Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZQK8JF)

• DOT Name: Active breakpoint cluster region-related protein (ABR)
• Gene Name: ABR
• Related Disease:
  Anaplastic astrocytoma
  Acute myelogenous leukaemia
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Castration-resistant prostate carcinoma
  Epilepsy
  Haemophilia A
  Hemophilia
  leukaemia
  Leukemia
  Prostate carcinoma
  Vitiligo
  Adrenoleukodystrophy
  Ear malformation
  Primitive neuroectodermal tumor
  Cardiomyopathy
  Neoplasm
  Prostate cancer
  Prostate neoplasm
  Rett syndrome
  Tibial aplasia-ectrodactyly syndrome
• UniProt ID: ABR_HUMAN
• Pfam ID: PF00168 ; PF19057 ; PF00620 ; PF00621
• Sequence:
  MEPLSHRGLPRLSWIDTLYSNFSYGTDEYDGEGNEEQKGPPEGSETMPYIDESPTMSPQL
  SARSQGGGDGVSPTPPEGLAPGVEAGKGLEMRKLVLSGFLASEEIYINQLEALLLPMKPL
  KATATTSQPVLTIQQIETIFYKIQDIYEIHKEFYDNLCPKVQQWDSQVTMGHLFQKLASQ
  LGVYKAFVDNYKVALETAEKCSQSNNQFQKISEELKVKGPKDSKDSHTSVTMEALLYKPI
  DRVTRSTLVLHDLLKHTPVDHPDYPLLQDALRISQNFLSSINEDIDPRRTAVTTPKGETR
  QLVKDGFLVEVSESSRKLRHVFLFTDVLLCAKLKKTSAGKHQQYDCKWYIPLADLVFPSP
  EESEASPQVHPFPDHELEDMKMKISALKSEIQKEKANKGQSRAIERLKKKMFENEFLLLL
  NSPTIPFRIHNRNGKSYLFLLSSDYERSEWREAIQKLQKKDLQAFVLSSVELQVLTGSCF
  KLRTVHNIPVTSNKDDDESPGLYGFLHVIVHSAKGFKQSANLYCTLEVDSFGYFVSKAKT
  RVFRDTAEPKWDEEFEIELEGSQSLRILCYEKCYDKTKVNKDNNEIVDKIMGKGQIQLDP
  QTVETKNWHTDVIEMNGIKVEFSMKFTSRDMSLKRTPSKKQTGVFGVKISVVTKRERSKV
  PYIVRQCVEEVEKRGIEEVGIYRISGVATDIQALKAVFDANNKDILLMLSDMDINAIAGT
  LKLYFRELPEPLLTDRLYPAFMEGIALSDPAAKENCMMHLLRSLPDPNLITFLFLLEHLK
  RVAEKEPINKMSLHNLATVFGPTLLRPSEVESKAHLTSAADIWSHDVMAQVQVLLYYLQH
  PPISFAELKRNTLYFSTDV
• Function: Protein with a unique structure having two opposing regulatory activities toward small GTP-binding proteins. The C-terminus is a GTPase-activating protein domain which stimulates GTP hydrolysis by RAC1, RAC2 and CDC42. Accelerates the intrinsic rate of GTP hydrolysis of RAC1 or CDC42, leading to down-regulation of the active GTP-bound form. The central Dbl homology (DH) domain functions as a guanine nucleotide exchange factor (GEF) that modulates the GTPases CDC42, RHOA and RAC1. Promotes the conversion of CDC42, RHOA and RAC1 from the GDP-bound to the GTP-bound form. Functions as an important negative regulator of neuronal RAC1 activity. Regulates macrophage functions such as CSF-1 directed motility and phagocytosis through the modulation of RAC1 activity.
• Tissue Specificity: Highly enriched in the brain. Much weaker expression in heart, lung and muscle.
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RAC3 GTPase cycle (R-HSA-9013423)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anaplastic astrocytoma	DISSBE0K	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[7]
Epilepsy	DISBB28L	Strong	Biomarker	[8]
Haemophilia A	DIS0RQ2E	Strong	Biomarker	[9]
Hemophilia	DIS1S8P6	Strong	Biomarker	[9]
leukaemia	DISS7D1V	Strong	Altered Expression	[2]
Leukemia	DISNAKFL	Strong	Altered Expression	[2]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[7]
Vitiligo	DISR05SL	Strong	Genetic Variation	[10]
Adrenoleukodystrophy	DISTUD1F	moderate	Biomarker	[11]
Ear malformation	DISVJGPS	moderate	Biomarker	[12]
Primitive neuroectodermal tumor	DISFHXHA	moderate	Biomarker	[13]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[14]
Neoplasm	DISZKGEW	Limited	Biomarker	[15]
Prostate cancer	DISF190Y	Limited	Biomarker	[7]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[16]
Rett syndrome	DISGG5UV	Limited	Biomarker	[17]
Tibial aplasia-ectrodactyly syndrome	DISN7IN9	Limited	Biomarker	[18]

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 Active breakpoint cluster region-related protein (ABR).	[19]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Active breakpoint cluster region-related protein (ABR).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Active breakpoint cluster region-related protein (ABR).	[32]

