Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT1AESL)

• DOT Name: Schlafen family member 5 (SLFN5)
• Gene Name: SLFN5
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Clear cell renal carcinoma
  Glioblastoma multiforme
  Glioma
  Lung cancer
  Lung carcinoma
  Melanoma
  Renal cell carcinoma
  Gastric cancer
  Pancreatic cancer
  Stomach cancer
  Breast cancer
  Breast carcinoma
  Fibrosarcoma
• UniProt ID: SLFN5_HUMAN
• PDB ID: 6RR9; 7CUX; 7PPJ; 7Q3Z
• Pfam ID: PF17057 ; PF09848 ; PF04326 ; PF21026
• Sequence:
  MSLRIDVDTNFPECVVDAGKVTLGTQQRQEMDPRLREKQNEIILRAVCALLNSGGGIIKA
  EIENKGYNYERHGVGLDVPPIFRSHLDKMQKENHFLIFVKSWNTEAGVPLATLCSNLYHR
  ERTSTDVMDSQEALAFLKCRTQTPTNINVSNSLGPQAAQGSVQYEGNINVSAAALFDRKR
  LQYLEKLNLPESTHVEFVMFSTDVSHCVKDRLPKCVSAFANTEGGYVFFGVHDETCQVIG
  CEKEKIDLTSLRASIDGCIKKLPVHHFCTQRPEIKYVLNFLEVHDKGALRGYVCAIKVEK
  FCCAVFAKVPSSWQVKDNRVRQLPTREWTAWMMEADPDLSRCPEMVLQLSLSSATPRSKP
  VCIHKNSECLKEQQKRYFPVFSDRVVYTPESLYKELFSQHKGLRDLINTEMRPFSQGILI
  FSQSWAVDLGLQEKQGVICDALLISQNNTPILYTIFSKWDAGCKGYSMIVAYSLKQKLVN
  KGGYTGRLCITPLVCVLNSDRKAQSVYSSYLQIYPESYNFMTPQHMEALLQSLVIVLLGF
  KSFLSEELGSEVLNLLTNKQYELLSKNLRKTRELFVHGLPGSGKTILALRIMEKIRNVFH
  CEPANILYICENQPLKKLVSFSKKNICQPVTRKTFMKNNFEHIQHIIIDDAQNFRTEDGD
  WYGKAKFITQTARDGPGVLWIFLDYFQTYHLSCSGLPPPSDQYPREEINRVVRNAGPIAN
  YLQQVMQEARQNPPPNLPPGSLVMLYEPKWAQGVPGNLEIIEDLNLEEILIYVANKCRFL
  LRNGYSPKDIAVLFTKASEVEKYKDRLLTAMRKRKLSQLHEESDLLLQIGDASDVLTDHI
  VLDSVCRFSGLERNIVFGINPGVAPPAGAYNLLLCLASRAKRHLYILKASV
• Function: May have a role in hematopoietic cell differentiation.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[2]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	Strong	Altered Expression	[2]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[2]
Melanoma	DIS1RRCY	Strong	Altered Expression	[3]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	moderate	Genetic Variation	[5]
Pancreatic cancer	DISJC981	moderate	Biomarker	[6]
Stomach cancer	DISKIJSX	moderate	Genetic Variation	[5]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[2]
Fibrosarcoma	DISWX7MU	Limited	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Schlafen family member 5 (SLFN5).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Schlafen family member 5 (SLFN5).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Schlafen family member 5 (SLFN5).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Schlafen family member 5 (SLFN5).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Schlafen family member 5 (SLFN5).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Schlafen family member 5 (SLFN5).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Schlafen family member 5 (SLFN5).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Schlafen family member 5 (SLFN5).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Schlafen family member 5 (SLFN5).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Schlafen family member 5 (SLFN5).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Schlafen family member 5 (SLFN5).	[16]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Schlafen family member 5 (SLFN5).	[17]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Schlafen family member 5 (SLFN5).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Schlafen family member 5 (SLFN5).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Schlafen family member 5 (SLFN5).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Schlafen family member 5 (SLFN5).	[20]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Schlafen family member 5 (SLFN5).	[21]
PEITC	DMOMN31	Phase 2	PEITC increases the expression of Schlafen family member 5 (SLFN5).	[22]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Schlafen family member 5 (SLFN5).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Schlafen family member 5 (SLFN5).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Schlafen family member 5 (SLFN5).	[25]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Schlafen family member 5 (SLFN5).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Schlafen family member 5 (SLFN5).	[27]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Schlafen family member 5 (SLFN5).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Schlafen family member 5 (SLFN5).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Schlafen family member 5 (SLFN5).	[29]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Schlafen family member 5 (SLFN5).	[30]

References

• [1] Human SLFN5 is a transcriptional co-repressor of STAT1-mediated interferon responses and promotes the malignant phenotype in glioblastoma.Oncogene. 2017 Oct 26;36(43):6006-6019. doi: 10.1038/onc.2017.205. Epub 2017 Jul 3.
• [2] SLFN5 suppresses cancer cell migration and invasion by inhibiting MT1-MMP expression via AKT/GSK-3/-catenin pathway.Cell Signal. 2019 Jul;59:1-12. doi: 10.1016/j.cellsig.2019.03.004. Epub 2019 Mar 4.
• [3] Role of interferon {alpha} (IFN{alpha})-inducible Schlafen-5 in regulation of anchorage-independent growth and invasion of malignant melanoma cells.J Biol Chem. 2010 Dec 17;285(51):40333-41. doi: 10.1074/jbc.M110.151076. Epub 2010 Oct 18.
• [4] Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells.Mol Cell Biol. 2015 Aug;35(15):2684-98. doi: 10.1128/MCB.00019-15. Epub 2015 May 26.
• [5] SCHLAFEN 5 expression correlates with intestinal metaplasia that progresses to gastric cancer.J Gastroenterol. 2017 Jan;52(1):39-49. doi: 10.1007/s00535-016-1202-4. Epub 2016 Mar 31.
• [6] Silenced ZNF154 Is Associated with Longer Survival in Resectable Pancreatic Cancer.Int J Mol Sci. 2019 Oct 31;20(21):5437. doi: 10.3390/ijms20215437.
• [7] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [8] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [9] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [14] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [15] 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.
• [16] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [17] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [18] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [22] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [23] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [24] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [25] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [26] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [27] 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.
• [28] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [29] 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.
• [30] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.