	Inhibition of human AKR1C2 dehydrogenase activity by fluorometric assay	Structure-based optimization and biological evaluation of human 20α-hydroxysteroid dehydrogenase (AKR1C1) salicylic acid-based inhibitors. — Eur J Med Chem
CHEMBL3527793	ADMET	Drug metabolism in human recombinant AKR1C2 expressing HEK293 cells treated with 20 uM boceprevir assessed as 100 uM diazepam-mediated inhibition of AKR1C2-mediated metabolite formation after 120 mins in presence of NADPH by LC-MS/MS/FSA me	Characterization of human liver enzymes involved in the biotransformation of boceprevir, a hepatitis C virus protease inhibitor. — Drug Metab Dispos

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02389244	PHASE2	ACTIVE_NOT_RECRUITING	A Phase II Study Evaluating Efficacy and Safety of Regorafenib in Patients With Metastatic Bone Sarcomas
NCT06414434	PHASE1	ACTIVE_NOT_RECRUITING	BTX-A51 in Patients With Liposarcoma or CIC-rearranged Sarcoma
NCT06820957	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Testing a New Combination of Anti-cancer Drugs in Patients Newly Diagnosed With Ewing Sarcoma Who Have Cancer That Has Spread to Other Parts of the Body