Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZGD3LJ)

• DOT Name: Ran GTPase-activating protein 1 (RANGAP1)
• Synonyms: RanGAP1
• Gene Name: RANGAP1
• Related Disease:
  Cone-rod dystrophy
  Cone-rod dystrophy 2
  Autism spectrum disorder
  B-cell lymphoma
  B-cell neoplasm
  Burkitt lymphoma
  Classic Hodgkin lymphoma
  Cystic fibrosis
  Episodic kinesigenic dyskinesia 1
  Fragile X syndrome
  Gastric cancer
  Glioma
  leukaemia
  Leukemia
  Mantle cell lymphoma
  Myotonic dystrophy
  Postaxial polydactyly
  Schizophrenia
  Sciatic neuropathy
  Split hand-foot malformation
  Stomach cancer
  Narcolepsy
  Amyotrophic lateral sclerosis
  Non-insulin dependent diabetes
  Spinocerebellar ataxia type 3
• UniProt ID: RAGP1_HUMAN
• PDB ID: 1Z5S; 2GRN; 2GRO; 2GRP; 2GRQ; 2GRR; 2IO2; 2IO3; 2IY0; 3UIN; 3UIO; 3UIP; 5D2M
• Pfam ID: PF13516 ; PF07834
• Sequence:
  MASEDIAKLAETLAKTQVAGGQLSFKGKSLKLNTAEDAKDVIKEIEDFDSLEALRLEGNT
  VGVEAARVIAKALEKKSELKRCHWSDMFTGRLRTEIPPALISLGEGLITAGAQLVELDLS
  DNAFGPDGVQGFEALLKSSACFTLQELKLNNCGMGIGGGKILAAALTECHRKSSAQGKPL
  ALKVFVAGRNRLENDGATALAEAFRVIGTLEEVHMPQNGINHPGITALAQAFAVNPLLRV
  INLNDNTFTEKGAVAMAETLKTLRQVEVINFGDCLVRSKGAVAIADAIRGGLPKLKELNL
  SFCEIKRDAALAVAEAMADKAELEKLDLNGNTLGEEGCEQLQEVLEGFNMAKVLASLSDD
  EDEEEEEEGEEEEEEAEEEEEEDEEEEEEEEEEEEEEPQQRGQGEKSATPSRKILDPNTG
  EPAPVLSSPPPADVSTFLAFPSPEKLLRLGPKSSVLIAQQTDTSDPEKVVSAFLKVSSVF
  KDEATVRMAVQDAVDALMQKAFNSSSFNSNTFLTRLLVHMGLLKSEDKVKAIANLYGPLM
  ALNHMVQQDYFPKALAPLLLAFVTKPNSALESCSFARHSLLQTLYKV
• Function: GTPase activator for RAN. Converts cytoplasmic GTP-bound RAN to GDP-bound RAN, which is essential for RAN-mediated nuclear import and export. Mediates dissociation of cargo from nuclear export complexes containing XPO1, RAN and RANBP2 after nuclear export.
• Tissue Specificity: Highly expressed in brain, thymus and testis.
• KEGG Pathway: Nucleocytoplasmic transport (hsa03013)
• Reactome Pathway:
  Rev-mediated nuclear export of HIV RNA (R-HSA-165054)
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  SUMOylation of DNA replication proteins (R-HSA-4615885)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Mitotic Prometaphase (R-HSA-68877)
  Postmitotic nuclear pore complex (NPC) reformation (R-HSA-9615933)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  SUMOylation of nuclear envelope proteins (R-HSA-9793242)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cone-rod dystrophy	DISY9RWN	Definitive	Biomarker	[1]
Cone-rod dystrophy 2	DISX2RWY	Definitive	Biomarker	[1]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[2]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[3]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[4]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[4]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[4]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[5]
Episodic kinesigenic dyskinesia 1	DISGVQMP	Strong	Biomarker	[6]
Fragile X syndrome	DISE8W3A	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	Strong	Biomarker	[8]
Glioma	DIS5RPEH	Strong	Altered Expression	[9]
leukaemia	DISS7D1V	Strong	Altered Expression	[4]
Leukemia	DISNAKFL	Strong	Altered Expression	[4]
Mantle cell lymphoma	DISFREOV	Strong	Altered Expression	[4]
Myotonic dystrophy	DISNBEMX	Strong	Genetic Variation	[10]
Postaxial polydactyly	DIS085OV	Strong	Biomarker	[11]
Schizophrenia	DISSRV2N	Strong	Biomarker	[12]
Sciatic neuropathy	DISMGDKX	Strong	Biomarker	[13]
Split hand-foot malformation	DIS8PKGD	Strong	Genetic Variation	[14]
Stomach cancer	DISKIJSX	Strong	Biomarker	[8]
Narcolepsy	DISLCNLI	moderate	Biomarker	[15]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[16]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[17]
Spinocerebellar ataxia type 3	DISQBQID	Limited	Genetic Variation	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ran GTPase-activating protein 1 (RANGAP1).	[19]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the phosphorylation of Ran GTPase-activating protein 1 (RANGAP1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ran GTPase-activating protein 1 (RANGAP1).	[32]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Ran GTPase-activating protein 1 (RANGAP1).	[34]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Ran GTPase-activating protein 1 (RANGAP1).	[34]
	DM9CEI5		increases the phosphorylation of Ran GTPase-activating protein 1 (RANGAP1).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[23]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[25]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[26]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[27]
Selenium	DM25CGV	Approved	Selenium increases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[28]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[30]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[28]
APR-246	DMNFADH	Phase 2	APR-246 increases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[33]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[35]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[24]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Ran GTPase-activating protein 1 (RANGAP1).	[36]

