Details of Drug Off-Target (DOT)

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

• DOT Name: Lamin-B2 (LMNB2)
• Gene Name: LMNB2
• Related Disease:
  Acquired partial lipodystrophy
  Advanced cancer
  Atrichia with papular lesions
  Cerebellar ataxia
  Familial partial lipodystrophy
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Mandibuloacral dysplasia
  Microcephaly 27, primary, autosomal dominant
  Neoplasm
  Non-small-cell lung cancer
  Progressive myoclonic epilepsy type 9
  Progressive myoclonus epilepsy
  Promyelocytic leukaemia
  Schizophrenia
  Unverricht-Lundborg syndrome
  Leukodystrophy
  Lipodystrophy
  Microcephaly
  Emery-Dreifuss muscular dystrophy
  Lipodystrophy, partial, acquired, susceptibility to
  Partial lipodystrophy
• UniProt ID: LMNB2_HUMAN
• PDB ID: 2LLL
• Pfam ID: PF00038 ; PF00932
• Sequence:
  MSPPSPGRRREQRRPRAAATMATPLPGRAGGPATPLSPTRLSRLQEKEELRELNDRLAHY
  IDRVRALELENDRLLLKISEKEEVTTREVSGIKALYESELADARRVLDETARERARLQIE
  IGKLRAELDEVNKSAKKREGELTVAQGRVKDLESLFHRSEVELAAALSDKRGLESDVAEL
  RAQLAKAEDGHAVAKKQLEKETLMRVDLENRCQSLQEELDFRKSVFEEEVRETRRRHERR
  LVEVDSSRQQEYDFKMAQALEELRSQHDEQVRLYKLELEQTYQAKLDSAKLSSDQNDKAA
  SAAREELKEARMRLESLSYQLSGLQKQASAAEDRIRELEEAMAGERDKFRKMLDAKEQEM
  TEMRDVMQQQLAEYQELLDVKLALDMEINAYRKLLEGEEERLKLSPSPSSRVTVSRATSS
  SSGSLSATGRLGRSKRKRLEVEEPLGSGPSVLGTGTGGSGGFHLAQQASASGSVSIEEID
  LEGKFVQLKNNSDKDQSLGNWRIKRQVLEGEEIAYKFTPKYILRAGQMVTVWAAGAGVAH
  SPPSTLVWKGQSSWGTGESFRTVLVNADGEEVAMRTVKKSSVMRENENGEEEEEEAEFGE
  EDLFHQQGDPRTTSRGCYVM
• Function: Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane. Lamins provide a framework for the nuclear envelope, bridging the nuclear envelope and chromatin, thereby playing an important role in nuclear assembly, chromatin organization, nuclear membrane and telomere dynamics. The structural integrity of the lamina is strictly controlled by the cell cycle, as seen by the disintegration and formation of the nuclear envelope in prophase and telophase, respectively.
• KEGG Pathway:
  Apoptosis (hsa04210)
  Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acquired partial lipodystrophy	DISWXX4G	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Atrichia with papular lesions	DIS80CUB	Strong	Biomarker	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[4]
Familial partial lipodystrophy	DISFVL9J	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[6]
Mandibuloacral dysplasia	DISMOYL1	Strong	Biomarker	[3]
Microcephaly 27, primary, autosomal dominant	DIS8B5US	Strong	Autosomal dominant	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[2]
Progressive myoclonic epilepsy type 9	DISWD0RI	Strong	Autosomal recessive	[4]
Progressive myoclonus epilepsy	DISAMCNS	Strong	Genetic Variation	[4]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[8]
Unverricht-Lundborg syndrome	DISG4WLX	Strong	Genetic Variation	[4]
Leukodystrophy	DISVY1TT	moderate	Genetic Variation	[9]
Lipodystrophy	DIS3SGVD	moderate	Genetic Variation	[10]
Microcephaly	DIS2GRD8	Moderate	Autosomal dominant	[7]
Emery-Dreifuss muscular dystrophy	DISYTPR5	Limited	Genetic Variation	[11]
Lipodystrophy, partial, acquired, susceptibility to	DIS9T3IC	Limited	Autosomal dominant	[10]
Partial lipodystrophy	DIS2HKKW	Limited	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Lamin-B2 (LMNB2).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Lamin-B2 (LMNB2).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Lamin-B2 (LMNB2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lamin-B2 (LMNB2).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Lamin-B2 (LMNB2).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lamin-B2 (LMNB2).	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Lamin-B2 (LMNB2).	[16]
Aminoglutethimide	DMWFHMZ	Approved	Aminoglutethimide decreases the expression of Lamin-B2 (LMNB2).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Lamin-B2 (LMNB2).	[18]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Lamin-B2 (LMNB2).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Lamin-B2 (LMNB2).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Lamin-B2 (LMNB2).	[22]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Lamin-B2 (LMNB2).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Lamin-B2 (LMNB2).	[25]
AM251	DMTAWHL	Investigative	AM251 decreases the expression of Lamin-B2 (LMNB2).	[26]
Paraoxon	DMN4ZKC	Investigative	Paraoxon increases the expression of Lamin-B2 (LMNB2).	[27]
Flavone	DMEQH6J	Investigative	Flavone decreases the expression of Lamin-B2 (LMNB2).	[28]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Lamin-B2 (LMNB2).	[19]

