Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX2O0ZX)

• DOT Name: Septin-11 (SEPTIN11)
• Gene Name: SEPTIN11
• Related Disease:
  Acute lymphocytic leukaemia
  Amyotrophic neuralgia
  Bipolar disorder
  Childhood acute lymphoblastic leukemia
  Differentiated thyroid carcinoma
  Hepatocellular carcinoma
  Neoplasm
  Obesity
  Schizophrenia
  Acute myelogenous leukaemia
  leukaemia
  Leukemia
  Methylmalonic acidemia
• UniProt ID: SEP11_HUMAN
• PDB ID: 6UPQ
• Pfam ID: PF00735
• Sequence:
  MAVAVGRPSNEELRNLSLSGHVGFDSLPDQLVNKSTSQGFCFNILCVGETGIGKSTLMDT
  LFNTKFESDPATHNEPGVRLKARSYELQESNVRLKLTIVDTVGFGDQINKDDSYKPIVEY
  IDAQFEAYLQEELKIKRSLFNYHDTRIHACLYFIAPTGHSLKSLDLVTMKKLDSKVNIIP
  IIAKADTIAKNELHKFKSKIMSELVSNGVQIYQFPTDEETVAEINATMSVHLPFAVVGST
  EEVKIGNKMAKARQYPWGVVQVENENHCDFVKLREMLIRVNMEDLREQTHTRHYELYRRC
  KLEEMGFKDTDPDSKPFSLQETYEAKRNEFLGELQKKEEEMRQMFVMRVKEKEAELKEAE
  KELHEKFDLLKRTHQEEKKKVEDKKKELEEEVNNFQKKKAAAQLLQSQAQQSGAQQTKKD
  KDKKNASFT
• Function: Filament-forming cytoskeletal GTPase. May play a role in cytokinesis (Potential). May play a role in the cytoarchitecture of neurons, including dendritic arborization and dendritic spines, and in GABAergic synaptic connectivity. During Listeria monocytogenes infection, not required for the bacterial entry process, but restricts its efficacy.
• Tissue Specificity: Widely expressed, except in leukocytes.
• KEGG Pathway:
  Bacterial invasion of epithelial cells (hsa05100)
  Shigellosis (hsa05131)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[1]
Amyotrophic neuralgia	DISOTIUZ	Strong	Genetic Variation	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[1]
Differentiated thyroid carcinoma	DIS1V20Y	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[6]
Obesity	DIS47Y1K	Strong	Biomarker	[7]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[8]
leukaemia	DISS7D1V	Limited	Biomarker	[8]
Leukemia	DISNAKFL	Limited	Biomarker	[8]
Methylmalonic acidemia	DISHY8VB	Limited	Biomarker	[9]

13 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 Septin-11 (SEPTIN11).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Septin-11 (SEPTIN11).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Septin-11 (SEPTIN11).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Septin-11 (SEPTIN11).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Septin-11 (SEPTIN11).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Septin-11 (SEPTIN11).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Septin-11 (SEPTIN11).	[17]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Septin-11 (SEPTIN11).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Septin-11 (SEPTIN11).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Septin-11 (SEPTIN11).	[19]
Eugenol	DM7US1H	Patented	Eugenol decreases the expression of Septin-11 (SEPTIN11).	[20]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Septin-11 (SEPTIN11).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Septin-11 (SEPTIN11).	[22]

1 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 Septin-11 (SEPTIN11).	[15]

References

• [1] A translocation in acute lymphoblastic leukemia that cytogenetically mimics the recurrent MLL-AFF1 translocation and fuses SEPT11 to MLL.Cancer Genet Cytogenet. 2010 Aug;201(1):48-51. doi: 10.1016/j.cancergencyto.2010.05.002.
• [2] SEPT9 sequence alternations causing hereditary neuralgic amyotrophy are associated with altered interactions with SEPT4/SEPT11 and resistance to Rho/Rhotekin-signaling.Hum Mutat. 2007 Oct;28(10):1005-13. doi: 10.1002/humu.20554.
• [3] Common proteomic changes in the hippocampus in schizophrenia and bipolar disorder and particular evidence for involvement of cornu ammonis regions 2 and 3.Arch Gen Psychiatry. 2011 May;68(5):477-88. doi: 10.1001/archgenpsychiatry.2011.43.
• [4] Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer.Nat Commun. 2017 Jul 13;8:15966. doi: 10.1038/ncomms15966.
• [5] LOH analysis of genes around D4S2964 identifies ARD1B as a prognostic predictor of hepatocellular carcinoma.World J Gastroenterol. 2010 Apr 28;16(16):2046-54. doi: 10.3748/wjg.v16.i16.2046.
• [6] Expression pattern of the septin gene family in acute myeloid leukemias with and without MLL-SEPT fusion genes.Leuk Res. 2010 May;34(5):615-21. doi: 10.1016/j.leukres.2009.08.018. Epub 2009 Sep 12.
• [7] The cytoskeletal protein septin 11 is associated with human obesity and is involved in adipocyte lipid storage and metabolism.Diabetologia. 2017 Feb;60(2):324-335. doi: 10.1007/s00125-016-4155-5. Epub 2016 Nov 19.
• [8] FLJ10849, a septin family gene, fuses MLL in a novel leukemia cell line CNLBC1 derived from chronic neutrophilic leukemia in transformation with t(4;11)(q21;q23).Leukemia. 2004 May;18(5):998-1005. doi: 10.1038/sj.leu.2403334.
• [9] Quantitative analysis of mitochondrial protein expression in methylmalonic acidemia by two-dimensional difference gel electrophoresis.J Proteome Res. 2006 Jul;5(7):1602-10. doi: 10.1021/pr050481r.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [12] 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.
• [13] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [14] 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.
• [15] 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.
• [16] An approach to elucidate potential mechanism of renal toxicity of arsenic trioxide. Exp Hematol. 2007 Feb;35(2):252-62.
• [17] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [18] 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.
• [19] 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.
• [20] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [21] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [22] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.