Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTF10I9)

• DTT Name: Nitric-oxide synthase inducible (NOS2)
• Synonyms: iNOS; Peptidyl-cysteine S-nitrosylase NOS2; Nitric oxide synthase, inducible; NOS2A; NOS type II; Inducible NOS; Inducible NO synthase; Hepatocyte NOS; HEP-NOS
• Gene Name: NOS2
• DTT Type: Clinical trial target; [1]
• Related Disease:
  Osteoarthritis [ICD-11: FA00-FA05]
  Sepsis [ICD-11: 1G40-1G41]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]
  Chronic kidney disease [ICD-11: GB61]
• BioChemical Class: Paired donor oxygen oxidoreductase
• UniProt ID: NOS2_HUMAN
• TTD ID: T02703
• EC Number: EC 1.14.13.39
• Sequence:
  MACPWKFLFKTKFHQYAMNGEKDINNNVEKAPCATSSPVTQDDLQYHNLSKQQNESPQPL
  VETGKKSPESLVKLDATPLSSPRHVRIKNWGSGMTFQDTLHHKAKGILTCRSKSCLGSIM
  TPKSLTRGPRDKPTPPDELLPQAIEFVNQYYGSFKEAKIEEHLARVEAVTKEIETTGTYQ
  LTGDELIFATKQAWRNAPRCIGRIQWSNLQVFDARSCSTAREMFEHICRHVRYSTNNGNI
  RSAITVFPQRSDGKHDFRVWNAQLIRYAGYQMPDGSIRGDPANVEFTQLCIDLGWKPKYG
  RFDVVPLVLQANGRDPELFEIPPDLVLEVAMEHPKYEWFRELELKWYALPAVANMLLEVG
  GLEFPGCPFNGWYMGTEIGVRDFCDVQRYNILEEVGRRMGLETHKLASLWKDQAVVEINI
  AVLHSFQKQNVTIMDHHSAAESFMKYMQNEYRSRGGCPADWIWLVPPMSGSITPVFHQEM
  LNYVLSPFYYYQVEAWKTHVWQDEKRRPKRREIPLKVLVKAVLFACMLMRKTMASRVRVT
  ILFATETGKSEALAWDLGALFSCAFNPKVVCMDKYRLSCLEEERLLLVVTSTFGNGDCPG
  NGEKLKKSLFMLKELNNKFRYAVFGLGSSMYPRFCAFAHDIDQKLSHLGASQLTPMGEGD
  ELSGQEDAFRSWAVQTFKAACETFDVRGKQHIQIPKLYTSNVTWDPHHYRLVQDSQPLDL
  SKALSSMHAKNVFTMRLKSRQNLQSPTSSRATILVELSCEDGQGLNYLPGEHLGVCPGNQ
  PALVQGILERVVDGPTPHQTVRLEALDESGSYWVSDKRLPPCSLSQALTYFLDITTPPTQ
  LLLQKLAQVATEEPERQRLEALCQPSEYSKWKFTNSPTFLEVLEEFPSLRVSAGFLLSQL
  PILKPRFYSISSSRDHTPTEIHLTVAVVTYHTRDGQGPLHHGVCSTWLNSLKPQDPVPCF
  VRNASGFHLPEDPSHPCILIGPGTGIAPFRSFWQQRLHDSQHKGVRGGRMTLVFGCRRPD
  EDHIYQEEMLEMAQKGVLHAVHTAYSRLPGKPKVYVQDILRQQLASEVLRVLHKEPGHLY
  VCGDVRMARDVAHTLKQLVAAKLKLNEEQVEDYFFQLKSQKRYHEDIFGAVFPYEAKKDR
  VAVQPSSLEMSAL
• Function: Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such PTGS2/COX2 (By similarity). As component of the iNOS-S100A8/9 transnitrosylase complex involved in the selective inflammatory stimulus-dependent S-nitrosylation of GAPDH on 'Cys-247' implicated in regulation of the GAIT complex activity and probably multiple targets including ANXA5, EZR, MSN and VIM. Involved in inflammation, enhances the synthesis of proinflammatory mediators such as IL6 and IL8.
• KEGG Pathway:
  Arginine biosynthesis (hsa00220)
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
  Calcium signaling pathway (hsa04020)
  HIF-1 signaling pathway (hsa04066)
  Peroxisome (hsa04146)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Leishmaniasis (hsa05140)
  Chagas disease (American trypanosomiasis) (hsa05142)
  Toxoplasmosis (hsa05145)
  Amoebiasis (hsa05146)
  Tuberculosis (hsa05152)
  Pathways in cancer (hsa05200)
  Small cell lung cancer (hsa05222)
• Reactome Pathway:
  Nitric oxide stimulates guanylate cyclase (R-HSA-392154)
  ROS production in response to bacteria (R-HSA-1222556)
• BioCyc Pathway: MetaCyc:HS00205-MON

