Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Leukotriene A-4 hydrolase (LTA4H)
• Synonyms: Leukotriene A4 hydrolase; Leukotriene A(4)Leukotriene A-4 hydrolase hydrolase; Leukotriene A(4) hydrolase; LTA4; LTA-H; LTA-4hydrolase; LTA-4 hydrolase
• Gene Name: LTA4H
• DTT Type: Successful target; [1]
• BioChemical Class: Ether bond hydrolase
• UniProt ID: LKHA4_HUMAN
• TTD ID: T03691
• EC Number: EC 3.3.2.6
• Sequence:
  MPEIVDTCSLASPASVCRTKHLHLRCSVDFTRRTLTGTAALTVQSQEDNLRSLVLDTKDL
  TIEKVVINGQEVKYALGERQSYKGSPMEISLPIALSKNQEIVIEISFETSPKSSALQWLT
  PEQTSGKEHPYLFSQCQAIHCRAILPCQDTPSVKLTYTAEVSVPKELVALMSAIRDGETP
  DPEDPSRKIYKFIQKVPIPCYLIALVVGALESRQIGPRTLVWSEKEQVEKSAYEFSETES
  MLKIAEDLGGPYVWGQYDLLVLPPSFPYGGMENPCLTFVTPTLLAGDKSLSNVIAHEISH
  SWTGNLVTNKTWDHFWLNEGHTVYLERHICGRLFGEKFRHFNALGGWGELQNSVKTFGET
  HPFTKLVVDLTDIDPDVAYSSVPYEKGFALLFYLEQLLGGPEIFLGFLKAYVEKFSYKSI
  TTDDWKDFLYSYFKDKVDVLNQVDWNAWLYSPGLPPIKPNYDMTLTNACIALSQRWITAK
  EDDLNSFNATDLKDLSSHQLNEFLAQTLQRAPLPLGHIKRMQEVYNFNAINNSEIRFRWL
  RLCIQSKWEDAIPLALKMATEQGRMKFTRPLFKDLAAFDKSHDQAVRTYQEHKASMHPVT
  AMLVGKDLKVD
• Function: Has also aminopeptidase activity. Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Biosynthesis of D-series resolvins (R-HSA-9018676)
  Biosynthesis of protectins (R-HSA-9018681)
  Biosynthesis of E-series 18(S)-resolvins (R-HSA-9018896)
  Biosynthesis of aspirin-triggered D-series resolvins (R-HSA-9020265)
  Biosynthesis of E-series 18(R)-resolvins (R-HSA-9023661)
  Synthesis of Leukotrienes (LT) and Eoxins (EX) (R-HSA-2142691)
• BioCyc Pathway: MetaCyc:HS03372-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
Bestatin	DM8L9D4	Acute myeloid leukaemia	2A60	Approved	[1]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LYS006	DMI17QR	Ulcerative colitis	DD71	Phase 2	[2]
Acebilustat	DM19UTO	Chronic blistering skin disorder	ME63.3	Phase 1	[3]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
DG051	DM3I0GS	Myocardial infarction	BA41-BA43	Discontinued in Phase 2	[4]

62 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(4-(thiophen-2-yl)phenyl)methanamine	DMV2CKN	Discovery agent	N.A.	Investigative	[5]
(4-fluorophenyl)(pyridin-4-yl)methanone	DMOS68D	Discovery agent	N.A.	Investigative	[5]
(R)-2-((4-benzylphenoxy)methyl)piperidine	DMXUHV3	Discovery agent	N.A.	Investigative	[6]
(R)-2-((4-phenoxyphenoxy)methyl)piperidine	DM6KJ3D	Discovery agent	N.A.	Investigative	[6]
(R)-2-(4-Benzylphenoxymethyl)pyrrolidine	DM1GCV3	Discovery agent	N.A.	Investigative	[7]
(R)-N-benzyl-4-(pyrrolidin-2-ylmethoxy)aniline	DMM8TE0	Discovery agent	N.A.	Investigative	[5]
(R/S)-2-((4-benzylphenoxy)methyl)piperazine	DM3MEQB	Discovery agent	N.A.	Investigative	[6]
(R/S)-2-((4-benzylphenoxy)methyl)piperidine	DMRXD82	Discovery agent	N.A.	Investigative	[6]
(R/S)-2-((4-phenoxyphenoxy)methyl)piperidine	DMDA285	Discovery agent	N.A.	Investigative	[6]
(S)-2-((4-phenoxyphenoxy)methyl)piperidine	DM2VOAS	Discovery agent	N.A.	Investigative	[6]
1-(2,2'-bithiophen-5-yl)methanamine	DMNX6CE	Discovery agent	N.A.	Investigative	[5]
1-(4-Phenoxyphenyl)piperazine	DMVCM0I	Discovery agent	N.A.	Investigative	[7]
