AKR1B1

Summary

AKR1B1 (aldo-keto reductase family 1 member B, HGNC:381) is a protein-coding gene on chromosome 7q33, encoding Aldo-keto reductase family 1 member B1 (P15121). Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols.

This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. This member catalyzes the reduction of a number of aldehydes, including the aldehyde form of glucose, and is thereby implicated in the development of diabetic complications by catalyzing the reduction of glucose to sorbitol. Multiple pseudogenes have been identified for this gene. The nomenclature system used by the HUGO Gene Nomenclature Committee to define human aldo-keto reductase family members is known to differ from that used by the Mouse Genome Informatics database.

Source: NCBI Gene 231 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 39 total
• Druggable target: yes — 39 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001628

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:381
Approved symbol	AKR1B1
Name	aldo-keto reductase family 1 member B
Location	7q33
Locus type	gene with protein product
Status	Approved
Aliases	AR
Ensembl gene	ENSG00000085662
Ensembl biotype	protein_coding
OMIM	103880
Entrez	231

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 22 protein_coding, 8 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000285930, ENST00000426422, ENST00000434222, ENST00000462784, ENST00000465351, ENST00000467251, ENST00000467829, ENST00000484592, ENST00000487438, ENST00000489022, ENST00000491741, ENST00000497983, ENST00000498373, ENST00000498771, ENST00000896049, ENST00000896050, ENST00000896051, ENST00000896052, ENST00000896053, ENST00000916179, ENST00000916180, ENST00000916181, ENST00000916182, ENST00000916183, ENST00000916184, ENST00000916185, ENST00000916186, ENST00000916187, ENST00000916188, ENST00000916189, ENST00000916190, ENST00000916191, ENST00000971767, ENST00000971768, ENST00000971769

RefSeq mRNA: 2 — MANE Select: NM_001628 NM_001346142, NM_001628

CCDS: CCDS5831

Canonical transcript exons

ENST00000285930 — 10 exons

Exon	Start	End
ENSE00001174667	134442356	134442770
ENSE00001930160	134458997	134459100
ENSE00002506579	134447980	134448061
ENSE00003491180	134445238	134445320
ENSE00003535653	134449720	134449797
ENSE00003540896	134450786	134450902
ENSE00003572588	134447298	134447381
ENSE00003580574	134448997	134449119
ENSE00003589489	134451586	134451753
ENSE00003595398	134448387	134448493

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 55.8135 / max 1094.9382, expressed in 1699 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86316	50.6897	1697
86317	2.5682	1419
86315	2.5079	1249
86314	0.0477	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	99.95	gold quality
right adrenal gland cortex	UBERON:0035827	99.95	gold quality
left adrenal gland	UBERON:0001234	99.93	gold quality
adrenal cortex	UBERON:0001235	99.93	gold quality
left adrenal gland cortex	UBERON:0035825	99.93	gold quality
olfactory bulb	UBERON:0002264	99.92	gold quality
adrenal gland	UBERON:0002369	99.73	gold quality
metanephros cortex	UBERON:0010533	99.41	gold quality
dorsal root ganglion	UBERON:0000044	99.19	gold quality
seminal vesicle	UBERON:0000998	99.16	gold quality
apex of heart	UBERON:0002098	99.06	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.80	gold quality
trigeminal ganglion	UBERON:0001675	98.69	gold quality
gastrocnemius	UBERON:0001388	98.67	gold quality
tibial nerve	UBERON:0001323	98.65	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.64	gold quality
renal medulla	UBERON:0000362	98.60	gold quality
gluteal muscle	UBERON:0002000	98.58	gold quality
placenta	UBERON:0001987	98.50	gold quality
heart left ventricle	UBERON:0002084	98.45	gold quality
cardiac ventricle	UBERON:0002082	98.41	gold quality
body of tongue	UBERON:0011876	98.36	gold quality
muscle of leg	UBERON:0001383	98.33	gold quality
pons	UBERON:0000988	98.30	gold quality
muscle organ	UBERON:0001630	98.30	gold quality
skeletal muscle organ	UBERON:0014892	98.30	gold quality
skeletal muscle tissue	UBERON:0001134	98.25	gold quality
vastus lateralis	UBERON:0001379	98.24	gold quality
triceps brachii	UBERON:0001509	98.22	gold quality
quadriceps femoris	UBERON:0001377	98.21	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-8060	yes	1388.65
E-MTAB-6701	yes	37.18
E-CURD-112	yes	36.46
E-HCAD-10	yes	22.82
E-CURD-114	yes	11.03
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, EGR1, NFAT5, NFE2L2, NFKB1, NFKB2, NR5A1, RELA, TXK, USF1

miRNA regulators (miRDB)

26 targeting AKR1B1, 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-9-5P	100.00	72.28	2361
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-370-5P	99.78	66.81	706
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-1304-5P	98.90	68.58	1054
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-4274	98.59	66.10	630
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-891A-3P	98.05	67.99	970
HSA-MIR-506-5P	98.02	67.41	1065
HSA-MIR-3132	97.96	67.91	711
HSA-MIR-3661	97.83	67.30	705
HSA-MIR-197-5P	97.23	68.10	596
HSA-MIR-631	97.05	66.93	602
HSA-MIR-1236-5P	96.62	66.38	856
HSA-MIR-431-5P	96.16	66.50	652

Literature-anchored findings (GeneRIF, showing 40)

