Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL86FEQ)

• DOT Name: Rho GTPase-activating protein 45 (ARHGAP45)
• Gene Name: ARHGAP45
• Related Disease:
  Acute graft versus host disease
  Advanced cancer
  Benign neoplasm
  Graft-versus-host disease
  Influenza
  Neoplasm
  Pre-eclampsia
  Chronic graft versus host disease
  Sjogren syndrome
  Melanoma
• UniProt ID: HMHA1_HUMAN
• PDB ID: 3D25; 3FT3
• Pfam ID: PF00620
• Sequence:
  MFSRKKRELMKTPSISKKNRAGSPSPQPSGELPRKDGADAVFPGPSLEPPAGSSGVKATG
  TLKRPTSLSRHASAAGFPLSGAASWTLGRSHRSPLTAASPGELPTEGAGPDVVEDISHLL
  ADVARFAEGLEKLKECVLRDDLLEARRPRAHECLGEALRVMHQIISKYPLLNTVETLTAA
  GTLIAKVKAFHYESNNDLEKQEFEKALETIAVAFSSTVSEFLMGEVDSSTLLAVPPGDSS
  QSMESLYGPGSEGTPPSLEDCDAGCLPAEEVDVLLQRCEGGVDAALLYAKNMAKYMKDLI
  SYLEKRTTLEMEFAKGLQKIAHNCRQSVMQEPHMPLLSIYSLALEQDLEFGHSMVQAVGT
  LQTQTFMQPLTLRRLEHEKRRKEIKEAWHRAQRKLQEAESNLRKAKQGYVQRCEDHDKAR
  FLVAKAEEEQAGSAPGAGSTATKTLDKRRRLEEEAKNKAEEAMATYRTCVADAKTQKQEL
  EDTKVTALRQIQEVIRQSDQTIKSATISYYQMMHMQTAPLPVHFQMLCESSKLYDPGQQY
  ASHVRQLQRDQEPDVHYDFEPHVSANAWSPVMRARKSSFNVSDVARPEAAGSPPEEGGCT
  EGTPAKDHRAGRGHQVHKSWPLSISDSDSGLDPGPGAGDFKKFERTSSSGTMSSTEELVD
  PDGGAGASAFEQADLNGMTPELPVAVPSGPFRHEGLSKAARTHRLRKLRTPAKCRECNSY
  VYFQGAECEECCLACHKKCLETLAIQCGHKKLQGRLQLFGQDFSHAARSAPDGVPFIVKK
  CVCEIERRALRTKGIYRVNGVKTRVEKLCQAFENGKELVELSQASPHDISNVLKLYLRQL
  PEPLISFRLYHELVGLAKDSLKAEAEAKAASRGRQDGSESEAVAVALAGRLRELLRDLPP
  ENRASLQYLLRHLRRIVEVEQDNKMTPGNLGIVFGPTLLRPRPTEATVSLSSLVDYPHQA
  RVIETLIVHYGLVFEEEPEETPGGQDESSNQRAEVVVQVPYLEAGEAVVYPLQEAAADGC
  RESRVVSNDSDSDLEEASELLSSSEASALGHLSFLEQQQSEASLEVASGSHSGSEEQLEA
  TAREDGDGDEDGPAQQLSGFNTNQSNNVLQAPLPPMRLRGGRMTLGSCRERQPEFV
• Function: Contains a GTPase activator for the Rho-type GTPases (RhoGAP) domain that would be able to negatively regulate the actin cytoskeleton as well as cell spreading. However, also contains N-terminally a BAR-domin which is able to play an autoinhibitory effect on this RhoGAP activity; Precursor of the histocompatibility antigen HA-1. More generally, minor histocompatibility antigens (mHags) refer to immunogenic peptide which, when complexed with MHC, can generate an immune response after recognition by specific T-cells. The peptides are derived from polymorphic intracellular proteins, which are cleaved by normal pathways of antigen processing. The binding of these peptides to MHC class I or class II molecules and its expression on the cell surface can stimulate T-cell responses and thereby trigger graft rejection or graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation from HLA-identical sibling donor. GVHD is a frequent complication after bone marrow transplantation (BMT), due to mismatch of minor histocompatibility antigen in HLA-matched sibling marrow transplants. Specifically, mismatching for mHag HA-1 which is recognized as immunodominant, is shown to be associated with the development of severe GVHD after HLA-identical BMT. HA-1 is presented to the cell surface by MHC class I HLA-A*0201, but also by other HLA-A alleles. This complex specifically elicits donor-cytotoxic T-lymphocyte (CTL) reactivity against hematologic malignancies after treatment by HLA-identical allogenic BMT. It induces cell recognition and lysis by CTL.
• Tissue Specificity: Expressed on cells of the hematopoietic lineage. Detected in dendritic cells and epidermal Langerhans cells. Expressed in peripheral blood mononuclear cells, in all leukemia/lymphoma cell lines. Detected also in some solid tumors and tissues such as cancerous and non-cancerous tissue.
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute graft versus host disease	DIS8KLVM	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Benign neoplasm	DISDUXAD	Strong	Biomarker	[2]
Graft-versus-host disease	DIS0QADF	Strong	Biomarker	[3]
Influenza	DIS3PNU3	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Pre-eclampsia	DISY7Q29	Strong	Biomarker	[5]
Chronic graft versus host disease	DIS1MM9J	moderate	Biomarker	[3]
Sjogren syndrome	DISUBX7H	Disputed	Genetic Variation	[6]
Melanoma	DIS1RRCY	Limited	Biomarker	[7]

