Details of Drug Off-Target (DOT)

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

• DOT Name: Ras and Rab interactor 1 (RIN1)
• Synonyms: Ras inhibitor JC99; Ras interaction/interference protein 1
• Gene Name: RIN1
• Related Disease:
  Bladder transitional cell carcinoma
  Lung adenocarcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Hematologic disease
  Hepatocellular carcinoma
  Leukemia
  Melanoma
  Neoplasm
  Non-small-cell lung cancer
  Oral cancer
  Promyelocytic leukaemia
  Advanced cancer
  Adenocarcinoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Gastric adenocarcinoma
  Post-traumatic stress disorder
  Renal cell carcinoma
• UniProt ID: RIN1_HUMAN
• Pfam ID: PF00788 ; PF02204
• Sequence:
  MESPGESGAGSPGAPSPSSFTTGHLAREKPAQDPLYDVPNASGGQAGGPQRPGRVVSLRE
  RLLLTRPVWLQLQANAAAALHMLRTEPPGTFLVRKSNTRQCQALCMRLPEASGPSFVSSH
  YILESPGGVSLEGSELMFPDLVQLICAYCHTRDILLLPLQLPRAIHHAATHKELEAISHL
  GIEFWSSSLNIKAQRGPAGGPVLPQLKARSPQELDQGTGAALCFFNPLFPGDLGPTKREK
  FKRSFKVRVSTETSSPLSPPAVPPPPVPVLPGAVPSQTERLPPCQLLRRESSVGYRVPAG
  SGPSLPPMPSLQEVDCGSPSSSEEEGVPGSRGSPATSPHLGRRRPLLRSMSAAFCSLLAP
  ERQVGRAAAALMQDRHTAAGQLVQDLLTQVRAGPEPQELQGIRQALSRARAMLSAELGPE
  KLLSPKRLEHVLEKSLHCSVLKPLRPILAARLRRRLAADGSLGRLAEGLRLARAQGPGAF
  GSHLSLPSPVELEQVRQKLLQLLRTYSPSAQVKRLLQACKLLYMALRTQEGEGAGADEFL
  PLLSLVLAHCDLPELLLEAEYMSELLEPSLLTGEGGYYLTSLSASLALLSGLGQAHTLPL
  SPVQELRRSLSLWEQRRLPATHCFQHLLRVAYQDPSSGCTSKTLAVPPEASIATLNQLCA
  TKFRVTQPNTFGLFLYKEQGYHRLPPGALAHRLPTTGYLVYRRAEWPETQGAVTEEEGSG
  QSEARSRGEEQGCQGDGDAGVKASPRDIREQSETTAEGGQGQAQEGPAQPGEPEAEGSRA
  AEE
• Function: Ras effector protein, which may serve as an inhibitory modulator of neuronal plasticity in aversive memory formation. Can affect Ras signaling at different levels. First, by competing with RAF1 protein for binding to activated Ras. Second, by enhancing signaling from ABL1 and ABL2, which regulate cytoskeletal remodeling. Third, by activating RAB5A, possibly by functioning as a guanine nucleotide exchange factor (GEF) for RAB5A, by exchanging bound GDP for free GTP, and facilitating Ras-activated receptor endocytosis.
• Tissue Specificity: Expressed in all tissues examined with high levels in brain, placenta and pancreas.
• KEGG Pathway: Ras sig.ling pathway (hsa04014)
• Reactome Pathway: RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder transitional cell carcinoma	DISNL46A	Definitive	Altered Expression	[1]
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Genetic Variation	[4]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[4]
Hematologic disease	DIS9XD9A	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Leukemia	DISNAKFL	Strong	Altered Expression	[7]
Melanoma	DIS1RRCY	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[10]
Oral cancer	DISLD42D	Strong	Biomarker	[11]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[12]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[13]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[14]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[13]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[15]
Colorectal neoplasm	DISR1UCN	Limited	Biomarker	[15]
Gastric adenocarcinoma	DISWWLTC	Limited	Biomarker	[14]
Post-traumatic stress disorder	DISHL1EY	Limited	Biomarker	[16]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[13]

6 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 Ras and Rab interactor 1 (RIN1).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ras and Rab interactor 1 (RIN1).	[22]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Ras and Rab interactor 1 (RIN1).	[23]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Ras and Rab interactor 1 (RIN1).	[30]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ras and Rab interactor 1 (RIN1).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Ras and Rab interactor 1 (RIN1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ras and Rab interactor 1 (RIN1).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ras and Rab interactor 1 (RIN1).	[19]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ras and Rab interactor 1 (RIN1).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras and Rab interactor 1 (RIN1).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ras and Rab interactor 1 (RIN1).	[24]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Ras and Rab interactor 1 (RIN1).	[25]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Ras and Rab interactor 1 (RIN1).	[26]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Ras and Rab interactor 1 (RIN1).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Ras and Rab interactor 1 (RIN1).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ras and Rab interactor 1 (RIN1).	[29]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Ras and Rab interactor 1 (RIN1).	[31]