• X-ray structure of human aldose reductase holoenzyme in complex with statil determined at a resolution of 2.1 A (PMID:12486717)
• Polymorphisms in aldose reductase is associated with those diabetic retinopathy patients who had proliferative retinopathy and maculopathy (PMID:12660865)
• AKR1B1 and CTSH may be good markers for prediction of sensitivity to certain drugs (PMID:14662023)
• polymorphic in diabetic nephropathy and retinopathy in type 2 diabetes (PMID:14694017)
• polymorphic in diabetic nephropathy and in retinopathy in type 2 diabetes (PMID:14694018)
• crystal structure analysis and molecular dynamics simulations (PMID:15162486)
• expression of cAMP-regulated AKR1B1 is decreased in adrenocortical cancer. (PMID:15181092)
• AR is a critical regulator of TNF-alpha-induced apoptotic signaling in endothelial cells (PMID:15251463)
• The C-106T polymorphism of the aldose reductase gene may contribute to an early development of neurophysiologic deterioration in type 2 diabetic patients. (PMID:15277434)
• Transgenic mice broadly overexpressing human aldose reductase show that AR plays a key role in ischemic injury and impairment of functional and metabolic recovery after ischemia. (PMID:15284219)
• AR is an obligatory mediator of TNF-alpha signaling leading to an increase in the expression of adhesion molecules and increased binding of monocytes to the endothelium. (PMID:15284221)
• C-106T polymorphism in the AR gene is a risk factor for development of diabetic nephropathy in type 2 diabetes in patients with poor glycaemic control (PMID:15637423)
• AKR1B1 polymorphisms were strongly associated with the rate of functional decline of diabetic complications. (PMID:16936152)
• AR is an obligatory mediator of growth factor-induced up-regulation of COX-2, PGE2, and growth of Caco-2 colon cancer cells. (PMID:17018629)
• Two X-ray data sets for a complex of human aldose reductase (h-AR) with the inhibitor IDD 594 and the cofactor NADP(+) were collected from two different parts of the same crystal to a resolution of 0.81 A at 15 and 60 K using cold helium gas as cryogen. (PMID:17139089)
• Expression of AKR1B1 was significantly decreased in PD cases. (PMID:17270157)
• A novel binding site conformation has been identified in a region of ALR2 where previous complex structures suggested only low adaptability of the binding pocket. (PMID:17418233)
• Aldose reductase acceleration may affect the peritoneum in nondiabetic patients undergoing peritoneal dialysis via carbonyl and oxidative stress. (PMID:17851230)
• Aldose reductase gene was identified in the genome-wide loss-of-function genetic screen as putative tumor suppressor located at 7q35. (PMID:17968325)
• Levels of ALR2 activity as well as sorbitol in erythrocytes may have value as a quantitative trait to be included among other markers to establish a risk profile for development of diabetic retinopathy. (PMID:18385795)
• Meta-analysis study shows the correlation between the (AC)n dinucleotide repeat polymorphism at the 5’ end and the occurrence of diabetic nephropathy in type 1 diabetic subjects in contrast to type 2 diabetic subjects, in which there was no association. (PMID:18434430)
• oxLDL-induced upregulation of aldose reductase in human macrophages is proinflammatory in foam cells and may represent a potential link among hyperlipidemia, atherosclerosis, and diabetes mellitus. (PMID:18451330)
• the binding site residues deviating between ALR1 and ALR2 influence ligand affinity in a complex interplay, presumably involving changes of dynamic properties and differences of the solvation/desolvation balance upon ligand binding (PMID:18495158)
• Genetic polymorphisms of ALR2 independently predicted new onset of renal and cardiorenal end points, with the latter being largely mediated through renal disease in Chinese type 2 diabetic patients. (PMID:18716049)
• By western blot analysis, AKR1B1 is present in human liver and brain tissue obtained at autopsy. (PMID:19273550)
• Triiodothyronine regulates AKR1B1 gene expression via a thyroxine receptor response element-dependant mechanism and associates liver cancer. (PMID:19422879)
• AR could mediate the TGF-beta1-induced FN production, which may associate with AP-1 activation. (PMID:19760097)
• Exposure to high glucose and overexpression AR increase the expression of fibronectin. (PMID:19821053)
• AR is a potent regulator of TGF-beta1 induced expression of FN in human mesangial cells. (PMID:19847669)
• Data show that curcumin inhibits ALR2 with an IC(50) of 10 microM in a non-competitive manner. (PMID:19850041)
• AKR1B3 acts as the PGFS in adipocytes and AKR1B3-produced PGF(2alpha) suppresses adipocyte differentiation by acting through FP receptors (PMID:20093363)
• AR and SOD2 are renal antigens of human membranous nephropathy and oxidative stress may drive glomerular SOD2 expression. (PMID:20150532)
• association of nine single nucleotide polymorphisms in ADPRT1, AKR1B1), RAGE, GFPT2 and PAI-1 genes with chronic renal insufficiency among Asian Indians with type 2 diabetes (PMID:20353610)
• AR mediates EGF- and bFGF-induced colon cancer cell proliferation by activating or expressing G(1)-S phase proteins such as E2F-1, cdks, and cyclins through the reactive oxygen species/phosphoinositide 3-kinase/AKT pathway. (PMID:20354121)
• The commonly reported association of AKR1B1 with diabetic retinopathy may be due to an association of the gene with younger age at onset of diabetes. (PMID:20424224)
• The human aldose reductase AKR1B1 is a highly functional PGF synthase responsible for PGF2alpha production in the human endometrium and a potential target for treatment of menstrual disorders. (PMID:20943776)
• The present data show a difference in the association of variations in ALR2, iNOS and TNFB genes with diabgetic retinopathy, when compared to our previous reports. (PMID:21067489)
• activated hAR arises from oxidative modification of Cys-298, a residue near the nicotinamide binding pocket. (PMID:21084309)
• findings suggest that AR plays an important role in the cellular response to oxidative stress by sequestering ROS and reactive aldehydes generated in keratinocytes (PMID:21182935)
• study shows that ALR C-106T polymorphism is not associated with carotid atherosclerosis in Chinese patients with type 2 diabetes. (PMID:21294693)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	akr1b1.1	ENSDARG00000006215
danio_rerio	akr1b1.2	ENSDARG00000045598
mus_musculus	Akr1b1	ENSMUSG00000001642
rattus_norvegicus	Akr1b1	ENSRNOG00000009513
rattus_norvegicus	Akr1b1-ps2	ENSRNOG00000023285
drosophila_melanogaster	Akr1B	FBGN0086254
caenorhabditis_elegans		WBGENE00009980
caenorhabditis_elegans		WBGENE00009981
caenorhabditis_elegans		WBGENE00012722
caenorhabditis_elegans		WBGENE00012723
caenorhabditis_elegans		WBGENE00015307

Paralogs (16): AKR7A2 (ENSG00000053371), KCNAB2 (ENSG00000069424), AKR1A1 (ENSG00000117448), AKR1D1 (ENSG00000122787), AKR1C2 (ENSG00000151632), 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 B1 — P15121 (reviewed: P15121)

Alternative names: Aldehyde reductase, Aldose reductase

All UniProt accessions (3): P15121, E9PCX2, E9PEF9

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols. Displays enzymatic activity towards endogenous metabolites such as aromatic and aliphatic aldehydes, ketones, monosacharides, bile acids and xenobiotics substrates. Key enzyme in the polyol pathway, catalyzes reduction of glucose to sorbitol during hyperglycemia. Reduces steroids and their derivatives and prostaglandins. Displays low enzymatic activity toward all-trans-retinal, 9-cis-retinal, and 13-cis-retinal. Catalyzes the reduction of diverse phospholipid aldehydes such as 1-palmitoyl-2-(5-oxovaleroyl)-sn -glycero-3-phosphoethanolamin (POVPC) and related phospholipid aldehydes that are generated from the oxydation of phosphotidylcholine and phosphatdyleethanolamides. Plays a role in detoxifying dietary and lipid-derived unsaturated carbonyls, such as crotonaldehyde, 4-hydroxynonenal, trans-2-hexenal, trans-2,4-hexadienal and their glutathione-conjugates carbonyls (GS-carbonyls).

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm.

Tissue specificity. Highly expressed in embryonic epithelial cells (EUE) in response to osmotic stress.

Activity regulation. Cys-299 may regulate the kinetic and inhibition properties of the enzyme, but does not participate in catalysis. Tolrestat inhibits retinal reduction.

Similarity. Belongs to the aldo/keto reductase family.

