Details of Drug Off-Target (DOT)

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

• DOT Name: Solute carrier family 22 member 17 (SLC22A17)
• Synonyms: 24p3 receptor; 24p3R; Brain-type organic cation transporter; Lipocalin-2 receptor; Neutrophil gelatinase-associated lipocalin receptor; NgalR
• Gene Name: SLC22A17
• UniProt ID: S22AH_HUMAN
• Pfam ID: PF00083
• Sequence:
  MAPRVATGTPEPNGGGGGKIDNTVEITPTSNGQVGTLGDAVPTEQLQGEREREREGEGDA
  GGDGLGSSLSLAVPPGPLSFEALLAQVGALGGGQQLQLGLCCLPVLFVALGMASDPIFTL
  APPLHCHYGAFPPNASGWEQPPNASGVSVASAALAASAASRVATSTDPSCSGFAPPDFNH
  CLKDWDYNGLPVLTTNAIGQWDLVCDLGWQVILEQILFILGFASGYLFLGYPADRFGRRG
  IVLLTLGLVGPCGVGGAAAGSSTGVMALRFLLGFLLAGVDLGVYLMRLELCDPTQRLRVA
  LAGELVGVGGHFLFLGLALVSKDWRFLQRMITAPCILFLFYGWPGLFLESARWLIVKRQI
  EEAQSVLRILAERNRPHGQMLGEEAQEALQDLENTCPLPATSSFSFASLLNYRNIWKNLL
  ILGFTNFIAHAIRHCYQPVGGGGSPSDFYLCSLLASGTAALACVFLGVTVDRFGRRGILL
  LSMTLTGIASLVLLGLWDCEHPIFPTVWAQQGNPNRDLNEAAITTFSVLGLFSSQAAAIL
  STLLAAEVIPTTVRGRGLGLIMALGALGGLSGPAQRLHMGHGAFLQHVVLAACALLCILS
  IMLLPETKRKLLPEVLRDGELCRRPSLLRQPPPTRCDHVPLLATPNPAL
• Function: Cell surface receptor for LCN2 (24p3) that plays a key role in iron homeostasis and transport. Able to bind iron-bound LCN2 (holo-24p3), followed by internalization of holo-24p3 and release of iron, thereby increasing intracellular iron concentration and leading to inhibition of apoptosis. Also binds iron-free LCN2 (apo-24p3), followed by internalization of apo-24p3 and its association with an intracellular siderophore, leading to iron chelation and iron transfer to the extracellular medium, thereby reducing intracellular iron concentration and resulting in apoptosis.
• Tissue Specificity: Expressed in brain.
• Reactome Pathway: Iron uptake and transport (R-HSA-917937)

Molecular Interaction Atlas (MIA) of This DOT

9 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 Solute carrier family 22 member 17 (SLC22A17).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Solute carrier family 22 member 17 (SLC22A17).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Solute carrier family 22 member 17 (SLC22A17).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Solute carrier family 22 member 17 (SLC22A17).	[4]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Solute carrier family 22 member 17 (SLC22A17).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Solute carrier family 22 member 17 (SLC22A17).	[7]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Solute carrier family 22 member 17 (SLC22A17).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Solute carrier family 22 member 17 (SLC22A17).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Solute carrier family 22 member 17 (SLC22A17).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Solute carrier family 22 member 17 (SLC22A17).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Solute carrier family 22 member 17 (SLC22A17).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Solute carrier family 22 member 17 (SLC22A17).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Solute carrier family 22 member 17 (SLC22A17).	[13]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [7] 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.
• [8] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] 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.
• [12] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [13] 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.