Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTBXM25)

• DOT Name: Ribonuclease SLFN12 (SLFN12)
• Synonyms: EC 3.1.-.-; Schlafen family member 12
• Gene Name: SLFN12
• Related Disease:
  Short bowel syndrome
  Advanced cancer
  Colon cancer
  Colon carcinoma
  Neoplasm
  Sezary syndrome
  Triple negative breast cancer
  Gastrointestinal stromal tumour
• UniProt ID: SLN12_HUMAN
• PDB ID: 7EG0; 7EG1; 7EG4; 7LRC; 7LRD; 7LRE
• EC Number: 3.1.-.-
• Pfam ID: PF17057 ; PF04326 ; PF21026
• Sequence:
  MNISVDLETNYAELVLDVGRVTLGENSRKKMKDCKLRKKQNESVSRAMCALLNSGGGVIK
  AEIENEDYSYTKDGIGLDLENSFSNILLFVPEYLDFMQNGNYFLIFVKSWSLNTSGLRIT
  TLSSNLYKRDITSAKVMNATAALEFLKDMKKTRGRLYLRPELLAKRPCVDIQEENNMKAL
  AGVFFDRTELDRKEKLTFTESTHVEIKNFSTEKLLQRIKEILPQYVSAFANTDGGYLFIG
  LNEDKEIIGFKAEMSDLDDLEREIEKSIRKMPVHHFCMEKKKINYSCKFLGVYDKGSLCG
  YVCALRVERFCCAVFAKEPDSWHVKDNRVMQLTRKEWIQFMVEAEPKFSSSYEEVISQIN
  TSLPAPHSWPLLEWQRQRHHCPGLSGRITYTPENLCRKLFLQHEGLKQLICEEMDSVRKG
  SLIFSRSWSVDLGLQENHKVLCDALLISQDSPPVLYTFHMVQDEEFKGYSTQTALTLKQK
  LAKIGGYTKKVCVMTKIFYLSPEGMTSCQYDLRSQVIYPESYYFTRRKYLLKALFKALKR
  LKSLRDQFSFAENLYQIIGIDCFQKNDKKMFKSCRRLT
• Function: Ribonuclease which is part of an E2/17beta-estradiol-induced pro-apoptotic signaling pathway. E2 stabilizes the PDE3A/SLFN12 complex in the cytosol, promoting the dephosphorylation of SLFN12 and activating its pro-apoptotic ribosomal RNA/rRNA ribonuclease activity. This apoptotic pathway might be relevant in tissues with high concentration of E2 and be for instance involved in placenta remodeling. May play a role in cell differentiation.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Short bowel syndrome	DISMB5FU	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Sezary syndrome	DISFMTC7	Strong	Genetic Variation	[5]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[4]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[6]

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 Ribonuclease SLFN12 (SLFN12).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ribonuclease SLFN12 (SLFN12).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ribonuclease SLFN12 (SLFN12).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Ribonuclease SLFN12 (SLFN12).	[10]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Ribonuclease SLFN12 (SLFN12).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ribonuclease SLFN12 (SLFN12).	[12]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Ribonuclease SLFN12 (SLFN12).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ribonuclease SLFN12 (SLFN12).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ribonuclease SLFN12 (SLFN12).	[15]

1 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 affects the methylation of Ribonuclease SLFN12 (SLFN12).	[13]

References

• [1] Regulation of epithelial differentiation in rat intestine by intraluminal delivery of an adenoviral vector or silencing RNA coding for Schlafen 3.PLoS One. 2013 Nov 11;8(11):e79745. doi: 10.1371/journal.pone.0079745. eCollection 2013.
• [2] Optimization of PDE3A Modulators for SLFN12-Dependent Cancer Cell Killing.ACS Med Chem Lett. 2019 Oct 18;10(11):1537-1542. doi: 10.1021/acsmedchemlett.9b00360. eCollection 2019 Nov 14.
• [3] Schlafen-3 decreases cancer stem cell marker expression and autocrine/juxtacrine signaling in FOLFOX-resistant colon cancer cells.Am J Physiol Gastrointest Liver Physiol. 2011 Aug;301(2):G347-55. doi: 10.1152/ajpgi.00403.2010. Epub 2011 May 19.
• [4] Schlafen12 Reduces the Aggressiveness of Triple Negative Breast Cancer through Post-Transcriptional Regulation of ZEB1 That Drives Stem Cell Differentiation.Cell Physiol Biochem. 2019;53(6):999-1014. doi: 10.33594/000000191.
• [5] Novel TBL1XR1, EPHA7 and SLFN12 mutations in a Sezary syndrome patient discovered by whole exome sequencing.Exp Dermatol. 2014 May;23(5):366-8. doi: 10.1111/exd.12405.
• [6] Phosphodiesterase 3A: a new player in development of interstitial cells of Cajal and a prospective target in gastrointestinal stromal tumors (GIST).Oncotarget. 2017 Jun 20;8(25):41026-41043. doi: 10.18632/oncotarget.17010.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.