RefSeq proteins (2): NP_001333071, NP_001619* (*=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

Pfam: PF00248

Enzyme classification (BRENDA):

• EC 1.1.1.188 — prostaglandin-F synthase (BRENDA: 15 organisms, 87 substrates, 86 inhibitors, 90 Km, 7 kcat entries)
• EC 1.1.1.21 — aldose reductase (BRENDA: 36 organisms, 259 substrates, 1272 inhibitors, 280 Km, 134 kcat entries)

Substrate kinetics (BRENDA)

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

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

Catalyzed reactions (Rhea), 12 shown:

• allyl alcohol + NADP(+) = acrolein + NADPH + H(+) (RHEA:12168)
• an alditol + NADP(+) = an aldose + NADPH + H(+) (RHEA:12789)
• glycerol + NADP(+) = D-glyceraldehyde + NADPH + H(+) (RHEA:23592)
• all-trans-retinol + NADP(+) = all-trans-retinal + NADPH + H(+) (RHEA:25033)
• glycerol + NADP(+) = L-glyceraldehyde + NADPH + H(+) (RHEA:38111)
• prostaglandin F2alpha + NADP(+) = prostaglandin H2 + NADPH + H(+) (RHEA:45312)
• 9-cis-retinol + NADP(+) = 9-cis-retinal + NADPH + H(+) (RHEA:54916)
• 13-cis-retinol + NADP(+) = 13-cis-retinal + NADPH + H(+) (RHEA:54920)
• a 4-hydroxynonen-1-ol + NADP(+) = a 4-hydroxynonenal + NADPH + H(+) (RHEA:58336)
• prenol + NADP(+) = 3-methyl-2-butenal + NADPH + H(+) (RHEA:58420)
• (E)-hex-2-en-1-ol + NADP(+) = (E)-hex-2-enal + NADPH + H(+) (RHEA:58424)
• (E,E)-2,4-hexadien-1-ol + NADP(+) = (E,E)-2,4-hexadienal + NADPH + H(+) (RHEA:58428)

UniProt features (60 total): strand 15, helix 14, sequence conflict 7, sequence variant 6, modified residue 5, mutagenesis site 4, binding site 3, turn 2, initiator methionine 1, chain 1, active site 1, site 1

Structure

Experimental structures (PDB)

177 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1US0	X-RAY DIFFRACTION	0.66
4LBS	X-RAY DIFFRACTION	0.76
3BCJ	X-RAY DIFFRACTION	0.78
2QXW	X-RAY DIFFRACTION	0.8
4LB3	X-RAY DIFFRACTION	0.8
4LB4	X-RAY DIFFRACTION	0.8
4LBR	X-RAY DIFFRACTION	0.8
2I16	X-RAY DIFFRACTION	0.81
2I17	X-RAY DIFFRACTION	0.81
2J8T	X-RAY DIFFRACTION	0.82
4LAU	X-RAY DIFFRACTION	0.84
2PF8	X-RAY DIFFRACTION	0.85
2PFH	X-RAY DIFFRACTION	0.85
4IGS	X-RAY DIFFRACTION	0.85
4LAZ	X-RAY DIFFRACTION	0.85
4QXI	X-RAY DIFFRACTION	0.87
2PEV	X-RAY DIFFRACTION	0.9
4GCA	X-RAY DIFFRACTION	0.9
1PWM	X-RAY DIFFRACTION	0.92
6F7R	X-RAY DIFFRACTION	0.92
6SYW	X-RAY DIFFRACTION	0.93
8A4N	X-RAY DIFFRACTION	0.93
3M4H	X-RAY DIFFRACTION	0.94
5OU0	X-RAY DIFFRACTION	0.94
6Y1P	X-RAY DIFFRACTION	0.94
8CNP	X-RAY DIFFRACTION	0.94
1Z8A	X-RAY DIFFRACTION	0.95
3LZ5	X-RAY DIFFRACTION	0.95
6TXP	X-RAY DIFFRACTION	0.95
8AE9	X-RAY DIFFRACTION	0.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15121-F1	98.34	0.98

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): 49 (proton donor); 78 (lowers pka of active site tyr)

Ligand- & substrate-binding residues (3): 10–19; 111; 211–273

Post-translational modifications (5): 222, 263, 2, 3, 95

Mutagenesis-validated functional residues (4):

Position	Phenotype
44	reduced glyceraldehyde oxidoreductase activity.
49	complete loss of glyceraldehyde oxidoreductase activity.
78	reduced glyceraldehyde oxidoreductase activity.
111	reduced glyceraldehyde oxidoreductase activity.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-196108	Pregnenolone biosynthesis
R-HSA-5652227	Fructose biosynthesis
R-HSA-70370	Galactose catabolism
R-HSA-1430728	Metabolism
R-HSA-196071	Metabolism of steroid hormones
R-HSA-556833	Metabolism of lipids
R-HSA-5652084	Fructose metabolism
R-HSA-71387	Metabolism of carbohydrates and carbohydrate derivatives
R-HSA-8957322	Metabolism of steroids

MSigDB gene sets: 924 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_SINGLE_FERTILIZATION, MODULE_93, MODULE_92, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, HORIUCHI_WTAP_TARGETS_DN, GOBP_MAMMARY_GLAND_MORPHOGENESIS, FARMER_BREAST_CANCER_CLUSTER_7, GOBP_GLAND_MORPHOGENESIS, GOBP_REGULATION_OF_BLOOD_PRESSURE

GO Biological Process (15): retinoid metabolic process (GO:0001523), epithelial cell maturation (GO:0002070), renal water homeostasis (GO:0003091), carbohydrate metabolic process (GO:0005975), C21-steroid hormone biosynthetic process (GO:0006700), regulation of urine volume (GO:0035809), negative regulation of apoptotic process (GO:0043066), daunorubicin metabolic process (GO:0044597), doxorubicin metabolic process (GO:0044598), fructose biosynthetic process (GO:0046370), cellular hyperosmotic salinity response (GO:0071475), metanephric collecting duct development (GO:0072205), lipid metabolic process (GO:0006629), prostaglandin metabolic process (GO:0006693), retinol metabolic process (GO:0042572)

