Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT5ZWB6)

• DTT Name: Dihydrodiol dehydrogenase type I (AKR1C3)
• Synonyms: Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase; Testosterone 17-beta-dehydrogenase 5; Prostaglandin F synthase; PGFS; KIAA0119; Indanol dehydrogenase; HSD17B5; HA1753; Dihydrodiol dehydrogenase 3; DDH1; DD3; DD-3; Chlordecone reductase homolog HAKRb; Aldo-keto reductase family 1 member C3; 3-alpha-hydroxysteroid dehydrogenase type 2; 3-alpha-HSD type II, brain; 3-alpha-HSD type 2; 17-beta-hydroxysteroid dehydrogenase type 5; 17-beta-HSD 5
• Gene Name: AKR1C3
• DTT Type: Successful target; [1]
• Related Disease: Female pelvic pain [ICD-11: GA34]
• BioChemical Class: Short-chain dehydrogenases reductase
• UniProt ID: AK1C3_HUMAN
• TTD ID: T60857
• EC Number: EC 1.-.-.-
• Sequence:
  MDSKHQCVKLNDGHFMPVLGFGTYAPPEVPRSKALEVTKLAIEAGFRHIDSAHLYNNEEQ
  VGLAIRSKIADGSVKREDIFYTSKLWSTFHRPELVRPALENSLKKAQLDYVDLYLIHSPM
  SLKPGEELSPTDENGKVIFDIVDLCTTWEAMEKCKDAGLAKSIGVSNFNRRQLEMILNKP
  GLKYKPVCNQVECHPYFNRSKLLDFCKSKDIVLVAYSALGSQRDKRWVDPNSPVLLEDPV
  LCALAKKHKRTPALIALRYQLQRGVVVLAKSYNEQRIRQNVQVFEFQLTAEDMKAIDGLD
  RNLHYFNSDSFASHPNYPYSDEY
• Function: Catalyzes the conversion of aldehydes and ketones to alcohols. Catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ) and the oxidation of 9-alpha,11-beta-PGF2 to PGD2. Functions as a bi-directional 3-alpha-, 17-beta- and 20-alpha HSD. Can interconvert active androgens, estrogens and progestins with their cognate inactive metabolites. Preferentially transforms androstenedione (4-dione) to testosterone.
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
  Ovarian steroidogenesis (hsa04913)
• Reactome Pathway: Retinoid metabolism and transport (R-HSA-975634)
• BioCyc Pathway: MetaCyc:HS03054-MON

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Flufenamic Acid	DMC8VNH	Dysmenorrhea	GA34.3	Approved	[1]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ASP-9521	DM8V0UL	Prostate cancer	2C82.0	Phase 1/2	[2], [3]

13 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Beta-naphthylacetic acids derivative 1	DM5KTDY	N. A.	N. A.	Patented	[4]
Indomethacin analog 1	DM3E5V6	N. A.	N. A.	Patented	[4]
Indomethacin analog 2	DMKFPJ7	N. A.	N. A.	Patented	[4]
Indomethacin analog 3	DM53JXE	N. A.	N. A.	Patented	[4]
Isoquinolone derivative 1	DMW6R0H	N. A.	N. A.	Patented	[4]
N-(benzimidazole/indole) benzoic acid derivative 1	DMGQWKH	N. A.	N. A.	Patented	[4]
N-(benzimidazole/indole) benzoic acid derivative 2	DMOPUFM	N. A.	N. A.	Patented	[4]
N-(benzimidazolylcarbonyl)-piperidine derivative 1	DM541QW	N. A.	N. A.	Patented	[4]
N-(indolylcarbonyl)-piperidine derivative 1	DMARHJ9	N. A.	N. A.	Patented	[4]
N-(naphthylamino)-benzoate derivative 1	DM310ES	N. A.	N. A.	Patented	[4]
N-(phenylamino)-benzoate derivative 1	DMNIWVG	N. A.	N. A.	Patented	[4]
N-(pyridinepyrroylylcarbonyl)-piperidine derivative 1	DMA85UD	N. A.	N. A.	Patented	[4]
Nitrogen/sulfur-substituted estrene derivative 1	DMD7OW0	N. A.	N. A.	Patented	[4]

