Details of Drug Off-Target (DOT)

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

• DOT Name: Guanine nucleotide-binding protein-like 3-like protein (GNL3L)
• Gene Name: GNL3L
• Related Disease:
  Advanced cancer
  Prostate cancer
  Prostate carcinoma
  Digestive system neoplasm
• UniProt ID: GNL3L_HUMAN
• Pfam ID: PF01926
• Sequence:
  MMKLRHKNKKPGEGSKGHKKISWPYPQPAKQNGKKATSKVPSAPHFVHPNDHANREAELK
  KKWVEEMREKQQAAREQERQKRRTIESYCQDVLRRQEEFEHKEEVLQELNMFPQLDDEAT
  RKAYYKEFRKVVEYSDVILEVLDARDPLGCRCFQMEEAVLRAQGNKKLVLVLNKIDLVPK
  EVVEKWLDYLRNELPTVAFKASTQHQVKNLNRCSVPVDQASESLLKSKACFGAENLMRVL
  GNYCRLGEVRTHIRVGVVGLPNVGKSSLINSLKRSRACSVGAVPGITKFMQEVYLDKFIR
  LLDAPGIVPGPNSEVGTILRNCVHVQKLADPVTPVETILQRCNLEEISNYYGVSGFQTTE
  HFLTAVAHRLGKKKKGGLYSQEQAAKAVLADWVSGKISFYIPPPATHTLPTHLSAEIVKE
  MTEVFDIEDTEQANEDTMECLATGESDELLGDTDPLEMEIKLLHSPMTKIADAIENKTTV
  YKIGDLTGYCTNPNRHQMGWAKRNVDHRPKSNSMVDVCSVDRRSVLQRIMETDPLQQGQA
  LASALKNKKKMQKRADKIASKLSDSMMSALDLSGNADDGVGD
• Function: Stabilizes TERF1 telomeric association by preventing TERF1 recruitment by PML. Stabilizes TERF1 protein by preventing its ubiquitination and hence proteasomal degradation. Does so by interfering with TERF1-binding to FBXO4 E3 ubiquitin-protein ligase. Required for cell proliferation. By stabilizing TRF1 protein during mitosis, promotes metaphase-to-anaphase transition. Stabilizes MDM2 protein by preventing its ubiquitination, and hence proteasomal degradation. By acting on MDM2, may affect TP53 activity. Required for normal processing of ribosomal pre-rRNA. Binds GTP.
• KEGG Pathway: Ribosome biogenesis in eukaryotes (hsa03008)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Altered Expression	[2]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[2]
Digestive system neoplasm	DISPOJCT	Limited	Altered Expression	[3]

14 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 Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[8]
Marinol	DM70IK5	Approved	Marinol increases the expression of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[9]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[10]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[10]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[19]

3 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 increases the methylation of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Guanine nucleotide-binding protein-like 3-like protein (GNL3L).	[15]

References

• [1] Maintenance of tumor initiating cells of defined genetic composition by nucleostemin.Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20388-93. doi: 10.1073/pnas.1015171108. Epub 2011 Jul 5.
• [2] The mechanism of growth-inhibitory effect of DOC-2/DAB2 in prostate cancer. Characterization of a novel GTPase-activating protein associated with N-terminal domain of DOC-2/DAB2.J Biol Chem. 2002 Apr 12;277(15):12622-31. doi: 10.1074/jbc.M110568200. Epub 2002 Jan 25.
• [3] GNL3L depletion destabilizes MDM2 and induces p53-dependent G2/M arrest.Oncogene. 2011 Apr 7;30(14):1716-26. doi: 10.1038/onc.2010.550. Epub 2010 Dec 6.
• [4] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] 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.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] 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.
• [9] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [18] 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.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.