GO Molecular Function (11): retinal dehydrogenase (NAD+) activity (GO:0001758), aldose reductase (NADPH) activity (GO:0004032), electron transfer activity (GO:0009055), prostaglandin H2 endoperoxidase reductase activity (GO:0036130), glyceraldehyde oxidoreductase activity (GO:0043795), allyl-alcohol dehydrogenase activity (GO:0047655), L-glucuronate reductase activity (GO:0047939), glycerol dehydrogenase (NADP+) activity (GO:0047956), all-trans-retinol dehydrogenase (NADP+) activity (GO:0052650), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (6): obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), cytosol (GO:0005829), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Metabolism of carbohydrates and carbohydrate derivatives	2
Metabolism	2
Metabolism of steroid hormones	1
Fructose metabolism	1
Metabolism of steroids	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	4
cellular anatomical structure	3
renal system process	2
primary metabolic process	2
glycoside metabolic process	2
polyketide metabolic process	2
ketone metabolic process	2
primary alcohol metabolic process	2
alcohol dehydrogenase (NADP+) activity	2
cytoplasm	2
diterpenoid metabolic process	1
epithelial cell development	1
cell maturation	1
multicellular organismal-level water homeostasis	1
C21-steroid hormone metabolic process	1
hormone biosynthetic process	1
steroid hormone biosynthetic process	1
regulation of body fluid levels	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
tertiary alcohol metabolic process	1
fructose metabolic process	1
hexose biosynthetic process	1
hyperosmotic salinity response	1
cellular response to salt stress	1
cellular hyperosmotic response	1
metanephros development	1
collecting duct development	1
prostanoid metabolic process	1
retinoid metabolic process	1
hormone metabolic process	1
olefinic compound metabolic process	1
aldehyde dehydrogenase (NAD+) activity	1
molecular_function	1
prostaglandin metabolic process	1
oxidoreductase activity, acting on the aldehyde or oxo group of donors	1
retinol metabolic process	1
binding	1
catalytic activity	1

Protein interactions and networks

STRING

2426 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AKR1B1	SORD	Q00796	974
AKR1B1	CBR1	P16152	906
AKR1B1	AKR7A2	O43488	885
AKR1B1	SLC6A12	P48065	840
AKR1B1	AKR7A3	O95154	823
AKR1B1	CBR3	O75828	799
AKR1B1	NFAT5	O94916	785
AKR1B1	MIOX	Q9UGB7	750
AKR1B1	SLC5A3	P53794	741
AKR1B1	DHFR	P00374	733
AKR1B1	SPR	P35270	725
AKR1B1	DHFR2	Q86XF0	703
AKR1B1	MGAM	O43451	671
AKR1B1	PLA2R1	Q13018	667
AKR1B1	SI	P14410	664

IntAct

50 interactions, top by confidence:

A	B	Type	Score
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
AKR1B1	EFCAB11	psi-mi:“MI:0915”(physical association)	0.560
AKR1B1		psi-mi:“MI:0915”(physical association)	0.550
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
PRMT2	AKR1B1	psi-mi:“MI:0403”(colocalization)	0.460
PRMT2	AKR1B1	psi-mi:“MI:0915”(physical association)	0.460
LMTK3	GPI	psi-mi:“MI:0914”(association)	0.420
AKR1B1	AKR1B15	psi-mi:“MI:0915”(physical association)	0.400
AKR1B1	WDR45B	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
AKR1B1	APLNR	psi-mi:“MI:0915”(physical association)	0.370
AKR1B1	bipA	psi-mi:“MI:0915”(physical association)	0.370
AKR1B1	SMAD1	psi-mi:“MI:0915”(physical association)	0.370
LRRK2		psi-mi:“MI:0914”(association)	0.350
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350

BioGRID (105): AKR1B15 (Affinity Capture-MS), AKR1B1 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B1 (Co-fractionation)

ESM2 similar proteins: C9JRZ8, M9PF61, O08782, O14088, O60218, O70473, O80944, O94735, P02532, P07943, P0DXG9, P0DXH7, P14550, P15121, P15122, P16116, P17264, P21300, P28475, P31210, P31867, P38715, P45376, P45377, P47137, P50578, P51635, P51857, P78736, P80276, P82125, Q0PGJ6, Q28FD1, Q3ZCJ2, Q54NZ7, Q568L5, Q5R5D5, Q5RJP0, Q5U1Y4, Q5ZK84

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
AKR1B1	“down-regulates quantity”	alpha-D-galactose	“chemical modification”
AKR1B1	“up-regulates quantity”	galactitol	“chemical modification”
AKR1B1	“down-regulates quantity”	NADPH(4-)	“chemical modification”
AKR1B1	“up-regulates quantity”	NADP(3-)	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	7
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1666 predictions. Top by Δscore:

Variant	Effect	Δscore
7:134445316:AAGAC:A	acceptor_gain	1.0000
7:134445317:AGAC:A	acceptor_gain	1.0000
7:134445318:GAC:G	acceptor_gain	1.0000
7:134445320:CCTA:C	acceptor_loss	1.0000
7:134445321:C:CC	acceptor_gain	1.0000
7:134445321:CTAA:C	acceptor_loss	1.0000
7:134447293:CTTA:C	donor_loss	1.0000
7:134447296:ACCTT:A	donor_loss	1.0000
7:134447381:CCTGT:C	acceptor_loss	1.0000
7:134447382:C:CC	acceptor_gain	1.0000
7:134447382:CTGTG:C	acceptor_loss	1.0000
7:134447383:T:G	acceptor_loss	1.0000
7:134447391:C:CT	acceptor_gain	1.0000
7:134447391:C:T	acceptor_gain	1.0000
7:134447875:T:TA	donor_gain	1.0000
7:134447905:T:TA	donor_gain	1.0000
7:134448057:TGGCC:T	acceptor_gain	1.0000
7:134448058:GGCC:G	acceptor_gain	1.0000
7:134448059:GCC:G	acceptor_gain	1.0000
7:134448060:CC:C	acceptor_gain	1.0000
7:134448060:CCC:C	acceptor_gain	1.0000
7:134448061:CC:C	acceptor_gain	1.0000
7:134448062:C:CC	acceptor_gain	1.0000
7:134448062:C:T	acceptor_gain	1.0000
7:134448489:TCAAT:T	acceptor_gain	1.0000
7:134448490:CAAT:C	acceptor_gain	1.0000
7:134448490:CAATC:C	acceptor_gain	1.0000
7:134448992:TTTAC:T	donor_loss	1.0000
7:134448993:TTACC:T	donor_loss	1.0000
7:134448994:TACC:T	donor_loss	1.0000

AlphaMissense

2102 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:134449066:G:C	N161K	0.998
7:134449066:G:T	N161K	0.998
7:134450806:G:C	H111D	0.997
7:134450899:A:G	W80R	0.997
7:134450899:A:T	W80R	0.997
7:134451586:C:A	K78N	0.997
7:134451586:C:G	K78N	0.997
7:134445255:C:A	R297S	0.996
7:134445255:C:G	R297S	0.996
7:134447334:C:A	K263N	0.996
7:134447334:C:G	K263N	0.996
7:134449725:A:G	W142R	0.996
7:134449725:A:T	W142R	0.996
7:134451589:G:C	S77R	0.996
7:134451589:G:T	S77R	0.996
7:134451591:T:G	S77R	0.996
7:134451675:A:G	Y49H	0.996
7:134451688:G:C	D44E	0.996
7:134451688:G:T	D44E	0.996
7:134451689:T:A	D44V	0.996
7:134451716:G:T	A35D	0.996
7:134459014:C:A	G17W	0.996
7:134450803:A:G	W112R	0.995
7:134450803:A:T	W112R	0.995
7:134451587:T:A	K78M	0.995
7:134451690:C:G	D44H	0.995
7:134459008:C:G	G19R	0.995
7:134445256:C:A	R297M	0.994
7:134445256:C:G	R297T	0.994
7:134448405:C:T	G214D	0.994

dbSNP variants (sampled 300 via entrez): RS1000010294 (7:134444711 T>C), RS1000316560 (7:134460158 C>G), RS1000686867 (7:134459655 C>T), RS1000815390 (7:134456202 T>C,G), RS1001047022 (7:134455622 C>T), RS1001077784 (7:134455858 C>T), RS1001149645 (7:134456060 G>A), RS1001460589 (7:134443769 T>C), RS1001636000 (7:134449859 TG>T), RS1001667164 (7:134450114 TAA>T), RS1001833024 (7:134449902 G>A), RS1001879609 (7:134455536 T>A), RS1001961920 (7:134444933 C>A,T), RS1002180858 (7:134455284 A>G), RS1002457187 (7:134461002 C>T)