1-(pentyloxy)-4-phenoxybenzene	DMJQ7T0	Discovery agent	N.A.	Investigative	[8]
1-butoxy-4-phenoxybenzene	DMXMATS	Discovery agent	N.A.	Investigative	[8]
1-[4-(4-Iodophenoxy)phenyl]piperazine	DM0I2RH	Discovery agent	N.A.	Investigative	[7]
1-[4-(Benzothiazol-2-yloxy)benzyl]piperidin-4-ol	DM4F1GJ	Discovery agent	N.A.	Investigative	[9]
2-(4-benzylphenoxy)ethanamine	DM6R4MG	Discovery agent	N.A.	Investigative	[8]
2-(4-phenoxyphenoxy)ethanamine	DM7TBUJ	Discovery agent	N.A.	Investigative	[8]
2-(4-Piperidin-1-ylmethylphenoxy)benzothiazole	DM98WVL	Discovery agent	N.A.	Investigative	[9]
2-(7-(benzyloxy)-1H-indol-3-yl)ethanamine	DMD2QVO	Discovery agent	N.A.	Investigative	[10]
2-Amino-N-[4-(phenylmethoxy)phenyl]-acetamide	DMRY06D	Discovery agent	N.A.	Investigative	[5]
2-[4-(2-Azepan-1-ylethoxy)phenoxy]benzooxazole	DMDMK5V	Discovery agent	N.A.	Investigative	[9]
2-[4-(2-Azepan-1-ylethoxy)phenoxy]benzothiazole	DM923WK	Discovery agent	N.A.	Investigative	[9]
2-[4-(2-Morpholin-4-ylethoxy)phenoxy]benzooxazole	DMECQB4	Discovery agent	N.A.	Investigative	[9]
2-[4-(2-Piperidin-1-ylethyl)phenoxy]benzothiazole	DMMYJ3R	Discovery agent	N.A.	Investigative	[9]
3-(Benzyloxy)Pyridin-2-Amine	DM35VEI	Discovery agent	N.A.	Investigative	[11]
4-(2-amino-1,3-thiazol-4-yl)phenol	DMH5CAQ	Discovery agent	N.A.	Investigative	[5]
4-(4-(pentyloxy)phenoxy)phenol	DMYXHUO	Discovery agent	N.A.	Investigative	[8]
4-(4-butoxyphenoxy)phenol	DMI2EM5	Discovery agent	N.A.	Investigative	[8]
4-(4-propoxyphenoxy)phenol	DMBZHUA	Discovery agent	N.A.	Investigative	[8]
4-amino-N-[4-(benzyloxy)phenyl]butanamide	DMDX0VP	Discovery agent	N.A.	Investigative	[5]
4-[2-(4-Benzylphenoxy)ethyl]pyridine	DMDI32S	Discovery agent	N.A.	Investigative	[7]
4S-4,5-Diamino-N-(4-phenoxyphenyl)pentanamide	DMQNT8D	Discovery agent	N.A.	Investigative	[12]
5-[2-(1H-pyrrol-1-yl)ethoxy]-1H-indole	DMLFY2T	Discovery agent	N.A.	Investigative	[5]
5-[2-(4-hydroxyphenyl)ethyl]benzene-1,3-diol	DM1KO7U	Discovery agent	N.A.	Investigative	[5]
8(S)-amino-2(R)-methyl-7-oxononanoic acid	DMT1NW2	Discovery agent	N.A.	Investigative	[13]
Acetate Ion	DMD08RH	Discovery agent	N.A.	Investigative	[11]
JNJ-10392980	DMZH0K8	Discovery agent	N.A.	Investigative	[9]
N-(pyridin-3-ylmethyl)aniline	DMIN60B	Discovery agent	N.A.	Investigative	[5]
N-methyl-1-(2-thiophen-2-ylphenyl)methanamine	DMUJ18P	Discovery agent	N.A.	Investigative	[5]
N1-[4-(Phenylmethoxy)phenyl]-D-aspartamine	DM4Q86B	Discovery agent	N.A.	Investigative	[12]
N1-[4-(Phenylmethoxy)phenyl]-D-glutamine	DMK10WX	Discovery agent	N.A.	Investigative	[12]
N1-[4-(Phenylmethoxy)phenyl]-L-aspartamine	DMLEMUX	Discovery agent	N.A.	Investigative	[12]
N1-[4-(Phenylmethoxy)phenyl]-L-glutamine	DM9XCZS	Discovery agent	N.A.	Investigative	[12]
N4-[4-(Phenylmethoxy)phenyl]-L-aspartamine	DMV7ORJ	Discovery agent	N.A.	Investigative	[12]
N5-(4-Phenoxyphenyl)-L-glutamine	DMNVK6T	Discovery agent	N.A.	Investigative	[12]
N5-[(4-Phenoxy)-3-pyridyl]-L-glutamamide	DMXUODT	Discovery agent	N.A.	Investigative	[12]
N5-[4-(1H-pyrrol-1-yl)phenyl]-L-glutamamide	DMJT4UR	Discovery agent	N.A.	Investigative	[12]