Molecular Interaction Atlas (MIA) of This DTT

11 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Curcumin	DMQPH29	Solid tumour/cancer	2A00-2F9Z	Phase 3	[2]
MPL-S	DMNDCFY	Endotoxic shock	1G41	Phase 3	[1]
SD-6010	DM9DEYL	Osteoarthritis	FA00-FA05	Phase 3	[3]
Pimagedine HCl	DMPWH30	Diabetic kidney disease	GB61.Z	Phase 2/3	[4]
BXT-51072	DMD8GNB	Cardiovascular disease	BA00-BE2Z	Phase 2	[5]
CR-3294	DMHJEZS	Diarrhea	ME05.1	Phase 2	[6], [7]
GW274150	DMZMCB1	Asthma	CA23	Phase 2	[8], [9]
HP-228	DMNZ35F	Postoperative pain	MG30-MG3Z	Phase 2	[10]
KD-7040	DME1WV2	Pain	MG30-MG3Z	Phase 2	[11]
LT-1951	DM5N04G	Coronary artery disease	BA80	Phase 1/2	[12]
Aminoguanidine	DMJQDUC	Diabetic retinopathy	9B71.0	Phase 1	[13]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
NOStentin	DMWDE8K	Artery stenosis	BD52	Discontinued in Phase 1	[14]
ONO-1714	DML7Q56	Sepsis	1G40-1G41	Discontinued in Phase 1	[15], [16]
L-NIL	DM6Y49D	N. A.	N. A.	Terminated	[17]