11 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 Active breakpoint cluster region-related protein (ABR).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Active breakpoint cluster region-related protein (ABR).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Active breakpoint cluster region-related protein (ABR).	[22]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Active breakpoint cluster region-related protein (ABR).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Active breakpoint cluster region-related protein (ABR).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Active breakpoint cluster region-related protein (ABR).	[26]
Selenium	DM25CGV	Approved	Selenium increases the expression of Active breakpoint cluster region-related protein (ABR).	[27]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Active breakpoint cluster region-related protein (ABR).	[28]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Active breakpoint cluster region-related protein (ABR).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Active breakpoint cluster region-related protein (ABR).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Active breakpoint cluster region-related protein (ABR).	[31]

References

• [1] Deletion of chromosome arm 17p DNA sequences in pediatric high-grade and juvenile pilocytic astrocytomas.Genes Chromosomes Cancer. 1995 Mar;12(3):165-72. doi: 10.1002/gcc.2870120303.
• [2] ABR, a novel inducer of transcription factor C/EBP, contributes to myeloid differentiation and is a favorable prognostic factor in acute myeloid leukemia.Oncotarget. 2017 Oct 26;8(61):103626-103639. doi: 10.18632/oncotarget.22093. eCollection 2017 Nov 28.
• [3] Spatial organization of ABR and CRK genes on human chromosome band 17p13.3.Oncogene. 1995 Mar 2;10(5):1009-11.
• [4] Beneficial effects of quinoline-3-carboxamide (ABR-215757) on atherosclerotic plaque morphology in S100A12 transgenic ApoE nullmice.Atherosclerosis. 2013 May;228(1):69-79. doi: 10.1016/j.atherosclerosis.2013.02.023. Epub 2013 Feb 28.
• [5] Specific effect of immunomodulatory quinoline-3-carboxamide ABR-215757 in GM-CSF stimulated bone marrow cell cultures: block of initiation of proliferation of Gr-1+ cells.Int Immunopharmacol. 2011 Aug;11(8):1045-51. doi: 10.1016/j.intimp.2011.02.025. Epub 2011 Mar 6.
• [6] Functionalization of nanotextured substrates for enhanced identification of metastatic breast cancer cells.Nanotechnology. 2017 Sep 20;28(38):385101. doi: 10.1088/1361-6528/aa7f84. Epub 2017 Jul 13.
• [7] A hnRNP KAR-Related Signature Reflects Progression toward Castration-Resistant Prostate Cancer.Int J Mol Sci. 2018 Jun 30;19(7):1920. doi: 10.3390/ijms19071920.
• [8] Epilepsy stigma in Saudi Arabia: The roles of mind-body dualism, supernatural beliefs, and religiosity.Epilepsy Behav. 2019 Jun;95:175-180. doi: 10.1016/j.yebeh.2019.04.022. Epub 2019 May 6.
• [9] Development of Haemophilia Treatment in the Eastern Part of Germany over the Last Decade in the Kompetenznetz Hmorrhagische Diathese Ost (KHDO).Hamostaseologie. 2020 Feb;40(1):119-127. doi: 10.1055/s-0039-3399493. Epub 2019 Nov 11.
• [10] Hearing loss in vitiligo: current concepts and review.Eur Arch Otorhinolaryngol. 2017 Jun;274(6):2367-2372. doi: 10.1007/s00405-017-4452-8. Epub 2017 Feb 14.
• [11] Auditory brainstem response and audiologic findings in adrenoleukodystrophy: its variant and carrier.Otolaryngol Head Neck Surg. 1988 Mar;98(3):215-20. doi: 10.1177/019459988809800307.
• [12] Electrically evoked ABR during cochlear implantation and postoperative development of speech and hearing abilities in infants with common cavity deformity as a type of inner ear malformation.Acta Otolaryngol. 2020 Jan;140(1):14-21. doi: 10.1080/00016489.2019.1692147. Epub 2019 Nov 25.
• [13] Deletion within the D17S34 locus in a primitive neuroectodermal tumor.Cancer Res. 1997 Jan 1;57(1):32-4.
• [14] Transcription Factor EB Activation Rescues Advanced B-Crystallin Mutation-Induced Cardiomyopathy by Normalizing Desmin Localization.J Am Heart Assoc. 2019 Feb 19;8(4):e010866. doi: 10.1161/JAHA.118.010866.
• [15] Extracellular S100A9 Protein in Bone Marrow Supports Multiple Myeloma Survival by Stimulating Angiogenesis and Cytokine Secretion.Cancer Immunol Res. 2017 Oct;5(10):839-846. doi: 10.1158/2326-6066.CIR-17-0192. Epub 2017 Sep 13.
• [16] The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response.Cell Death Dis. 2014 Apr 24;5(4):e1195. doi: 10.1038/cddis.2014.157.
• [17] Auditory brainstem response findings in Rett syndrome.Brain Dev. 1987;9(5):514-6. doi: 10.1016/s0387-7604(87)80075-x.
• [18] The duplication 17p13.3 phenotype: analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes.Am J Med Genet A. 2013 Aug;161A(8):1833-52. doi: 10.1002/ajmg.a.35996. Epub 2013 Jun 27.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [21] 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.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [24] 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.
• [25] Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults. Environ Health Perspect. 2019 May;127(5):57011. doi: 10.1289/EHP3849. Epub 2019 May 28.
• [26] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [27] 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.
• [28] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [29] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [30] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [31] 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.
• [32] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.