Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT26Z2KN)

• DOT Name: DNA damage-inducible transcript 4-like protein (DDIT4L)
• Synonyms: HIF-1 responsive protein RTP801-like; Protein regulated in development and DNA damage response 2; REDD-2
• Gene Name: DDIT4L
• Related Disease: Melanoma
• UniProt ID: DDT4L_HUMAN
• Pfam ID: PF07809
• Sequence:
  MVATGSLSSKNPASISELLDCGYHPESLLSDFDYWDYVVPEPNLNEVIFEESTCQNLVKM
  LENCLSKSKQTKLGCSKVLVPEKLTQRIAQDVLRLSSTEPCGLRGCVMHVNLEIENVCKK
  LDRIVCDSSVVPTFELTLVFKQENCSWTSFRDFFFSRGRFSSGFRRTLILSSGFRLVKKK
  LYSLIGTTVIEGS
• Function: Inhibits cell growth by regulating the TOR signaling pathway upstream of the TSC1-TSC2 complex and downstream of AKT1.
• Tissue Specificity: Up-regulated in atherosclerotic plaques relative to healthy segments of the same artery.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Strong	Biomarker	[1]

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 DNA damage-inducible transcript 4-like protein (DDIT4L).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of DNA damage-inducible transcript 4-like protein (DDIT4L).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA damage-inducible transcript 4-like protein (DDIT4L).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of DNA damage-inducible transcript 4-like protein (DDIT4L).	[4]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of DNA damage-inducible transcript 4-like protein (DDIT4L).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA damage-inducible transcript 4-like protein (DDIT4L).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of DNA damage-inducible transcript 4-like protein (DDIT4L).	[7]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of DNA damage-inducible transcript 4-like protein (DDIT4L).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of DNA damage-inducible transcript 4-like protein (DDIT4L).	[9]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of DNA damage-inducible transcript 4-like protein (DDIT4L).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA damage-inducible transcript 4-like protein (DDIT4L).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of DNA damage-inducible transcript 4-like protein (DDIT4L).	[13]

References

• [1] Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas.Cancer Res. 2006 Jun 15;66(12):6080-6. doi: 10.1158/0008-5472.CAN-06-0157.
• [2] 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.
• [3] 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.
• [4] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [8] Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells. J Biochem Mol Toxicol. 2020 Oct;34(10):e22547. doi: 10.1002/jbt.22547. Epub 2020 Jun 26.
• [9] 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.
• [10] Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB. Carcinogenesis. 2008 Apr;29(4):779-89.
• [11] 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.
• [12] 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.
• [13] 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.