N5-[4-(2-methylphenoxy)phenyl]-L-glutamamide	DMR2C94	Discovery agent	N.A.	Investigative	[12]
N5-[4-(2-Oxo-3-phenylpropoxy)phenyl]-L-glutamine	DM97H52	Discovery agent	N.A.	Investigative	[12]
N5-[4-(2-phenylethoxy)phenyl]-L-glutamine	DMR1XJN	Discovery agent	N.A.	Investigative	[12]
N5-[4-(3-methylphenoxy)phenyl]-L-glutamamide	DMTO8KS	Discovery agent	N.A.	Investigative	[12]
N5-[4-(3-Phenylpropoxy)phenyl]-L-glutamine	DMINK9Q	Discovery agent	N.A.	Investigative	[12]
N5-[4-(4-(3-Furyl)phenoxy)phenyl]-L-glutamamide	DM6PXMJ	Discovery agent	N.A.	Investigative	[12]
N5-[4-(4-methylphenoxy)phenyl]-L-glutamamide	DMMV1CB	Discovery agent	N.A.	Investigative	[12]
N5-[4-(N-Phenylamino)phenyl]-L-glutamine	DMH8VYM	Discovery agent	N.A.	Investigative	[12]
N5-[4-(Phenylmethoxy)phenyl]-D-glutamine	DMUVP5L	Discovery agent	N.A.	Investigative	[12]
N5-[4-(Phenylmethoxy)phenyl]-L-glutamamide	DMMYIJ0	Discovery agent	N.A.	Investigative	[12]
N5-[4-(Phenylmethoxy)phenyl]-L-glutamine	DMCG26A	Discovery agent	N.A.	Investigative	[12]
N5-[4-Benzylphenyl]-L-glutamamide	DMH6O4G	Discovery agent	N.A.	Investigative	[12]
N6-[4-(4-methylphenoxy)phenyl]-L-homoglutamine	DMBT2HW	Discovery agent	N.A.	Investigative	[12]
SA-6541	DMVA5FE	Inflammation	1A00-CA43.1	Investigative	[14]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2C82	Bone marrow	1.31E-48	-1.22	-2.21

References

• [1] DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.
• [2] Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A(4) Hydrolase. J Med Chem. 2021 Feb 25;64(4):1889-1903.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] BAY x 1005 attenuates atherosclerosis in apoE/LDLR - double knockout mice. J Physiol Pharmacol. 2007 Sep;58(3):583-8.
• [5] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [6] Discovery of novel leukotriene A4 hydrolase inhibitors based on piperidine and piperazine scaffolds. Bioorg Med Chem Lett. 2010 May 1;20(9):2851-4.
• [7] Discovery of 4-[(2S)-2-{[4-(4-chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl]butanoic acid (DG-051) as a novel leukotriene A4 hydrolase inhibitor of ... J Med Chem. 2010 Jan 28;53(2):573-85.
• [8] Activation and inhibition of leukotriene A4 hydrolase aminopeptidase activity by diphenyl ether and derivatives. Bioorg Med Chem Lett. 2008 Dec 15;18(24):6549-52.
• [9] Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity. J Med Chem. 2008 Jul 24;51(14):4150-69.
• [10] Discovery of multitarget inhibitors by combining molecular docking with common pharmacophore matching. J Med Chem. 2008 Dec 25;51(24):7882-8.
• [11] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [12] Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase. Bioorg Med Chem. 2008 May 1;16(9):4963-83.
• [13] Isolation and structure of leukotriene-A4 hydrolase inhibitor: 8(S)-amino-2(R)-methyl-7-oxononanoic acid produced by Streptomyces diastaticus. J Nat Prod. 1996 Oct;59(10):962-4.
• [14] Synthesis and biological evaluation of N-mercaptoacylcysteine derivatives as leukotriene A4 hydrolase inhibitors. Bioorg Med Chem Lett. 2009 Jan 15;19(2):442-6.