Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGE9ETG)

• DOT Name: Metalloreductase STEAP2 (STEAP2)
• Synonyms: EC 1.16.1.-; Prostate cancer-associated protein 1; Protein up-regulated in metastatic prostate cancer; PUMPCn; Six-transmembrane epithelial antigen of prostate 2; SixTransMembrane protein of prostate 1
• Gene Name: STEAP2
• UniProt ID: STEA2_HUMAN
• PDB ID: 7TAI
• EC Number: 1.16.1.-
• Pfam ID: PF03807 ; PF01794
• Sequence:
  MESISMMGSPKSLSETFLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS
  RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM
  RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE
  LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA
  RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ
  CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY
  ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQSTLGYVALLISTFHVLIYGWKRAFE
  EEYYRFYTPPNFVLALVLPSIVILGKIILFLPCISRKLKRIKKGWEKSQFLEEGMGGTIP
  HVSPERVTVM
• Function: Integral membrane protein that functions as a NADPH-dependent ferric-chelate reductase, using NADPH from one side of the membrane to reduce a Fe(3+) chelate that is bound on the other side of the membrane. Mediates sequential transmembrane electron transfer from NADPH to FAD and onto heme, and finally to the Fe(3+) chelate. Can also reduce Cu(2+) to Cu(1+).
• Tissue Specificity: Expressed at high levels in prostate and at significantly lower levels in heart, brain, kidney, pancreas, and ovary.
• KEGG Pathway: Mineral absorption (hsa04978)
• Reactome Pathway: Transferrin endocytosis and recycling (R-HSA-917977)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Lovastatin	DM9OZWQ	Approved	Metalloreductase STEAP2 (STEAP2) decreases the response to substance of Lovastatin.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Metalloreductase STEAP2 (STEAP2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Metalloreductase STEAP2 (STEAP2).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Metalloreductase STEAP2 (STEAP2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Metalloreductase STEAP2 (STEAP2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Metalloreductase STEAP2 (STEAP2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Metalloreductase STEAP2 (STEAP2).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Metalloreductase STEAP2 (STEAP2).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Metalloreductase STEAP2 (STEAP2).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Metalloreductase STEAP2 (STEAP2).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Metalloreductase STEAP2 (STEAP2).	[10]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Metalloreductase STEAP2 (STEAP2).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Metalloreductase STEAP2 (STEAP2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Metalloreductase STEAP2 (STEAP2).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Metalloreductase STEAP2 (STEAP2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Metalloreductase STEAP2 (STEAP2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Metalloreductase STEAP2 (STEAP2).	[17]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Metalloreductase STEAP2 (STEAP2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Metalloreductase STEAP2 (STEAP2).	[11]

References

• [1] In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells. Arch Toxicol. 2016 Mar;90(3):677-89. doi: 10.1007/s00204-015-1483-z. Epub 2015 Feb 26.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [7] 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.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [14] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [15] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [16] 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.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.
• [19] NCI60 cancer cell line panel data and RNAi analysis help identify EAF2 as a modulator of simvastatin and lovastatin response in HCT-116 cells. PLoS One. 2011 Apr 4;6(4):e18306. doi: 10.1371/journal.pone.0018306.