Disease associations

OMIM: gene MIM:103880 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006221_1	White matter growth	9.000000e-09
GCST006585_2847	Blood protein levels	8.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009335	white matter growth measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1900 (SINGLE PROTEIN), CHEMBL4802032 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

39 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,363,259 (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
CHEMBL1020	TOLMETIN	4	60,332
CHEMBL135	ESTRADIOL	4	123,080
CHEMBL1401	NITAZOXANIDE	4	9,504
CHEMBL1405	ESTRONE	4	36,722
CHEMBL15770	SULINDAC	4	80,712
CHEMBL1622	FOLIC ACID	4	525,158
CHEMBL436	TOLRESTAT	4	3,768
CHEMBL56337	EPALRESTAT	4	110
CHEMBL6	INDOMETHACIN	4	156,366
CHEMBL686	MEFENAMIC ACID	4	61,835
CHEMBL140	CURCUMIN	3	93,882
CHEMBL145	CAFFEIC ACID	3	36,305
CHEMBL165	RESVERATROL	3	60,144
CHEMBL266497	SORBINIL	3	2,026
CHEMBL334830	RANIRESTAT	3	351
CHEMBL50	QUERCETIN	3	74,559
CHEMBL51483	GOSSYPOL	3	13,973
CHEMBL10372	ZOPOLRESTAT	2	3,266
CHEMBL10413	ZENARESTAT	2	2,803
CHEMBL12208	HYMECROMONE	2	18,363
CHEMBL151	LUTEOLIN	2
CHEMBL169	URSOLIC ACID	2
CHEMBL1914489	AZD1981	2
CHEMBL2057301	SEPRANOLONE	2
CHEMBL23588	FLUFENAMIC ACID	2
CHEMBL250450	ISOQUERCETIN	2
CHEMBL269455	IMIRESTAT	2
CHEMBL273910	MINALRESTAT	2
CHEMBL284616	CHLOROGENIC ACID	2
CHEMBL312109	OXEPINAC	2

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 1.-.-.- Oxidoreductases

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

Ligand	Action	Affinity	Parameter
govorestat	Inhibition	10.0	pIC50
AK198	Inhibition	8.89	pIC50
lidorestat	Inhibition	8.3	pIC50
tolrestat	Inhibition	7.33	pIC50
mangiferin	Binding	7.27	pKd
sorbinil	Inhibition	5.27	pIC50
zenarestat	Inhibition	5.0	pIC50
zopolrestat	Inhibition	4.41	pIC50

Binding affinities (BindingDB)

146 measured of 174 human assays (176 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CP-744809	IC50	0.84 nM
2-{[6-methoxy-5-(trifluoromethyl)naphthalen-1-yl]-N-methylmethanethioamido}acetic acid	IC50	1 nM
2-(2-{[(4-bromo-2-fluorophenyl)methyl]carbamothioyl}-5-fluorophenoxy)acetic acid	IC50	3 nM
6-[(5-fluoro-3-methyl-1-benzofuran-2-)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	3 nM
6-{[3-methyl-5-(trifluoromethyl)-1-benzofuran-2-]sulfonyl}-2,3-dihydropyridazin-3-one	IC50	5 nM
Minalrestat (2)	KD	5.5 nM
6-[(5-chloro-3-ethyl-1-benzofuran-2-)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	6 nM
6-[(3,5-dimethyl-1-benzofuran-2-)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	13 nM
2-(5-chloro-2-{[(3-nitrophenyl)methyl]carbamoyl}phenoxy)acetic acid	KD	14 nM
ALR2 inhibitor, 11	KD	15 nM
(2S,4S)-6-fluoro-2’,5’-dioxo-2,3-dihydrospiro[1-benzopyran-4,4’-imidazolidine]-2-carboxamide	KD	16 nM
6-[(3-phenyl-1-benzofuran-2-)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	23 nM
ALR2 inhibitor, 8	KD	23 nM
6-[(5-chloro-1-benzofuran-2-)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	25 nM
6-{[(2-chloro-6-fluorophenyl)methane]sulfonyl}-2,3-dihydropyridazin-3-one	IC50	26 nM
6-[(5-chloro-3-phenyl-1-benzofuran-2-)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	34 nM
6-{[(2,3-dichlorophenyl)methane]sulfonyl}-2,3-dihydropyridazin-3-one	IC50	35 nM
ALR2 inhibitor, 12	KD	38 nM
6-({[2-fluoro-3-(trifluoromethyl)phenyl]methane}sulfonyl)-2,3-dihydropyridazin-3-one	IC50	44 nM
6-{[3-(4-fluorophenyl)-1-benzofuran-2-]sulfonyl}-2,3-dihydropyridazin-3-one	IC50	49 nM
6-[(2,6-dichlorobenzene)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	50 nM
6-{[(2,6-dichlorophenyl)methane]sulfonyl}-2,3-dihydropyridazin-3-one	IC50	52 nM
6-{[(3-chloro-2-fluorophenyl)methane]sulfonyl}-2,3-dihydropyridazin-3-one	IC50	54 nM
6-[(2,3-dichlorobenzene)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	55 nM
6-[(5-chloro-3-methyl-1-benzothiophene-2-)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	55 nM
(4-oxo-3-{[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl}-3,4-dihydrophthalazin-1-yl)acetic acid	IC50	60 nM
6-({[3-(trifluoromethyl)phenyl]methane}sulfonyl)-2,3-dihydropyridazin-3-one	IC50	72 nM
6-[(2,5-dichlorobenzene)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	73 nM
6-[(5,7-dichloro-1-benzofuran-2-)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	87 nM
6-{[5-chloro-3-(propan-2-yl)-1-benzofuran-2-]sulfonyl}-2,3-dihydropyridazin-3-one	IC50	92 nM
6-{[(2-chlorophenyl)methane]sulfonyl}-2,3-dihydropyridazin-3-one	IC50	118 nM
2-(carboxymethyl)-1-oxo-1,2-dihydronaphtho[1,2-d]isothiazole-4-carboxylic acid 3,3-dioxide	IC50	140 nM
6-[(4-bromo-2-fluorobenzene)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	140 nM
6-[(3-methyl-1-benzofuran-2-)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	140 nM
Heterocyclic Sulfonylpyridazinone, 19w	IC50	150 nM
Heterocyclic Sulfonylpyridazinone, 19h	IC50	150 nM
6-(alpha-Naphthylmethylbenzenesulfonyl)-2H-pyridazin-3-one	IC50	150 nM
6-[(5-methyl-1-benzothiophene-2-)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	160 nM
Phenyl-Substituted Sulfonylpyridazinone, 8c	IC50	170 nM
6-{[3-(trifluoromethyl)benzene]sulfonyl}-2,3-dihydropyridazin-3-one	IC50	175 nM
Phenyl-Substituted Sulfonylpyridazinone, 8l	IC50	190 nM
6-[(6-chloro-3-methyl-1-benzofuran-2-)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	190 nM
6-[(5,7-dichloro-1H-indole-2-)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	200 nM
Phenyl-Substituted Sulfonylpyridazinone, 8a	IC50	210 nM
6-[(5-methoxy-1-benzofuran-2-)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	230 nM
6-[(3-chlorobenzene)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	240 nM
6-{[(2,3-difluorophenyl)methane]sulfonyl}-2,3-dihydropyridazin-3-one	IC50	257 nM
6-[(2-chloro-4-fluorobenzene)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	280 nM
6-[(4-bromobenzene)sulfonyl]-2,3-dihydropyridazin-3-one	IC50	350 nM
6-{[4-(trifluoromethyl)benzene]sulfonyl}-2,3-dihydropyridazin-3-one	IC50	360 nM