References

• [1] Genetic linkage of cone-rod retinal dystrophy to chromosome 19q and evidence for segregation distortion.Nat Genet. 1994 Feb;6(2):210-3. doi: 10.1038/ng0294-210.
• [2] Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders.Sci Rep. 2017 Jul 21;7(1):6116. doi: 10.1038/s41598-017-06440-4.
• [3] ON 01910.Na inhibits growth of diffuse large B-cell lymphoma by cytoplasmic sequestration of sumoylated C-MYB/TRAF6 complex. Transl Res. 2016 Sep;175:129-143.e13. doi: 10.1016/j.trsl.2016.04.001. Epub 2016 Apr 13.
• [4] Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-cell lymphoma. PLoS One. 2013 Nov 6;8(11):e79863. doi: 10.1371/journal.pone.0079863. eCollection 2013.
• [5] Segregation of delta F508 and normal CFTR alleles in human sperm.Hum Mol Genet. 1993 Apr;2(4):445-8. doi: 10.1093/hmg/2.4.445.
• [6] Segregation analysis of autosomal dominant polycystic kidney disease.Genet Epidemiol. 1993;10(3):189-200. doi: 10.1002/gepi.1370100305.
• [7] Investigation of the segregation of the fragile X mutation in daughters of obligate carrier women.Am J Med Genet. 1988 May-Jun;30(1-2):633-9. doi: 10.1002/ajmg.1320300164.
• [8] Circular RNA circ-RanGAP1 regulates VEGFA expression by targeting miR-877-3p to facilitate gastric cancer invasion and metastasis.Cancer Lett. 2020 Feb 28;471:38-48. doi: 10.1016/j.canlet.2019.11.038. Epub 2019 Dec 5.
• [9] Inhibition of RNA transportation induces glioma cell apoptosis via downregulation of RanGAP1 expression.Chem Biol Interact. 2015 May 5;232:49-57. doi: 10.1016/j.cbi.2015.02.019. Epub 2015 Mar 3.
• [10] Dynamic balance of segregation distortion and selection maintains normal allele sizes at the myotonic dystrophy locus.Math Biosci. 1998 Jan 1;147(1):93-112. doi: 10.1016/s0025-5564(97)00082-5.
• [11] Segregation distortion in the offspring of Afro-American fathers with postaxial polydactyly.Am J Hum Genet. 1995 May;56(5):1207-11.
• [12] Comparative proteome analysis of the hippocampus implicates chromosome 6q in schizophrenia.Mol Psychiatry. 2000 Jan;5(1):85-90. doi: 10.1038/sj.mp.4000580.
• [13] Localized regulation of axonal RanGTPase controls retrograde injury signaling in peripheral nerve.Neuron. 2008 Jul 31;59(2):241-52. doi: 10.1016/j.neuron.2008.05.029.
• [14] Heterozygous DLX5 nonsense mutation associated with isolated split-hand/foot malformation with reduced penetrance and variable expressivity in two unrelated families.Birth Defects Res A Clin Mol Teratol. 2014 Oct;100(10):764-71. doi: 10.1002/bdra.23298. Epub 2014 Sep 5.
• [15] No male segregation distortion of DR2 haplotypes in Japanese narcoleptic patients.Hum Immunol. 1988 Sep;23(1):23-6. doi: 10.1016/0198-8859(88)90014-6.
• [16] The C9orf72 repeat expansion disrupts nucleocytoplasmic transport.Nature. 2015 Sep 3;525(7567):56-61. doi: 10.1038/nature14973. Epub 2015 Aug 26.
• [17] Sib-pair analysis of adenosine deaminase locus in NIDDM.Diabetes. 1992 Dec;41(12):1640-3. doi: 10.2337/diab.41.12.1640.
• [18] Segregation distortion of wild-type alleles at the Machado-Joseph disease locus: a study in normal families from the Azores islands (Portugal).J Hum Genet. 2008;53(4):333-339. doi: 10.1007/s10038-008-0261-7. Epub 2008 Feb 20.
• [19] 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.
• [20] 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.
• [21] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [22] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [23] 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.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [25] 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.
• [26] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [27] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [28] 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.
• [29] Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-cell lymphoma. PLoS One. 2013 Nov 6;8(11):e79863. doi: 10.1371/journal.pone.0079863. eCollection 2013.
• [30] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [31] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [32] 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.
• [33] 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.
• [34] 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.
• [35] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [36] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [37] A novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer angiogenesis and metastasis pathways. Cancer Res. 2011 Jan 15;71(2):473-83. doi: 10.1158/0008-5472.CAN-10-1303. Epub 2011 Jan 11.