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 Rho GTPase-activating protein 45 (ARHGAP45).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Rho GTPase-activating protein 45 (ARHGAP45).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Rho GTPase-activating protein 45 (ARHGAP45).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Rho GTPase-activating protein 45 (ARHGAP45).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Rho GTPase-activating protein 45 (ARHGAP45).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Rho GTPase-activating protein 45 (ARHGAP45).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[2]
Ofloxacin	DM0VQN3	Approved	Ofloxacin affects the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[14]
Acetazolamide	DM1AF5U	Approved	Acetazolamide affects the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[14]
Indapamide	DMGN1PW	Approved	Indapamide affects the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[14]
Brinzolamide	DMBAPFG	Approved	Brinzolamide affects the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[14]
Cefepime	DMHVWIK	Approved	Cefepime affects the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[16]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[9]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Rho GTPase-activating protein 45 (ARHGAP45).	[2]

References

• [1] Correlation between disparity for the minor histocompatibility antigen HA-1 and the development of acute graft-versus-host disease after allogeneic marrow transplantation.Blood. 1999 Oct 15;94(8):2911-4.
• [2] Hypomethylating drugs convert HA-1-negative solid tumors into targets for stem cell-based immunotherapy. Blood. 2009 Mar 19;113(12):2715-22. doi: 10.1182/blood-2008-05-158956. Epub 2008 Dec 18.
• [3] Does minor histocompatibility antigen HA-1 disparity affect the occurrence of graft-versus-host disease in tunisian recipients of hematopoietic stem cells?.Clinics (Sao Paulo). 2010;65(11):1099-103. doi: 10.1590/s1807-59322010001100007.
• [4] Direct sequence determination of the influenza B HA-1 gene after PCR amplification of clinical specimens from an infected volunteer.J Virol Methods. 1993 Sep;44(1):35-44. doi: 10.1016/0166-0934(93)90005-c.
• [5] Trophoblast expression of the minor histocompatibility antigen HA-1 is regulated by oxygen and is increased in placentas from preeclamptic women.Placenta. 2015 Aug;36(8):832-8. doi: 10.1016/j.placenta.2015.05.018. Epub 2015 Jun 6.
• [6] Homozygosity for the 168His variant of the minor histocompatibility antigen HA-1 is associated with reduced risk of primary Sjgren's syndrome.Eur J Immunol. 2005 Jan;35(1):305-17. doi: 10.1002/eji.200425406.
• [7] Multiple pro-tumorigenic functions of the human minor Histocompatibility Antigen-1 (HA-1) in melanoma progression.J Dermatol Sci. 2017 Nov;88(2):216-224. doi: 10.1016/j.jdermsci.2017.07.004. Epub 2017 Jul 8.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] 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.
• [13] Hypomethylating drugs convert HA-1-negative solid tumors into targets for stem cell-based immunotherapy. Blood. 2009 Mar 19;113(12):2715-22. doi: 10.1182/blood-2008-05-158956. Epub 2008 Dec 18.
• [14] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [18] 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.
• [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] 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.
• [21] 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.