References

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• [2] Lamin B2 binding to minichromosome maintenance complex component 7 promotes non-small cell lung carcinogenesis.Oncotarget. 2017 Aug 18;8(62):104813-104830. doi: 10.18632/oncotarget.20338. eCollection 2017 Dec 1.
• [3] Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism.J Lipid Res. 2007 Jul;48(7):1433-44. doi: 10.1194/jlr.R700004-JLR200. Epub 2007 Mar 20.
• [4] Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia. Hum Mol Genet. 2015 Aug 15;24(16):4483-90. doi: 10.1093/hmg/ddv171. Epub 2015 May 7.
• [5] miR-122 Inhibits Hepatocarcinoma Cell Progression by Targeting LMNB2.Oncol Res. 2020 Feb 7;28(1):41-49. doi: 10.3727/096504019X15615433287579. Epub 2019 Sep 26.
• [6] Dual strands of the miR-145 duplex (miR-145-5p and miR-145-3p) regulate oncogenes in lung adenocarcinoma pathogenesis.J Hum Genet. 2018 Oct;63(10):1015-1028. doi: 10.1038/s10038-018-0497-9. Epub 2018 Aug 6.
• [7] Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy. Genet Med. 2021 Feb;23(2):408-414. doi: 10.1038/s41436-020-00980-3. Epub 2020 Oct 9.
• [8] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [9] "Laminopathies": a wide spectrum of human diseases.Exp Cell Res. 2007 Jun 10;313(10):2121-33. doi: 10.1016/j.yexcr.2007.03.028. Epub 2007 Mar 30.
• [10] Sequencing of the reannotated LMNB2 gene reveals novel mutations in patients with acquired partial lipodystrophy. Am J Hum Genet. 2006 Aug;79(2):383-9. doi: 10.1086/505885. Epub 2006 Jun 5.
• [11] Functions and dysfunctions of the nuclear lamin Ig-fold domain in nuclear assembly, growth, and Emery-Dreifuss muscular dystrophy.Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15494-9. doi: 10.1073/pnas.0507612102. Epub 2005 Oct 14.
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• [15] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [16] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [17] Proteomic profile of aminoglutethimide-induced apoptosis in HL-60 cells: role of myeloperoxidase and arylamine free radicals. Chem Biol Interact. 2015 Sep 5;239:129-38.
• [18] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [19] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [20] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [21] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [22] 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.
• [23] 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.
• [24] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [25] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [26] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.
• [27] Paraoxon-induced protein expression changes to SH-SY5Y cells. Chem Res Toxicol. 2010 Nov 15;23(11):1656-62. doi: 10.1021/tx100192f. Epub 2010 Oct 8.
• [28] Identification of biomarkers for the initiation of apoptosis in human preneoplastic colonocytes by proteome analysis. Int J Cancer. 2004 Mar 20;109(2):220-9. doi: 10.1002/ijc.11692.