Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2AH8VJ)

• DOT Name: Mesencephalic astrocyte-derived neurotrophic factor (MANF)
• Synonyms: Arginine-rich protein; Protein ARMET
• Gene Name: MANF
• UniProt ID: MANF_HUMAN
• PDB ID: 2KVD; 2KVE; 2W51
• Pfam ID: PF10208 ; PF20145
• Sequence:
  MRRMWATQGLAVALALSVLPGSRALRPGDCEVCISYLGRFYQDLKDRDVTFSPATIENEL
  IKFCREARGKENRLCYYIGATDDAATKIINEVSKPLAHHIPVEKICEKLKKKDSQICELK
  YDKQIDLSTVDLKKLRVKELKKILDDWGETCKGCAEKSDYIRKINELMPKYAPKAASART
  DL
• Function: Selectively promotes the survival of dopaminergic neurons of the ventral mid-brain. Modulates GABAergic transmission to the dopaminergic neurons of the substantia nigra. Enhances spontaneous, as well as evoked, GABAergic inhibitory postsynaptic currents in dopaminergic neurons. Inhibits cell proliferation and endoplasmic reticulum (ER) stress-induced cell death. Retained in the ER/sarcoplasmic reticulum (SR) through association with the endoplasmic reticulum chaperone protein HSPA5 under normal conditions. Up-regulated and secreted by the ER/SR in response to ER stress and hypoxia. Following secretion by the ER/SR, directly binds to 3-O-sulfogalactosylceramide, a lipid sulfatide in the outer cell membrane of target cells. Sulfatide binding promotes its cellular uptake by endocytosis, and is required for its role in alleviating ER stress and cell toxicity under hypoxic and ER stress conditions.
• Reactome Pathway: Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[11]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[12]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[20]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[21]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF).	[22]

References

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• [12] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [13] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
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• [16] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [17] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
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• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [21] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [22] Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells. Toxicol In Vitro. 2018 Feb;46:102-112.