ChEMBL bioactivities

958 potent at pChembl≥5 of 1124 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.89	IC50	0.13	nM	CHEMBL2260162
9.82	IC50	0.15	nM	CHEMBL2260155
9.77	IC50	0.17	nM	CHEMBL1645381
9.59	IC50	0.26	nM	CHEMBL2260152
9.55	IC50	0.28	nM	CHEMBL1645384
9.31	IC50	0.49	nM	CHEMBL2260158
9.18	IC50	0.66	nM	CHEMBL2260153
9.09	IC50	0.82	nM	CHEMBL2260163
9.08	IC50	0.84	nM	CHEMBL240725
9.00	IC50	1	nM	CHEMBL20207
9.00	IC50	1	nM	CHEMBL240725
9.00	IC50	1	nM	ZOPOLRESTAT
8.92	IC50	1.19	nM	CHEMBL2260159
8.88	IC50	1.32	nM	CHEMBL2260161
8.72	IC50	1.9	nM	ZOPOLRESTAT
8.70	IC50	2	nM	CHEMBL20024
8.68	IC50	2.1	nM	CHEMBL69956
8.68	IC50	2.1	nM	ZOPOLRESTAT
8.52	IC50	3	nM	CHEMBL198096
8.51	IC50	3.1	nM	ZOPOLRESTAT
8.51	IC50	3.1	nM	CHEMBL20169
8.51	IC50	3.1	nM	CHEMBL20740
8.49	IC50	3.2	nM	CHEMBL73560
8.49	IC50	3.2	nM	CHEMBL143234
8.48	IC50	3.3	nM	CHEMBL71966
8.46	IC50	3.5	nM	CHEMBL20015
8.40	IC50	4	nM	CHEMBL278991
8.40	IC50	4	nM	CHEMBL304995
8.40	IC50	4	nM	ZOPOLRESTAT
8.38	IC50	4.17	nM	CHEMBL2260156
8.34	IC50	4.6	nM	CHEMBL73505
8.32	IC50	4.8	nM	ZOPOLRESTAT
8.30	IC50	5	nM	CHEMBL73560
8.30	IC50	5	nM	CHEMBL282689
8.30	IC50	5	nM	CHEMBL20518
8.30	IC50	5	nM	LIDORESTAT
8.30	IC50	5	nM	CHEMBL190931
8.30	IC50	5	nM	CHEMBL370123
8.28	IC50	5.2	nM	CHEMBL68580
8.23	IC50	5.9	nM	CHEMBL20161
8.22	IC50	6	nM	CHEMBL192886
8.22	IC50	6	nM	CHEMBL440567
8.22	IC50	6	nM	CHEMBL241577
8.22	IC50	6	nM	CHEMBL5286261
8.21	IC50	6.2	nM	CHEMBL416001
8.21	IC50	6.14	nM	CHEMBL2260160
8.21	IC50	6.18	nM	CHEMBL2260154
8.21	Ki	6.2	nM	CHEMBL4459307
8.20	IC50	6.3	nM	CHEMBL20637
8.19	IC50	6.4	nM	CHEMBL422647