115 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
((E)-7-But-2-enyl)-azepan-(2Z)-ylideneamine	DMCW65Q	Discovery agent	N.A.	Investigative	[18]
(4S,5R)-4,5-Diethyl-oxazolidin-(2Z)-ylideneamine	DMM6QV5	Discovery agent	N.A.	Investigative	[19]
(4S,5R)-4,5-Dimethyl-oxazolidin-(2Z)-ylideneamine	DM0V9HB	Discovery agent	N.A.	Investigative	[19]
(4S,5R)-4,5-Dipropyl-oxazolidin-(2Z)-ylideneamine	DMDC84U	Discovery agent	N.A.	Investigative	[19]
(4S,5S)-4,5-Diethyl-oxazolidin-(2Z)-ylideneamine	DM1VJUZ	Discovery agent	N.A.	Investigative	[19]
(4S,5S)-4,5-Dipropyl-oxazolidin-(2Z)-ylideneamine	DM5EKF4	Discovery agent	N.A.	Investigative	[19]
(5-Imino-[1,4]thiazepan-3-yl)-methanol	DMBKZDJ	Discovery agent	N.A.	Investigative	[20]
(5S,6R)-[Octahydro-quinolin-(2E)-ylidene]amine	DMT9CXD	Discovery agent	N.A.	Investigative	[21]
(5S,6S)-[Octahydro-quinolin-(2E)-ylidene]amine	DMP4UC1	Discovery agent	N.A.	Investigative	[21]
(6r,1'r,2's)-5,6,7,8 Tetrahydrobiopterin	DMOD9R7	Discovery agent	N.A.	Investigative	[22]
(E)-4-Methyl-6-(prop-1-enyl)pyridin-2-amine	DM75OHG	Discovery agent	N.A.	Investigative	[23]
(R)-3-Propyl-[1,4]thiazepan-(5E)-ylideneamine	DM1Y9MZ	Discovery agent	N.A.	Investigative	[20]
(S)-2-Amino-5-(N-methyl-guanidino)-pentanoic acid	DMZSWDM	Discovery agent	N.A.	Investigative	[24]
(S)-2-Amino-6-[(E)-ethylimino]-hexanoic acid	DMRG80O	Discovery agent	N.A.	Investigative	[24]
(S)-3-Propyl-[1,4]thiazepan-(5E)-ylideneamine	DMIG9H3	Discovery agent	N.A.	Investigative	[20]
(S)-6-Amino-2-(2-imino-ethylamino)-hexanoic acid	DMG58HM	Discovery agent	N.A.	Investigative	[20]
(S)-N-(1-phenylethyl)acetimidamide hydrobromide	DMLR0N3	Discovery agent	N.A.	Investigative	[25]
1-(6-Amino-4-methylpyridin-2-yl)propan-2-ol	DMUS9Z3	Discovery agent	N.A.	Investigative	[23]
1400W	DMLZT64	Discovery agent	N.A.	Investigative	[26], [27], [25]
2-(2-Amino-ethyl)-7-imino-azepane	DM3JM7V	Discovery agent	N.A.	Investigative	[18]
2-amino-4-methylpyridine	DM1OED2	Discovery agent	N.A.	Investigative	[28], [29]
2-Amino-5-(N-nitro-guanidino)-pentanoic acid	DMDUZ2H	Discovery agent	N.A.	Investigative	[24]
2-Aminothiazoline	DM9YCAH	Discovery agent	N.A.	Investigative	[30]
2-Methyl-[1,4]thiazepan-(5E)-ylideneamine	DMX1IC4	Discovery agent	N.A.	Investigative	[20]
3,4-Dihydro-1H-quinolin-(2E)-ylideneamine	DM0I6UT	Discovery agent	N.A.	Investigative	[21]
3,4-Dimethyl-pyrrolidin-(2Z)-ylideneamine	DMMO6QI	Discovery agent	N.A.	Investigative	[30]
3-(2-Amino-ethyl)-5-imino-[1,4]oxazepane	DM95R6O	Discovery agent	N.A.	Investigative	[18]
3-(2-Nitro-ethyl)-[1,4]oxazepan-(5Z)-ylideneamine	DMYXQ7L	Discovery agent	N.A.	Investigative	[18]
3-Bromo-1H-indazole-7-carbonitrile	DMZGWL2	Discovery agent	N.A.	Investigative	[31]
3-bromo-7-nitro-1H-indazole	DMM7DHB	Discovery agent	N.A.	Investigative	[22], [32]
3-Butyl-[1,4]oxazepan-(5Z)-ylideneamine	DMRI503	Discovery agent	N.A.	Investigative	[18]
3-Butyl-[1,4]thiazepan-(5E)-ylideneamine	DM6A80U	Discovery agent	N.A.	Investigative	[20]
3-Ethyl-[1,4]thiazepan-(5E)-ylideneamine	DMX2JKQ	Discovery agent	N.A.	Investigative	[20]
3-Isobutyl-[1,4]thiazepan-(5E)-ylideneamine	DMQXP7C	Discovery agent	N.A.	Investigative	[20]
3-Methyl-pyrrolidin-(2Z)-ylideneamine	DMHVUF8	Discovery agent	N.A.	Investigative	[30]
3-Methyl-[1,4]thiazepan-(5E)-ylideneamine	DMCOH46	Discovery agent	N.A.	Investigative	[20]
3-Propyl-[1,4]thiazepan-(5E)-ylideneamine	DMYACO7	Discovery agent	N.A.	Investigative	[20]