References

• [1] Overexpression of RIN1 associates with tumor grade and progression in patients of bladder urothelial carcinoma.Tumour Biol. 2012 Jun;33(3):847-55. doi: 10.1007/s13277-011-0311-1. Epub 2012 Jan 17.
• [2] Cell proliferation and epidermal growth factor signaling in non-small cell lung adenocarcinoma cell lines are dependent on Rin1.J Biol Chem. 2009 Sep 25;284(39):26331-9. doi: 10.1074/jbc.M109.033514. Epub 2009 Jul 1.
• [3] RIN1 is a breast tumor suppressor gene.Cancer Res. 2007 Dec 15;67(24):11510-6. doi: 10.1158/0008-5472.CAN-07-1147.
• [4] RIN1-Ras-ERK pathway plays an important role in carcinogenesis in colon cancer cell line LoVo.Oncol Res. 2011;19(12):527-34. doi: 10.3727/096504012x13340632812514.
• [5] Inverse regulation of bridging integrator 1 and BCR-ABL1 in chronic myeloid leukemia.Tumour Biol. 2016 Jan;37(1):217-25. doi: 10.1007/s13277-015-3772-9. Epub 2015 Jul 21.
• [6] Low RIN1 expression in HCC is associated with tumor invasion and unfavorable prognosis.Am J Clin Pathol. 2013 Jul;140(1):73-81. doi: 10.1309/AJCPEGWYDD86WWJK.
• [7] Regulation of the oncogenic activity of BCR-ABL by a tightly bound substrate protein RIN1.Immunity. 1997 Jun;6(6):773-82. doi: 10.1016/s1074-7613(00)80452-5.
• [8] RIN1 exhibits oncogenic property to suppress apoptosis and its aberrant accumulation associates with poor prognosis in melanoma.Tumour Biol. 2012 Oct;33(5):1511-8. doi: 10.1007/s13277-012-0402-7. Epub 2012 May 25.
• [9] The tyrosine phosphatase PTPN14 (Pez) inhibits metastasis by altering protein trafficking.Sci Signal. 2015 Feb 17;8(364):ra18. doi: 10.1126/scisignal.2005547.
• [10] Prognostic significance of RIN1 gene expression in human non-small cell lung cancer.Acta Histochem. 2012 Sep;114(5):463-8. doi: 10.1016/j.acthis.2011.08.008. Epub 2011 Sep 16.
• [11] A consistent pattern of RIN1 rearrangements in oral squamous cell carcinoma cell lines supports a breakage-fusion-bridge cycle model for 11q13 amplification.Genes Chromosomes Cancer. 2000 Jun;28(2):153-63.
• [12] Identification of signature genes by microarray for acute myeloid leukemia without maturation and acute promyelocytic leukemia with t(15;17)(q22;q12)(PML/RARalpha).Int J Oncol. 2003 Sep;23(3):617-25.
• [13] RIN1 promotes renal cell carcinoma malignancy by activating EGFR signaling through Rab25.Cancer Sci. 2017 Aug;108(8):1620-1627. doi: 10.1111/cas.13297. Epub 2017 Jul 3.
• [14] High RIN1 expression is associated with poor prognosis in patients with gastric adenocarcinoma.Tumour Biol. 2012 Oct;33(5):1557-63. doi: 10.1007/s13277-012-0409-0. Epub 2012 May 6.
• [15] Analysis of RIN1 gene expression in colorectal cancer.Oncol Rep. 2007 May;17(5):1171-5.
• [16] Change of Rin1 and Stathmin in the Animal Model of Traumatic Stresses.Front Behav Neurosci. 2017 Apr 26;11:62. doi: 10.3389/fnbeh.2017.00062. eCollection 2017.
• [17] 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.
• [18] Effect of all-trans retinoic acid on sodium/iodide symporter expression, radioiodine uptake and gene expression profiles in a human anaplastic thyroid carcinoma cell line. Nucl Med Biol. 2006 Oct;33(7):875-82. doi: 10.1016/j.nucmedbio.2006.07.004.
• [19] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [20] 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.
• [21] 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.
• [22] 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.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [25] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [26] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [27] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [28] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [29] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [30] 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.
• [31] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.