Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWIK6HT)

• DOT Name: Ninein-like protein (NINL)
• Gene Name: NINL
• Related Disease:
  Mycoses
  Ankylosing spondylitis
  Ciliopathy
  Head-neck squamous cell carcinoma
  Leber congenital amaurosis
  Lung cancer
  Lung carcinoma
  Neoplasm
  Pathologic nystagmus
  Spondylitis
  Squamous cell carcinoma
  Usher syndrome
  Adult lymphoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Lymphoma
  Pediatric lymphoma
  Classic Hodgkin lymphoma
• UniProt ID: NINL_HUMAN
• Pfam ID: PF13499
• Sequence:
  MDEEENHYVSQLREVYSSCDTTGTGFLDRQELTQLCLKLHLEQQLPVLLQTLLGNDHFAR
  VNFEEFKEGFVAVLSSNAGVRPSDEDSSSLESAASSAIPPKYVNGSKWYGRRSRPELCDA
  ATEARRVPEQQTQASLKSHLWRSASLESVESPKSDEEAESTKEAQNELFEAQGQLQTWDS
  EDFGSPQKSCSPSFDTPESQIRGVWEELGVGSSGHLSEQELAVVCQSVGLQGLEKEELED
  LFNKLDQDGDGKVSLEEFQLGLFSHEPALLLESSTRVKPSKAWSHYQVPEESGCHTTTTS
  SLVSLCSSLRLFSSIDDGSGFAFPDQVLAMWTQEGIQNGREILQSLDFSVDEKVNLLELT
  WALDNELMTVDSAVQQAALACYHQELSYQQGQVEQLARERDKARQDLERAEKRNLEFVKE
  MDDCHSTLEQLTEKKIKHLEQGYRERLSLLRSEVEAERELFWEQAHRQRAALEWDVGRLQ
  AEEAGLREKLTLALKENSRLQKEIVEVVEKLSDSERLALKLQKDLEFVLKDKLEPQSAEL
  LAQEERFAAVLKEYELKCRDLQDRNDELQAELEGLWARLPKNRHSPSWSPDGRRRQLPGL
  GPAGISFLGNSAPVSIETELMMEQVKEHYQDLRTQLETKVNYYEREIAALKRNFEKERKD
  MEQARRREVSVLEGQKADLEELHEKSQEVIWGLQEQLQDTARGPEPEQMGLAPCCTQALC
  GLALRHHSHLQQIRREAEAELSGELSGLGALPARRDLTLELEEPPQGPLPRGSQRSEQLE
  LERALKLQPCASEKRAQMCVSLALEEEELELARGKRVDGPSLEAEMQALPKDGLVAGSGQ
  EGTRGLLPLRPGCGERPLAWLAPGDGRESEEAAGAGPRRRQAQDTEATQSPAPAPAPASH
  GPSERWSRMQPCGVDGDIVPKEPEPFGASAAGLEQPGARELPLLGTERDASQTQPRMWEP
  PLRPAASCRGQAERLQAIQEERARSWSRGTQEQASEQQARAEGALEPGCHKHSVEVARRG
  SLPSHLQLADPQGSWQEQLAAPEEGETKIALEREKDDMETKLLHLEDVVRALEKHVDLRE
  NDRLEFHRLSEENTLLKNDLGRVRQELEAAESTHDAQRKEIEVLKKDKEKACSEMEVLNR
  QNQNYKDQLSQLNVRVLQLGQEASTHQAQNEEHRVTIQMLTQSLEEVVRSGQQQSDQIQK
  LRVELECLNQEHQSLQLPWSELTQTLEESQDQVQGAHLRLRQAQAQHLQEVRLVPQDRVA
  ELHRLLSLQGEQARRRLDAQREEHEKQLKATEERVEEAEMILKNMEMLLQEKVDKLKEQF
  EKNTKSDLLLKELYVENAHLVRALQATEEKQRGAEKQSRLLEEKVRALNKLVSRIAPAAL
  SV
• Function: Involved in the microtubule organization in interphase cells. Overexpression induces the fragmentation of the Golgi, and causes lysosomes to disperse toward the cell periphery; it also interferes with mitotic spindle assembly. Involved in vesicle transport in photoreceptor cells. May play a role in ovarian carcinogenesis.
• Tissue Specificity: Expressed in KYSE-150 esophageal carcinoma, HeLa cervical carcinoma and U2OS osteosarcoma cells. Expression is regulated in a cell cycle-dependent manner and peaks during G2/M phase (at protein level). Expressed in fetal heart, skeletal muscle, liver, lung and cochlea, and in adult brain, testis, kidney and retina.
• Reactome Pathway:
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mycoses	DIS9K7PB	Definitive	Biomarker	[1]
Ankylosing spondylitis	DISRC6IR	Strong	Biomarker	[2]
Ciliopathy	DIS10G4I	Strong	Biomarker	[3]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[4]
Leber congenital amaurosis	DISMGH8F	Strong	Biomarker	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[6]
Lung carcinoma	DISTR26C	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Pathologic nystagmus	DIS1QSPO	Strong	Biomarker	[8]
Spondylitis	DIS3HV6E	Strong	Biomarker	[2]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[4]
Usher syndrome	DIS9YIS7	Strong	Biomarker	[5]
Adult lymphoma	DISK8IZR	moderate	Biomarker	[9]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[9]
Breast cancer	DIS7DPX1	moderate	Biomarker	[10]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[10]
Lymphoma	DISN6V4S	moderate	Biomarker	[9]
Pediatric lymphoma	DIS51BK2	moderate	Biomarker	[9]
Classic Hodgkin lymphoma	DISV1LU6	Limited	Genetic Variation	[11]

