Details of Drug Off-Target (DOT)

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

• DOT Name: Lethal(3)malignant brain tumor-like protein 4 (L3MBTL4)
• Synonyms: H-l(3)mbt-like protein 4; L(3)mbt-like protein 4; L3mbt-like 4
• Gene Name: L3MBTL4
• Related Disease:
  Alzheimer disease
  Breast cancer
  Cholelithiasis
  High blood pressure
  Neoplasm
• UniProt ID: LMBL4_HUMAN
• Pfam ID: PF02820 ; PF00536 ; PF01530
• Sequence:
  MKQPNRKRKLNMDSKERLDQDGRLEQAEEEKKPKDSTTPLSHVPSAAAQGAWSWEWYLKE
  QKAVAAPVELFSKDQSFPEHENGFQIGMRLEGIDPRHPSVFCVLSVAEVCGYRLRLHFDG
  YLSCYDFWTNAGSPDIHPVGWCEKTKHELHIPKGYRKDKFVWMDYLKACKLQNAPKKLFR
  NRSPNGPMSKEFQVGMKLEAVDRKNPSLVCVATIADIVEDRLLVHFDNWDDSYDYWCDVN
  SPYVQPVGWCQENGRTLIAPQGYPNPENFSWTEYLEATQTNAVPAKVFKMRLPHGFLPNM
  KLEVVDKRNPRLIRVATIVDVDDQRVKVHFDGWDHKYDYWVEADSPDIHPIGWCDVTGHP
  LEVPQRTNDLKILPGQAVCPTPGCRGIGHIRGPRYSGHHSAFGCPYSDMNLKKEATLHDR
  LREQTQANLESDSSHSKSKSLCSLNFNGKHEKVNSQPRLVQQAKCLKIKGKEDIDLDNLF
  RVLVLHPRGLEYSVEQAQQVLHQSVSMSTVSAHPFRDLPLGREQHCKLLPGVADIRASQV
  ARWTVDEVAEFVQSLLGCEEHAKCFKKEQIDGKAFLLLTQTDIVKVMKIKLGPALKIYNS
  ILMFRHSQELPEEDIASGQEVRG
• Function: Putative Polycomb group (PcG) protein. PcG proteins maintain the transcriptionally repressive state of genes, probably via a modification of chromatin, rendering it heritably changed in its expressibility.
• KEGG Pathway: Polycomb repressive complex (hsa03083)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Cholelithiasis	DISERLZB	Strong	Genetic Variation	[3]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[4]
Neoplasm	DISZKGEW	Limited	Biomarker	[5]

8 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 Lethal(3)malignant brain tumor-like protein 4 (L3MBTL4).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Lethal(3)malignant brain tumor-like protein 4 (L3MBTL4).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lethal(3)malignant brain tumor-like protein 4 (L3MBTL4).	[8]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Lethal(3)malignant brain tumor-like protein 4 (L3MBTL4).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Lethal(3)malignant brain tumor-like protein 4 (L3MBTL4).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Lethal(3)malignant brain tumor-like protein 4 (L3MBTL4).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Lethal(3)malignant brain tumor-like protein 4 (L3MBTL4).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lethal(3)malignant brain tumor-like protein 4 (L3MBTL4).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Lethal(3)malignant brain tumor-like protein 4 (L3MBTL4).	[13]

References

• [1] Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
• [2] Loss, mutation and deregulation of L3MBTL4 in breast cancers.Mol Cancer. 2010 Aug 10;9:213. doi: 10.1186/1476-4598-9-213.
• [3] A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease.Nat Genet. 2007 Aug;39(8):995-9. doi: 10.1038/ng2101. Epub 2007 Jul 15.
• [4] Genome Wide Association Study Identifies L3MBTL4 as a Novel Susceptibility Gene for Hypertension.Sci Rep. 2016 Aug 2;6:30811. doi: 10.1038/srep30811.
• [5] Genomic profiling in high hyperdiploid acute myeloid leukemia: a retrospective study of 19 cases.Cancer Genet. 2011 Sep;204(9):516-21. doi: 10.1016/j.cancergen.2011.09.002.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] 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.
• [9] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] 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.