Details of Drug Off-Target (DOT)

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

• DOT Name: Schlafen family member 11 (SLFN11)
• Synonyms: EC 3.6.-.-
• Gene Name: SLFN11
• Related Disease:
  Advanced cancer
  Ataxia-telangiectasia
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Ewing sarcoma/peripheral primitive neuroectodermal tumor
  HIV infectious disease
  Neoplasm
  Neuroblastoma
  Polyarteritis nodosa
  Rhabdomyosarcoma
  Vasculitis due to ADA2 deficiency
  Ewing sarcoma
  Head-neck squamous cell carcinoma
  leukaemia
  Leukemia
  Adult glioblastoma
  Glioblastoma multiforme
  Small-cell lung cancer
  Zika virus infection
• UniProt ID: SLN11_HUMAN
• PDB ID: 7ZEL; 7ZEP; 7ZES
• EC Number: 3.6.-.-
• Pfam ID: PF17057 ; PF09848 ; PF04326 ; PF21026
• Sequence:
  MEANQCPLVVEPSYPDLVINVGEVTLGEENRKKLQKIQRDQEKERVMRAACALLNSGGGV
  IRMAKKVEHPVEMGLDLEQSLRELIQSSDLQAFFETKQQGRCFYIFVKSWSSGPFPEDRS
  VKPRLCSLSSSLYRRSETSVRSMDSREAFCFLKTKRKPKILEEGPFHKIHKGVYQELPNS
  DPADPNSDPADLIFQKDYLEYGEILPFPESQLVEFKQFSTKHFQEYVKRTIPEYVPAFAN
  TGGGYLFIGVDDKSREVLGCAKENVDPDSLRRKIEQAIYKLPCVHFCQPQRPITFTLKIV
  NVLKRGELYGYACMIRVNPFCCAVFSEAPNSWIVEDKYVCSLTTEKWVGMMTDTDPDLLQ
  LSEDFECQLSLSSGPPLSRPVYSKKGLEHKKELQQLLFSVPPGYLRYTPESLWRDLISEH
  RGLEELINKQMQPFFRGILIFSRSWAVDLNLQEKPGVICDALLIAQNSTPILYTILREQD
  AEGQDYCTRTAFTLKQKLVNMGGYTGKVCVRAKVLCLSPESSAEALEAAVSPMDYPASYS
  LAGTQHMEALLQSLVIVLLGFRSLLSDQLGCEVLNLLTAQQYEIFSRSLRKNRELFVHGL
  PGSGKTIMAMKIMEKIRNVFHCEAHRILYVCENQPLRNFISDRNICRAETRKTFLRENFE
  HIQHIVIDEAQNFRTEDGDWYGKAKSITRRAKGGPGILWIFLDYFQTSHLDCSGLPPLSD
  QYPREELTRIVRNADPIAKYLQKEMQVIRSNPSFNIPTGCLEVFPEAEWSQGVQGTLRIK
  KYLTVEQIMTCVADTCRRFFDRGYSPKDVAVLVSTAKEVEHYKYELLKAMRKKRVVQLSD
  ACDMLGDHIVLDSVRRFSGLERSIVFGIHPRTADPAILPNVLICLASRAKQHLYIFPWGG
  H
• Function: Inhibitor of DNA replication that promotes cell death in response to DNA damage. Acts as a guardian of the genome by killing cells with defective replication. Persistently blocks stressed replication forks by opening chromatin across replication initiation sites at stressed replication forks, possibly leading to unwind DNA ahead of the MCM helicase and block fork progression, ultimately leading to cell death. Acts independently of ATR. Also acts as an interferon (IFN)-induced antiviral protein which acts as an inhibitor of retrovirus protein synthesis. Specifically abrogates the production of retroviruses such as human immunodeficiency virus 1 (HIV-1) by acting as a specific inhibitor of the synthesis of retroviruses encoded proteins in a codon-usage-dependent manner. Binds to tRNAs and exploits the unique viral codon bias towards A/T nucleotides. The exact inhibition mechanism is unclear: may either sequester tRNAs, prevent their maturation via post-transcriptional processing or may accelerate their deacylation. Does not inhibit reverse transcription, integration or production and nuclear export of viral RNA.
• Tissue Specificity: Exhibits a wider expression range in ovarian and colon adenocarcinoma than in their corresponding healthy tissues.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Ataxia-telangiectasia	DISP3EVR	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Ewing sarcoma/peripheral primitive neuroectodermal tumor	DISD4VQC	Strong	Altered Expression	[5]
HIV infectious disease	DISO97HC	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[5]
Polyarteritis nodosa	DISRQ5X8	Strong	Biomarker	[8]
Rhabdomyosarcoma	DISNR7MS	Strong	Altered Expression	[5]
Vasculitis due to ADA2 deficiency	DIS1UHPY	Strong	Biomarker	[8]
Ewing sarcoma	DISQYLV3	moderate	Altered Expression	[9]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[10]
leukaemia	DISS7D1V	moderate	Altered Expression	[9]
Leukemia	DISNAKFL	moderate	Altered Expression	[9]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[11]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[11]
Small-cell lung cancer	DISK3LZD	Limited	Biomarker	[12]
Zika virus infection	DISQUCTY	Limited	Biomarker	[11]