PubChem BioAssay actives

1046 with measured affinity, of 1636 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-[(5-chloro-3-methyl-1-benzofuran-2-yl)sulfonyl]-1H-pyridazin-6-one	1797505: In Vitro Aldose Reductase Inhibition Assay from Article 10.1021/jm034065z: “A highly selective, non-hydantoin, non-carboxylic acid inhibitor of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran- 2-sulfonyl)-2-H-pyridazin-3-one.”	ic50	0.0008	uM
2-[3-[(7-chloro-1,3-benzothiazol-2-yl)methyl]-4-oxophthalazin-1-yl]acetic acid	34630: Inhibition of aldose reductase (aldo-keto reductase, AKR1B1) isolated from human placenta.	ic50	0.0010	uM
2-[[6-methoxy-5-(trifluoromethyl)naphthalene-1-carbothioyl]-methylamino]acetic acid	1802103: IC50-Activity Assay (AR) from Article 10.1021/acschembio.6b00382: “IDD388 Polyhalogenated Derivatives as Probes for an Improved Structure-Based Selectivity of AKR1B10 Inhibitors”	ic50	0.0010	uM
2-[4-oxo-3-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl]phthalazin-1-yl]acetic acid	159819: Compound was tested for the inhibition of the human placental aldose reductase using the substrate as glyceraldehyde.	ic50	0.0019	uM
2-[3-[(4-fluoro-1,3-benzothiazol-2-yl)methyl]-4-oxophthalazin-1-yl]acetic acid	34630: Inhibition of aldose reductase (aldo-keto reductase, AKR1B1) isolated from human placenta.	ic50	0.0020	uM
2-[8-oxo-7-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl]pyrido[2,3-d]pyridazin-5-yl]acetic acid	1557942: Inhibition of human Aldose reductase	ic50	0.0021	uM
2-[2-[(4-bromo-2-fluorophenyl)methylcarbamothioyl]-5-fluorophenoxy]acetic acid	1802103: IC50-Activity Assay (AR) from Article 10.1021/acschembio.6b00382: “IDD388 Polyhalogenated Derivatives as Probes for an Improved Structure-Based Selectivity of AKR1B10 Inhibitors”	ic50	0.0030	uM
3-[(5-fluoro-3-methyl-1-benzofuran-2-yl)sulfonyl]-1H-pyridazin-6-one	1797525: In Vitro Aldose Reductase Inhibition Assay from Article 10.1021/jm050462t: “A novel series of non-carboxylic acid, non-hydantoin inhibitors of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-pyridazin-3-one and congeners.”	ic50	0.0030	uM
2-[3-[(5-bromo-1,3-benzothiazol-2-yl)methyl]-4-oxophthalazin-1-yl]acetic acid	1557943: Inhibition of human placenta Aldose reductase	ic50	0.0031	uM
2-[4-oxo-3-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl]phthalazin-1-yl]acetic acid	309933: Inhibition of aldose reductase	ic50	0.0031	uM
2-[3-[(5,7-difluoro-1,3-benzoxazol-2-yl)methyl]-4-oxophthalazin-1-yl]acetic acid	1557943: Inhibition of human placenta Aldose reductase	ic50	0.0032	uM
2-[1-[(5,7-difluoro-1,3-benzothiazol-2-yl)methyl]-4,5-dimethyl-6-oxopyridazin-3-yl]acetic acid	1557942: Inhibition of human Aldose reductase	ic50	0.0032	uM
2-[1-[[3-(2,3-difluorophenyl)-1,2,4-oxadiazol-5-yl]methyl]-4,5-dimethyl-6-oxopyridazin-3-yl]acetic acid	34640: Inhibitory activity against aldose reductase isolated from human placenta	ic50	0.0033	uM
2-[3-[(4-chloro-1,3-benzothiazol-2-yl)methyl]-4-oxophthalazin-1-yl]acetic acid	34630: Inhibition of aldose reductase (aldo-keto reductase, AKR1B1) isolated from human placenta.	ic50	0.0035	uM
2-[3-[(5,7-dichloro-1,3-benzothiazol-2-yl)methyl]-4-oxophthalazin-1-yl]acetic acid	34630: Inhibition of aldose reductase (aldo-keto reductase, AKR1B1) isolated from human placenta.	ic50	0.0040	uM
2-[3-[(5,7-difluoro-1,3-benzothiazol-2-yl)methyl]-4-oxo-5,6,7,8-tetrahydrophthalazin-1-yl]acetic acid	34640: Inhibitory activity against aldose reductase isolated from human placenta	ic50	0.0040	uM
2-[5-chloro-1-[(5-fluoro-1,3-benzothiazol-2-yl)methyl]indazol-3-yl]acetic acid	34640: Inhibitory activity against aldose reductase isolated from human placenta	ic50	0.0046	uM
3-[[3-methyl-5-(trifluoromethyl)-1-benzofuran-2-yl]sulfonyl]-1H-pyridazin-6-one	1797525: In Vitro Aldose Reductase Inhibition Assay from Article 10.1021/jm050462t: “A novel series of non-carboxylic acid, non-hydantoin inhibitors of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-pyridazin-3-one and congeners.”	ic50	0.0050	uM
2-[3-[(4,7-difluoro-1,3-benzothiazol-2-yl)methyl]-4-oxophthalazin-1-yl]acetic acid	34630: Inhibition of aldose reductase (aldo-keto reductase, AKR1B1) isolated from human placenta.	ic50	0.0050	uM
2-[3-[(5-chloro-7-fluoro-1,3-benzothiazol-2-yl)methyl]-4-oxophthalazin-1-yl]acetic acid	34630: Inhibition of aldose reductase (aldo-keto reductase, AKR1B1) isolated from human placenta.	ic50	0.0050	uM
2-[3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]indol-1-yl]acetic acid	1797506: Enzyme Inhibition Assay from Article 10.1021/jm0492094: “Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.”	ic50	0.0050	uM
2-[6-methoxy-3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]indol-1-yl]acetic acid	1797506: Enzyme Inhibition Assay from Article 10.1021/jm0492094: “Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.”	ic50	0.0050	uM
2-[4-oxo-3-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl]-5,6,7,8-tetrahydrophthalazin-1-yl]acetic acid	1557942: Inhibition of human Aldose reductase	ic50	0.0052	uM
2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4,3’-pyrrolidine]-1,2’,3,5’-tetrone	1802839: SPR Assay from Article 10.1021/acschembio.7b00062: “Price for Opening the Transient Specificity Pocket in Human Aldose Reductase upon Ligand Binding: Structural, Thermodynamic, Kinetic, and Computational Analysis.”	kd	0.0055	uM
2-[3-[(5,7-dimethyl-1,3-benzothiazol-2-yl)methyl]-4-oxophthalazin-1-yl]acetic acid	34630: Inhibition of aldose reductase (aldo-keto reductase, AKR1B1) isolated from human placenta.	ic50	0.0059	uM
3-[(5-chloro-3-ethyl-1-benzofuran-2-yl)sulfonyl]-1H-pyridazin-6-one	1797525: In Vitro Aldose Reductase Inhibition Assay from Article 10.1021/jm050462t: “A novel series of non-carboxylic acid, non-hydantoin inhibitors of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-pyridazin-3-one and congeners.”	ic50	0.0060	uM
2-[5-chloro-2-[(3-nitrophenyl)methylcarbamoyl]phenoxy]acetic acid	309933: Inhibition of aldose reductase	ic50	0.0060	uM
2-[5-fluoro-2-[(3-nitrophenyl)methylcarbamothioyl]phenoxy]acetic acid	1942793: Inhibition of human recombinant ALR2 expressed in Escherichia coli by Coomassie reagent assay	ic50	0.0060	uM
2-[7-methyl-3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]indol-1-yl]acetic acid	1797506: Enzyme Inhibition Assay from Article 10.1021/jm0492094: “Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.”	ic50	0.0060	uM
2-[3-[(7-chloro-5-fluoro-1,3-benzothiazol-2-yl)methyl]-4-oxophthalazin-1-yl]acetic acid	34630: Inhibition of aldose reductase (aldo-keto reductase, AKR1B1) isolated from human placenta.	ic50	0.0062	uM
2-[(5Z)-4-oxo-5-[[3-(2-phenylethoxy)phenyl]methylidene]-2-sulfanylidene-1,3-thiazolidin-3-yl]acetic acid	1529995: Uncompetitive inhibition of human recombinant aldose reductase expressed in Escherichia coli BL21(DE3)pLysS assessed as dissociation constant of enzyme-inhibitor-substrate complex using L-idose as substrate by Morrison’s plot analysis	ki	0.0062	uM
2-[3-[(5,7-difluoro-1,3-benzothiazol-2-yl)methyl]-4-oxophthalazin-1-yl]acetic acid	34630: Inhibition of aldose reductase (aldo-keto reductase, AKR1B1) isolated from human placenta.	ic50	0.0063	uM
2-[3-[[3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl]methyl]-4-oxophthalazin-1-yl]acetic acid	34635: In vitro inhibitory activity against aldose reductase isolated from human placenta	ic50	0.0064	uM
2-[3-[[3-(2-bromophenyl)-1,2,4-oxadiazol-5-yl]methyl]-4-oxophthalazin-1-yl]acetic acid	34635: In vitro inhibitory activity against aldose reductase isolated from human placenta	ic50	0.0065	uM
7-hydroxy-2-(4-methoxyphenyl)imino-N-propan-2-ylchromene-3-carboxamide	779755: Inhibition of human recombinant N-terminal His6-tagged AKR1B1 expressed in Escherichia coli by fluorescence assay in presence of NADPH	ic50	0.0067	uM
2-[3-[(5-fluoro-1,3-benzothiazol-2-yl)methyl]-4-oxophthalazin-1-yl]acetic acid	34630: Inhibition of aldose reductase (aldo-keto reductase, AKR1B1) isolated from human placenta.	ic50	0.0069	uM
2-[4-cyano-5-fluoro-2-[(3-nitrophenyl)methylcarbamoyl]phenoxy]acetic acid	309933: Inhibition of aldose reductase	ic50	0.0070	uM
2-[6-fluoro-3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]indol-1-yl]acetic acid	1797506: Enzyme Inhibition Assay from Article 10.1021/jm0492094: “Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.”	ic50	0.0070	uM
2-[7-fluoro-3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]indol-1-yl]acetic acid	1797506: Enzyme Inhibition Assay from Article 10.1021/jm0492094: “Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.”	ic50	0.0070	uM
2-[3-[(5-chloro-1,3-benzothiazol-2-yl)methyl]-4-oxophthalazin-1-yl]acetic acid	34630: Inhibition of aldose reductase (aldo-keto reductase, AKR1B1) isolated from human placenta.	ic50	0.0071	uM
(2R,4S)-6-chloro-2-methylspiro[2,3-dihydropyrano[2,3-b]pyridine-4,5’-imidazolidine]-2’,4’-dione	34633: In vitro inhibitory activity against Aldose reductase isolated from human placenta	ic50	0.0075	uM
2-[3-[2-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)ethyl]indol-1-yl]acetic acid	1797506: Enzyme Inhibition Assay from Article 10.1021/jm0492094: “Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.”	ic50	0.0080	uM
2-[3-[(4-bromo-2-fluorophenyl)methyl]-7-chloro-2,4-dioxoquinazolin-1-yl]acetic acid	1797506: Enzyme Inhibition Assay from Article 10.1021/jm0492094: “Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.”	ic50	0.0080	uM
2-[6-chloro-3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]indol-1-yl]acetic acid	1797506: Enzyme Inhibition Assay from Article 10.1021/jm0492094: “Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.”	ic50	0.0080	uM
2-[5-methoxy-3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]indol-1-yl]acetic acid	1797506: Enzyme Inhibition Assay from Article 10.1021/jm0492094: “Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.”	ic50	0.0080	uM
2-[5-morpholin-4-yl-3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]indol-1-yl]acetic acid	1797506: Enzyme Inhibition Assay from Article 10.1021/jm0492094: “Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.”	ic50	0.0080	uM
2-[2-methyl-3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]indol-1-yl]acetic acid	1797506: Enzyme Inhibition Assay from Article 10.1021/jm0492094: “Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.”	ic50	0.0080	uM
2-[5-methyl-3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]indol-1-yl]acetic acid	1797506: Enzyme Inhibition Assay from Article 10.1021/jm0492094: “Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.”	ic50	0.0080	uM
(2S,4S)-6-fluoro-2’,5’-dioxospiro[2,3-dihydrochromene-4,4’-imidazolidine]-2-carboxamide	241413: Inhibitory concentration against human ALR2	ic50	0.0090	uM
2-[3-[(5-fluoro-1,3-benzothiazol-2-yl)methyl]indol-1-yl]acetic acid	1797506: Enzyme Inhibition Assay from Article 10.1021/jm0492094: “Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.”	ic50	0.0090	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects cotreatment, affects expression, decreases methylation, increases expression	7
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, decreases methylation	7
sodium arsenite	affects expression, affects cotreatment, increases abundance, increases expression	5
4-hydroxy-2-nonenal	affects reduction, increases reduction	4
Acrolein	affects reduction, increases reduction	4
Tetrachlorodibenzodioxin	affects expression, decreases expression	4
Aflatoxin B1	affects expression, increases expression	4
2-hexenal	affects reduction, increases reduction	3
NADP	increases oxidation, increases reduction, affects binding, increases activity, affects activity (+1 more)	3
Cyclosporine	increases expression, decreases expression	3
9,10-phenanthrenequinone	affects activity, increases reduction	2
propionaldehyde	affects reduction, increases reduction	2
bisphenol A	affects expression, decreases expression	2
nonanal	affects reduction, increases reduction	2
n-hexanal	affects reduction, increases reduction	2
2-butenal	increases reduction	2
2-nonenal	increases reduction, affects reduction	2
butyraldehyde	affects reduction, increases reduction	2
decanaldehyde	affects reduction, increases reduction	2
sorbinil	decreases activity, increases abundance, increases secretion, decreases response to substance, decreases reaction (+3 more)	2
2,3-hexanedione	increases reduction, increases chemical synthesis	2
4-hydroxy-2-hexenal	affects reduction, increases reduction	2
pentanal	affects reduction, increases reduction	2
heptanal	increases reduction, affects reduction	2
4-hydroxy-2-octenal	affects reduction, increases reduction	2
2-octenal	affects reduction, increases reduction	2
2-pentenal	affects reduction, increases reduction	2
hydroxypentenal	affects reduction, increases reduction	2
2,4-hexadienal	increases reduction	2
bisphenol S	increases expression, affects cotreatment, decreases expression	2