15 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2'-Monophosphoadenosine 5'-Diphosphoribose	DME9S8M	Discovery agent	N.A.	Investigative	[5]
2,2-Dibenzylcyclopentanol	DMFPYU8	Discovery agent	N.A.	Investigative	[6]
2-(4-Chlorobenzylidene)cyclopentanone	DMOH2YC	Discovery agent	N.A.	Investigative	[6]
2-(4-chlorobenzylidene)cyclopentyl ethyl ether	DMFE93N	Discovery agent	N.A.	Investigative	[6]
2-(4-chlorobenzylidene)cyclopentylmethyl ether	DMTW9B7	Discovery agent	N.A.	Investigative	[6]
2-Methyl-2,4-Pentanediol	DMD45CU	Discovery agent	N.A.	Investigative	[5]
2-[(2,2-diphenylacetyl)amino]benzoic acid	DMVSTG7	Discovery agent	N.A.	Investigative	[7]
3-Bromo-5-phenylsalicylc acid	DMZTDCL	Discovery agent	N.A.	Investigative	[8]
3-Phenylcyclopentanecarboxylic acid	DMJOD1T	Discovery agent	N.A.	Investigative	[6]
4-ANDROSTENE-3-17-DIONE	DMSE8NU	Discovery agent	N.A.	Investigative	[5], [9]
Acetate Ion	DMD08RH	Discovery agent	N.A.	Investigative	[5]
EM-1424	DMSLHDN	Discovery agent	N.A.	Investigative	[10]
EM1396	DMZ2EL1	Discovery agent	N.A.	Investigative	[10]
M-Phenoxybenzoic Acid For Cis-Isomer	DMJRK47	Discovery agent	N.A.	Investigative	[7]
Rutin	DMEHRAJ	Discovery agent	N.A.	Investigative	[5]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Prostate cancer	2C82	Prostate	4.06E-01	1.39	0.74

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Aldo-keto reductase 1C3 (AKR1C3) DME Info
• Gene Name: AKR1C3

2 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Doxorubicin	DMVP5YE	Solid tumour/cancer	2A00-2F9Z	Approved	[11]
Fenofibric acid	DMGO2MC	Cardiovascular disease	BA00-BE2Z	Approved	[12]

2 Clinical Trial Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Androsterone	DMITJAK	N. A.	N. A.	Phase 3	[13]
Trastuzumab Emtansine	DMU1LXS	HER2-positive breast cancer	2C60-2C65	Phase 2	[14]

3 Investigative Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4-oxo-nonenal	DMPX1J9	Discovery agent	N.A.	Investigative	[15]
Acenaphthenol	DMT3QYZ	Discovery agent	N.A.	Investigative	[13]
Indan-1-ol	DMMLQZJ	Discovery agent	N.A.	Investigative	[13]

References

• [1] Ouellet M, Percival MD: Effect of inhibitor time-dependency on selectivity towards cyclooxygenase isoforms. Biochem J. 1995 Feb 15;306 ( Pt 1):247-51.
• [2] Safety, tolerability and anti-tumour activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer: multi-centre phase I/II study. Invest New Drugs. 2014 Oct;32(5):995-1004.
• [3] In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17beta-hydroxysteroid dehydrogenase type 5 (17betaHSD5; AKR1C3). Invest New Drugs. 2014 Oct;32(5):860-70.
• [4] Aldo-Keto Reductase (AKR) 1C3 inhibitors: a patent review.Expert Opin Ther Pat. 2017 Dec;27(12):1329-1340.
• [5] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [6] New cyclopentane derivatives as inhibitors of steroid metabolizing enzymes AKR1C1 and AKR1C3. Eur J Med Chem. 2009 Jun;44(6):2563-71.
• [7] Nonsteroidal anti-inflammatory drugs and their analogues as inhibitors of aldo-keto reductase AKR1C3: new lead compounds for the development of ant... Bioorg Med Chem Lett. 2005 Dec 1;15(23):5170-5.
• [8] Structure-guided design, synthesis, and evaluation of salicylic acid-based inhibitors targeting a selectivity pocket in the active site of human 20... J Med Chem. 2009 May 28;52(10):3259-64.
• [9] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [10] Structure-based inhibitor design for an enzyme that binds different steroids: a potent inhibitor for human type 5 17beta-hydroxysteroid dehydrogenase. J Biol Chem. 2007 Mar 16;282(11):8368-79.
• [11] Inactivation of the anticancer drugs doxorubicin and oracin by aldo-keto reductase (AKR) 1C3. Toxicol Lett. 2008 Sep;181(1):1-6.
• [12] In vitro metabolism of fenofibric acid by carbonyl reducing enzymes. Chem Biol Interact. 2016 Oct 25;258:153-8.
• [13] Expression and characterization of four recombinant human dihydrodiol dehydrogenase isoforms: oxidation of trans-7, 8-dihydroxy-7,8-dihydrobenzo[a]pyrene to the activated o-quinone metabolite benzo[a]pyrene-7,8-dione. Biochemistry. 1998 May 12;37(19):6781-90.
• [14] The role of carbonyl reducing enzymes in oxcarbazepine in vitro metabolism in man. Chem Biol Interact. 2014 Sep 5;220:241-7.
• [15] Instability of C154Y variant of aldo-keto reductase 1C3. Chem Biol Interact. 2017 Oct 1;276:194-202.