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 Schlafen family member 11 (SLFN11).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Schlafen family member 11 (SLFN11).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Schlafen family member 11 (SLFN11).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Schlafen family member 11 (SLFN11).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Schlafen family member 11 (SLFN11).	[17]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Schlafen family member 11 (SLFN11).	[18]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Schlafen family member 11 (SLFN11).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Schlafen family member 11 (SLFN11).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Schlafen family member 11 (SLFN11).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Schlafen family member 11 (SLFN11).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Schlafen family member 11 (SLFN11).	[21]

References

• [1] SLFN11 is a general target for enhancing the sensitivity of cancer to chemotherapy (DNA-damaging agents).J Drug Target. 2020 Jan;28(1):33-40. doi: 10.1080/1061186X.2019.1616746. Epub 2019 Jun 27.
• [2] Schlafen11 Expression Is Associated With the Antitumor Activity of Trabectedin in Human Sarcoma Cell Lines.Anticancer Res. 2019 Jul;39(7):3553-3563. doi: 10.21873/anticanres.13501.
• [3] Schlafen-11 expression is associated with immune signatures and basal-like phenotype in breast cancer.Breast Cancer Res Treat. 2019 Sep;177(2):335-343. doi: 10.1007/s10549-019-05313-w. Epub 2019 Jun 20.
• [4] Methylation of SLFN11 is a marker of poor prognosis and cisplatin resistance in colorectal cancer.Epigenomics. 2017 Jun;9(6):849-862. doi: 10.2217/epi-2017-0019. Epub 2017 Apr 13.
• [5] Activity of MM-398, nanoliposomal irinotecan (nal-IRI), in Ewing's family tumor xenografts is associated with high exposure of tumor to drug and high SLFN11 expression.Clin Cancer Res. 2015 Mar 1;21(5):1139-50. doi: 10.1158/1078-0432.CCR-14-1882.
• [6] Dephosphorylation activates the interferon-stimulated Schlafen family member 11 in the DNA damage response.J Biol Chem. 2019 Oct 4;294(40):14674-14685. doi: 10.1074/jbc.RA118.006588. Epub 2019 Aug 8.
• [7] SLFN11 can sensitize tumor cells towards IFN--mediated T cell killing.PLoS One. 2019 Feb 12;14(2):e0212053. doi: 10.1371/journal.pone.0212053. eCollection 2019.
• [8] Integrated pan-cancer gene expression and drug sensitivity analysis reveals SLFN11 mRNA as a solid tumor biomarker predictive of sensitivity to DNA-damaging chemotherapy.PLoS One. 2019 Nov 4;14(11):e0224267. doi: 10.1371/journal.pone.0224267. eCollection 2019.
• [9] SLFN11 Is a Transcriptional Target of EWS-FLI1 and a Determinant of Drug Response in Ewing Sarcoma.Clin Cancer Res. 2015 Sep 15;21(18):4184-93. doi: 10.1158/1078-0432.CCR-14-2112. Epub 2015 Mar 16.
• [10] Radiosensitization of head and neck squamous cell carcinoma lines by DNA-PK inhibitors is more effective than PARP-1 inhibition and is enhanced by SLFN11 and hypoxia.Int J Radiat Biol. 2019 Dec;95(12):1597-1612. doi: 10.1080/09553002.2019.1664787. Epub 2019 Sep 17.
• [11] Schlafen 11 Restricts Flavivirus Replication.J Virol. 2019 Jul 17;93(15):e00104-19. doi: 10.1128/JVI.00104-19. Print 2019 Aug 1.
• [12] Novel targeted strategies to overcome resistance in small-cell lung cancer: focus on PARP inhibitors and rovalpituzumab tesirine.Expert Rev Anticancer Ther. 2019 Jun;19(6):461-471. doi: 10.1080/14737140.2019.1624530. Epub 2019 May 31.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] 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.
• [16] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [17] 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.
• [18] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [19] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [20] 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.
• [21] 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.
• [22] 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.