ChEMBL screening assays

231 unique, capped per target: 226 binding, 3 admet, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1020264	Binding	Inhibition of human muscle recombinant aldose reductase by spectrophotometry	Structures and aldose reductase inhibitory effects of bromophenols from the red alga Symphyocladia latiuscula. — J Nat Prod
CHEMBL1921048	Functional	Antagonist activity at AR	Discovery of potent, selective, and orally bioavailable alkynylphenoxyacetic acid CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases. — J Med Chem
CHEMBL4312976	ADMET	Drug metabolism in human liver microsomes assessed as aldehyde reductase-mediated (1-(4-Methoxybenzyl)pyrrolidine-2,2-diyl)dimethanol formation by UPLC-MS analysis	Hip To Be Square: Oxetanes as Design Elements To Alter Metabolic Pathways. — J Med Chem

Cellosaurus cell lines

14 cell lines: 14 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8BD	Abcam HCT 116 AR KO	Cancer cell line	Male
CVCL_B8SH	Abcam MCF-7 AR KO	Cancer cell line	Female
CVCL_B9DG	Abcam A-549 AR KO	Cancer cell line	Male
CVCL_D1V7	Abcam A-549 AKR1B1 KO	Cancer cell line	Male
CVCL_D1ZU	Abcam HCT 116 AKR1B1 KO	Cancer cell line	Male
CVCL_D2N3	Abcam THP-1 AKR1B1 KO	Cancer cell line	Male
CVCL_SC09	HAP1 AKR1B1 (-) 1	Cancer cell line	Male
CVCL_SD11	HAP1 AR (-) 1	Cancer cell line	Male
CVCL_SD12	HAP1 AR (-) 2	Cancer cell line	Male
CVCL_SD13	HAP1 AR (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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