Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOARHCS)

• DOT Name: Protein S100-A9 (S100A9)
• Synonyms: Calgranulin-B; Calprotectin L1H subunit; Leukocyte L1 complex heavy chain; Migration inhibitory factor-related protein 14; MRP-14; p14; S100 calcium-binding protein A9
• Gene Name: S100A9
• UniProt ID: S10A9_HUMAN
• PDB ID: 1IRJ; 1XK4; 4GGF; 4XJK; 5I8N; 5W1F; 6DS2; 7QUV; 7UI5
• Pfam ID: PF01023
• Sequence:
  MTCKMSQLERNIETIINTFHQYSVKLGHPDTLNQGEFKELVRKDLQNFLKKENKNEKVIE
  HIMEDLDTNADKQLSFEEFIMLMARLTWASHEKMHEGDEGPGHHHKPGLGEGTP
• Function: S100A9 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. It can induce neutrophil chemotaxis, adhesion, can increase the bactericidal activity of neutrophils by promoting phagocytosis via activation of SYK, PI3K/AKT, and ERK1/2 and can induce degranulation of neutrophils by a MAPK-dependent mechanism. Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions. The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase. Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transferring arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX. The extracellular functions involve pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its pro-inflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the pro-inflammatory cascade. Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth. Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3. Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK. Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants. Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. Has transnitrosylase activity; in oxidatively-modified low-densitity lipoprotein (LDL(ox))-induced S-nitrosylation of GAPDH on 'Cys-247' proposed to transfer the NO moiety from NOS2/iNOS to GAPDH via its own S-nitrosylated Cys-3. The iNOS-S100A8/A9 transnitrosylase complex is proposed to also direct selective inflammatory stimulus-dependent S-nitrosylation of multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif.
• Tissue Specificity: Calprotectin (S100A8/9) is predominantly expressed in myeloid cells. Except for inflammatory conditions, the expression is restricted to a specific stage of myeloid differentiation since both proteins are expressed in circulating neutrophils and monocytes but are absent in normal tissue macrophages and lymphocytes. Under chronic inflammatory conditions, such as psoriasis and malignant disorders, also expressed in the epidermis. Found in high concentrations at local sites of inflammation or in the serum of patients with inflammatory diseases such as rheumatoid, cystic fibrosis, inflammatory bowel disease, Crohn's disease, giant cell arteritis, cystic fibrosis, Sjogren's syndrome, systemic lupus erythematosus, and progressive systemic sclerosis. Involved in the formation and deposition of amyloids in the aging prostate known as corpora amylacea inclusions. Strongly up-regulated in many tumors, including gastric, esophageal, colon, pancreatic, bladder, ovarian, thyroid, breast and skin cancers.
• KEGG Pathway: IL-17 sig.ling pathway (hsa04657)
• Reactome Pathway:
  MyD88 (R-HSA-166058)
  MyD88 deficiency (TLR2/4) (R-HSA-5602498)
  IRAK4 deficiency (TLR2/4) (R-HSA-5603041)
  RHO GTPases Activate NADPH Oxidases (R-HSA-5668599)
  Regulation of TLR by endogenous ligand (R-HSA-5686938)
  Neutrophil degranulation (R-HSA-6798695)
  Metal sequestration by antimicrobial proteins (R-HSA-6799990)
  ER-Phagosome pathway (R-HSA-1236974)

Molecular Interaction Atlas (MIA) of This DOT

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Protein S100-A9 (S100A9).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein S100-A9 (S100A9).	[27]

41 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein S100-A9 (S100A9).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein S100-A9 (S100A9).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein S100-A9 (S100A9).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein S100-A9 (S100A9).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Protein S100-A9 (S100A9).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein S100-A9 (S100A9).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protein S100-A9 (S100A9).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Protein S100-A9 (S100A9).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Protein S100-A9 (S100A9).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Protein S100-A9 (S100A9).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein S100-A9 (S100A9).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Protein S100-A9 (S100A9).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Protein S100-A9 (S100A9).	[7]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Protein S100-A9 (S100A9).	[3]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Protein S100-A9 (S100A9).	[14]
Diclofenac	DMPIHLS	Approved	Diclofenac increases the expression of Protein S100-A9 (S100A9).	[13]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Protein S100-A9 (S100A9).	[15]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Protein S100-A9 (S100A9).	[10]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Protein S100-A9 (S100A9).	[16]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Protein S100-A9 (S100A9).	[3]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Protein S100-A9 (S100A9).	[13]
Bexarotene	DMOBIKY	Approved	Bexarotene increases the expression of Protein S100-A9 (S100A9).	[17]
Mebendazole	DMO14SG	Approved	Mebendazole increases the expression of Protein S100-A9 (S100A9).	[18]
Flutamide	DMK0O7U	Approved	Flutamide increases the expression of Protein S100-A9 (S100A9).	[13]
Norepinephrine	DMOUC09	Approved	Norepinephrine increases the expression of Protein S100-A9 (S100A9).	[19]
Primidone	DM0WX6I	Approved	Primidone increases the expression of Protein S100-A9 (S100A9).	[13]
Miglitol	DMXBQAM	Approved	Miglitol decreases the expression of Protein S100-A9 (S100A9).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein S100-A9 (S100A9).	[21]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Protein S100-A9 (S100A9).	[22]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol decreases the expression of Protein S100-A9 (S100A9).	[23]
Coprexa	DMA0WEK	Phase 3	Coprexa increases the expression of Protein S100-A9 (S100A9).	[24]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Protein S100-A9 (S100A9).	[25]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Protein S100-A9 (S100A9).	[7]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Protein S100-A9 (S100A9).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Protein S100-A9 (S100A9).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein S100-A9 (S100A9).	[28]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Protein S100-A9 (S100A9).	[29]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Protein S100-A9 (S100A9).	[30]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Protein S100-A9 (S100A9).	[31]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Protein S100-A9 (S100A9).	[32]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Protein S100-A9 (S100A9).	[3]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	D-glucose increases the secretion of Protein S100-A9 (S100A9).	[33]

References

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