4,5,6,7-tetrafluoro-3-methyl-1H-indazole	DMTC7J2	Discovery agent	N.A.	Investigative	[32]
4,5,6,7-tetrafluoro-3-perfluorophenyl-1H-indazole	DMZEY31	Discovery agent	N.A.	Investigative	[32]
4,5-Dimethyl-pyrrolidin-(2Z)-ylideneamine	DMB9CJM	Discovery agent	N.A.	Investigative	[30]
4-(1H-IMIDAZOL-1-YL)PHENOL	DM5JDYO	Discovery agent	N.A.	Investigative	[27]
4-Butyl-thiazolidin-(2E)-ylideneamine	DMKU4TR	Discovery agent	N.A.	Investigative	[30]
4-Ethyl-3-methyl-pyrrolidin-(2Z)-ylideneamine	DM5G3NU	Discovery agent	N.A.	Investigative	[30]
4-Ethyl-5-methyl-pyrrolidin-(2Z)-ylideneamine	DMOAQ1E	Discovery agent	N.A.	Investigative	[30]
4-Ethyl-oxazolidin-(2Z)-ylideneamine	DMG0Y3W	Discovery agent	N.A.	Investigative	[19]
4-Ethyl-pyrrolidin-(2Z)-ylideneamine	DMYIWAH	Discovery agent	N.A.	Investigative	[30]
4-Isopropyl-pyrrolidin-(2Z)-ylideneamine	DMVTEOQ	Discovery agent	N.A.	Investigative	[30]
4-Methyl-5-propyl-pyrrolidin-(2Z)-ylideneamine	DMN8Z3C	Discovery agent	N.A.	Investigative	[30]
4-Methyl-6-(2-methylprop-1-enyl)pyridin-2-amine	DMW7YHS	Discovery agent	N.A.	Investigative	[23]
4-methyl-6-propylpyridin-2-amine	DMY04D1	Discovery agent	N.A.	Investigative	[29]
4-Methyl-oxazolidin-(2Z)-ylideneamine	DME7W0Q	Discovery agent	N.A.	Investigative	[19]
4-Methyl-piperidin-(2E)-ylideneamine	DMNMXCE	Discovery agent	N.A.	Investigative	[21]
4-Methyl-pyrrolidin-(2Z)-ylideneamine	DM0YS36	Discovery agent	N.A.	Investigative	[30]
4-[(2-Methyl-1H-imidazol-1-yl)methyl]pyridine	DM8BPTQ	Discovery agent	N.A.	Investigative	[25]
4r-Fluoro-N6-Ethanimidoyl-L-Lysine	DMUGFS3	Discovery agent	N.A.	Investigative	[22]
5-Bromomethyl-oxazolidin-(2Z)-ylideneamine	DMH908V	Discovery agent	N.A.	Investigative	[19]
5-Ethyl-4-methyl-pyrrolidin-(2Z)-ylideneamine	DMQWOIG	Discovery agent	N.A.	Investigative	[30]
5-Ethyl-4-propyl-pyrrolidin-(2Z)-ylideneamine	DMSA8X2	Discovery agent	N.A.	Investigative	[30]
5-Ethyl-oxazolidin-(2Z)-ylideneamine	DM8Y4G5	Discovery agent	N.A.	Investigative	[19]
5-Methyl-4-propyl-pyrrolidin-(2Z)-ylideneamine	DM6DEOC	Discovery agent	N.A.	Investigative	[30]
5-Methyl-oxazolidin-(2Z)-ylideneamine	DMBQS31	Discovery agent	N.A.	Investigative	[19]
5-Methyl-pyrrolidin-(2Z)-ylideneamine	DM4QB3G	Discovery agent	N.A.	Investigative	[30]
5-Nitroindazole	DMH7SIX	Discovery agent	N.A.	Investigative	[22]
6-(2-Fluoropropyl)-4-methylpyridin-2-amine	DME1JLM	Discovery agent	N.A.	Investigative	[23]
6-(3-Fluoropropyl)-4-methylpyridin-2-amine	DMTJPZU	Discovery agent	N.A.	Investigative	[23]
6-(4-Fluorobutyl)-4-methylpyridin-2-amine	DM3EDBO	Discovery agent	N.A.	Investigative	[23]
6-isobutyl-4-methylpyridin-2-amine	DM2XB68	Discovery agent	N.A.	Investigative	[23]
6-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine	DMSLT3I	Discovery agent	N.A.	Investigative	[33]
6-Nitroindazole	DM2WZCX	Discovery agent	N.A.	Investigative	[22]
7,8-dihydrobiopterin	DMQU4XM	Discovery agent	N.A.	Investigative	[34], [22]
7-(2-Nitro-ethyl)-azepan-(2Z)-ylideneamine	DMK28IS	Discovery agent	N.A.	Investigative	[18]
7-Butyl-azepan-(2Z)-ylideneamine	DMVTK0A	Discovery agent	N.A.	Investigative	[18]
7-Methyl-[1,4]thiazepan-(5E)-ylideneamine	DMUCJA6	Discovery agent	N.A.	Investigative	[20]
7-nitro-1H-indazole	DMW4XKQ	Discovery agent	N.A.	Investigative	[22], [32]
Aminothiazoline	DMGEVBH	Discovery agent	N.A.	Investigative	[35]
AR-C102222	DMWVULN	Discovery agent	N.A.	Investigative	[29]
