Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKX1XIX)

• DOT Name: Lethal(3)malignant brain tumor-like protein 2 (L3MBTL2)
• Synonyms: H-l(3)mbt-like protein 2; L(3)mbt-like protein 2
• Gene Name: L3MBTL2
• Related Disease:
  Medulloblastoma
  Acute myelogenous leukaemia
  Alzheimer disease
  Brain neoplasm
  Breast carcinoma
  Hypogonadism, male
  Major depressive disorder
  Neoplasm
  Polycythemia vera
  Brain cancer
• UniProt ID: LMBL2_HUMAN
• PDB ID: 2W0T; 3CEY; 3F70
• Pfam ID: PF02820 ; PF21319
• Sequence:
  MEKPRSIEETPSSEPMEEEEDDDLELFGGYDSFRSYNSSVGSESSSYLEESSEAENEDRE
  AGELPTSPLHLLSPGTPRSLDGSGSEPAVCEMCGIVGTREAFFSKTKRFCSVSCSRSYSS
  NSKKASILARLQGKPPTKKAKVLHKAAWSAKIGAFLHSQGTGQLADGTPTGQDALVLGFD
  WGKFLKDHSYKAAPVSCFKHVPLYDQWEDVMKGMKVEVLNSDAVLPSRVYWIASVIQTAG
  YRVLLRYEGFENDASHDFWCNLGTVDVHPIGWCAINSKILVPPRTIHAKFTDWKGYLMKR
  LVGSRTLPVDFHIKMVESMKYPFRQGMRLEVVDKSQVSRTRMAVVDTVIGGRLRLLYEDG
  DSDDDFWCHMWSPLIHPVGWSRRVGHGIKMSERRSDMAHHPTFRKIYCDAVPYLFKKVRA
  VYTEGGWFEEGMKLEAIDPLNLGNICVATVCKVLLDGYLMICVDGGPSTDGLDWFCYHAS
  SHAIFPATFCQKNDIELTPPKGYEAQTFNWENYLEKTKSKAAPSRLFNMDCPNHGFKVGM
  KLEAVDLMEPRLICVATVKRVVHRLLSIHFDGWDSEYDQWVDCESPDIYPVGWCELTGYQ
  LQPPVAAEPATPLKAKEATKKKKKQFGKKRKRIPPTKTRPLRQGSKKPLLEDDPQGARKI
  SSEPVPGEIIAVRVKEEHLDVASPDKASSPELPVSVENIKQETDD
• 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. Its association with a chromatin-remodeling complex suggests that it may contribute to prevent expression of genes that trigger the cell into mitosis. Binds to monomethylated and dimethylated 'Lys-20' on histone H4. Binds histone H3 peptides that are monomethylated or dimethylated on 'Lys-4', 'Lys-9' or 'Lys-27'.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway:
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Medulloblastoma	DISZD2ZL	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Hypogonadism, male	DISV1F5R	Strong	Biomarker	[6]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Polycythemia vera	DISB5FPO	Strong	Genetic Variation	[2]
Brain cancer	DISBKFB7	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Lethal(3)malignant brain tumor-like protein 2 (L3MBTL2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Lethal(3)malignant brain tumor-like protein 2 (L3MBTL2).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Lethal(3)malignant brain tumor-like protein 2 (L3MBTL2).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Lethal(3)malignant brain tumor-like protein 2 (L3MBTL2).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Lethal(3)malignant brain tumor-like protein 2 (L3MBTL2).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Lethal(3)malignant brain tumor-like protein 2 (L3MBTL2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Lethal(3)malignant brain tumor-like protein 2 (L3MBTL2).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Lethal(3)malignant brain tumor-like protein 2 (L3MBTL2).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Lethal(3)malignant brain tumor-like protein 2 (L3MBTL2).	[11]

References

• [1] Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma.Nat Genet. 2009 Apr;41(4):465-72. doi: 10.1038/ng.336. Epub 2009 Mar 8.
• [2] Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: possible role in 20q- polycythemia vera.Blood. 2010 Oct 14;116(15):2812-21. doi: 10.1182/blood-2010-02-270611. Epub 2010 Jun 28.
• [3] The GWAS Risk Genes for Depression May Be Actively Involved in Alzheimer's Disease.J Alzheimers Dis. 2018;64(4):1149-1161. doi: 10.3233/JAD-180276.
• [4] The histone code reader PHD finger protein 7 controls sex-linked disparities in gene expression and malignancy in Drosophila.Sci Adv. 2019 Aug 14;5(8):eaaw7965. doi: 10.1126/sciadv.aaw7965. eCollection 2019 Aug.
• [5] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [6] L3MBTL2 regulates chromatin remodeling during spermatogenesis.Cell Death Differ. 2019 Nov;26(11):2194-2207. doi: 10.1038/s41418-019-0283-z. Epub 2019 Feb 13.
• [7] Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.Nat Genet. 2018 May;50(5):668-681. doi: 10.1038/s41588-018-0090-3. Epub 2018 Apr 26.
• [8] L(3)mbt and the LINT complex safeguard cellular identity in the Drosophila ovary.Development. 2018 Apr 4;145(7):dev160721. doi: 10.1242/dev.160721.
• [9] 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.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] 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.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [14] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [15] 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.
• [16] 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.