2 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 Ninein-like protein (NINL).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ninein-like protein (NINL).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ninein-like protein (NINL).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Ninein-like protein (NINL).	[14]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Ninein-like protein (NINL).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Ninein-like protein (NINL).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Ninein-like protein (NINL).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Ninein-like protein (NINL).	[15]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Ninein-like protein (NINL).	[19]

References

• [1] An Antimicrobial Peptide and Its Neuronal Receptor Regulate Dendrite Degeneration in Aging and Infection.Neuron. 2018 Jan 3;97(1):125-138.e5. doi: 10.1016/j.neuron.2017.12.001.
• [2] Incorporating natural language processing to improve classification of axial spondyloarthritis using electronic health records.Rheumatology (Oxford). 2020 May 1;59(5):1059-1065. doi: 10.1093/rheumatology/kez375.
• [3] The Ciliopathy Protein CC2D2A Associates with NINL and Functions in RAB8-MICAL3-Regulated Vesicle Trafficking.PLoS Genet. 2015 Oct 20;11(10):e1005575. doi: 10.1371/journal.pgen.1005575. eCollection 2015 Oct.
• [4] Ninein-like protein is overexpressed in head and neck squamous cell carcinoma and contributes to cancer growth and resistance to apoptosis.Oncol Rep. 2009 Oct;22(4):789-98. doi: 10.3892/or_00000501.
• [5] Usher syndrome and Leber congenital amaurosis are molecularly linked via a novel isoform of the centrosomal ninein-like protein.Hum Mol Genet. 2009 Jan 1;18(1):51-64. doi: 10.1093/hmg/ddn312. Epub 2008 Sep 30.
• [6] Profiling Lung Cancer Patients Using Electronic Health Records.J Med Syst. 2018 May 31;42(7):126. doi: 10.1007/s10916-018-0975-9.
• [7] Centrosomal Nlp is an oncogenic protein that is gene-amplified in human tumors and causes spontaneous tumorigenesis in transgenic mice.J Clin Invest. 2010 Feb;120(2):498-507. doi: 10.1172/JCI39447. Epub 2010 Jan 19.
• [8] Phenotype of three consanguineous Tunisian families with early-onset retinal degeneration caused by an R91W homozygous mutation in the RPE65 gene.Graefes Arch Clin Exp Ophthalmol. 2006 Sep;244(9):1104-12. doi: 10.1007/s00417-005-0096-2. Epub 2006 Feb 28.
• [9] The role of centrosomal Nlp in the control of mitotic progression and tumourigenesis.Br J Cancer. 2011 May 10;104(10):1523-8. doi: 10.1038/bjc.2011.130. Epub 2011 Apr 19.
• [10] Effects of the ninein-like protein centrosomal protein on breast cancer cell invasion and migration.Mol Med Rep. 2015 Aug;12(2):1659-64. doi: 10.3892/mmr.2015.3650. Epub 2015 Apr 20.
• [11] Development of lymphoma in Autoimmune Lymphoproliferative Syndrome (ALPS) and its relationship to Fas gene mutations.Leuk Lymphoma. 2004 Mar;45(3):423-31. doi: 10.1080/10428190310001593166.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] 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.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.