AR-C133057XX	DM71WQT	Discovery agent	N.A.	Investigative	[29]
Azepan-(2Z)-ylideneamine	DMZHV39	Discovery agent	N.A.	Investigative	[18]
Azocan-(2Z)-ylideneamine	DMQ13PZ	Discovery agent	N.A.	Investigative	[18]
Azonan-(2Z)-ylideneamine	DMTQSNK	Discovery agent	N.A.	Investigative	[24]
B-Octylglucoside	DMMO75G	Discovery agent	N.A.	Investigative	[22]
BYK-191023	DMAWMDN	Inflammation	1A00-CA43.1	Investigative	[36]
CDDO	DM03NUV	Discovery agent	N.A.	Investigative	[37]
Ethylisothiourea	DMV9OCU	N. A.	N. A.	Investigative	[22]
Heme	DMGC287	Discovery agent	N.A.	Investigative	[27]
Hexahydro-cyclopenta[c]pyrrol-(1Z)-ylideneamine	DMG0UVT	Discovery agent	N.A.	Investigative	[30]
KD-7332	DMJ2X64	Inflammation	1A00-CA43.1	Investigative	[36]
L-NIO	DME9FAV	Discovery agent	N.A.	Investigative	[38]
L-Thiocitrulline	DMP8O6R	Discovery agent	N.A.	Investigative	[22]
N,N-dimethylarginine	DM0Y8OW	Discovery agent	N.A.	Investigative	[39]
N-(5-Amino-6-oxo-heptyl)-acetamidine	DM47XR8	Discovery agent	N.A.	Investigative	[30]
N-benzylacetimidamide hydrobromide	DM26R4P	Discovery agent	N.A.	Investigative	[25]
N-omega-allyl-L-arginine	DM0BPCT	Discovery agent	N.A.	Investigative	[38]
N-Omega-Hydroxy-L-Arginine	DMOXQ3N	Discovery agent	N.A.	Investigative	[22]
N-omega-propargyl-L-arginine	DM9X3B7	Discovery agent	N.A.	Investigative	[38]
N-Omega-Propyl-L-Arginine	DM4X0WY	Discovery agent	N.A.	Investigative	[22]
N5-(1-iminobut-3-enyl)-L-ornithine	DMB62OI	Discovery agent	N.A.	Investigative	[38]
N5-(1-iminobutyl)-L-ornithine	DMT893N	Discovery agent	N.A.	Investigative	[38]
N5-(1-iminopropyl)-L-ornithine	DM05O7J	Discovery agent	N.A.	Investigative	[38]
Octahydro-isoindol-(1Z)-ylideneamine	DM4C70S	Discovery agent	N.A.	Investigative	[30]
Oxazolidin-(2Z)-ylideneamine	DM8109D	Discovery agent	N.A.	Investigative	[19]
PIBTU	DMQBAM6	Discovery agent	N.A.	Investigative	[40]
Piperidin-(2E)-ylideneamine	DMN8OR2	Discovery agent	N.A.	Investigative	[21]
Pyrrolidin-(2Z)-ylideneamine	DMS4ZFU	Discovery agent	N.A.	Investigative	[30]
Resveratrol Potassium4,-Sulfate	DMMFP57	Discovery agent	N.A.	Investigative	[41]
SKLB-010	DMUVAFO	Inflammation	1A00-CA43.1	Investigative	[36]
THIOCITRULLINE	DM7X8MH	Discovery agent	N.A.	Investigative	[42]
Thiocoumarin	DMPTSN0	Discovery agent	N.A.	Investigative	[27]
[1,3]Oxazinan-(2E)-ylideneamine	DMDX6W4	Discovery agent	N.A.	Investigative	[24]
[1,3]Thiazinan-(2E)-ylideneamine	DMOEIHC	Discovery agent	N.A.	Investigative	[24]
[1,4]Oxazepan-(3E)-ylideneamine	DMX58NK	Discovery agent	N.A.	Investigative	[20]
[1,4]Oxazepan-(5E)-ylideneamine	DMMUZVS	Discovery agent	N.A.	Investigative	[20]
[1,4]Thiazepan-(3E)-ylideneamine	DMCBFJQ	Discovery agent	N.A.	Investigative	[20]
[1,4]Thiazepan-(5E)-ylideneamine	DMFQ0Z4	Discovery agent	N.A.	Investigative	[20]
[1,5]Thiazocan-(4E)-ylideneamine	DMF62JR	Discovery agent	N.A.	Investigative	[18]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Coronary artery disease	BA80-BA8Z	Peripheral blood	9.15E-01	-0.02	-0.09
Asthma	CA23	Nasal and bronchial airway	5.49E-08	0.74	0.7
Osteoarthritis	FA20	Synovial tissue	4.24E-02	-0.27	-0.88
Sepsis with septic shock	1G41	Whole blood	6.14E-01	-0.07	-0.26

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

• DTT DME Name: Nitric oxide synthase inducible (NOS2) DME Info
• Gene Name: NOS2

1 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	[43]

References

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