Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2RE7A7)

• DOT Name: Ras-related C3 botulinum toxin substrate 3 (RAC3)
• Synonyms: EC 3.6.5.2; p21-Rac3
• Gene Name: RAC3
• Related Disease: Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies
• UniProt ID: RAC3_HUMAN
• PDB ID: 2C2H; 2G0N; 2IC5; 2OV2; 2QME; 6TM1
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MQAIKCVVVGDGAVGKTCLLISYTTNAFPGEYIPTVFDNYSANVMVDGKPVNLGLWDTAG
  QEDYDRLRPLSYPQTDVFLICFSLVSPASFENVRAKWYPEVRHHCPHTPILLVGTKLDLR
  DDKDTIERLRDKKLAPITYPQGLAMAREIGSVKYLECSALTQRGLKTVFDEAIRAVLCPP
  PVKKPGKKCTVF
• Function: Plasma membrane-associated small GTPase which cycles between an active GTP-bound and inactive GDP-bound state. In active state binds to a variety of effector proteins to regulate cellular responses, such as cell spreading and the formation of actin-based protusions including lamellipodia and membrane ruffles. Promotes cell adhesion and spreading on fibrinogen in a CIB1 and alpha-IIb/beta3 integrin-mediated manner.
• Tissue Specificity: Highest levels in brain, also detected in heart, placenta and pancreas.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  cAMP sig.ling pathway (hsa04024)
  Chemokine sig.ling pathway (hsa04062)
  Sphingolipid sig.ling pathway (hsa04071)
  Wnt sig.ling pathway (hsa04310)
  Axon guidance (hsa04360)
  VEGF sig.ling pathway (hsa04370)
  Focal adhesion (hsa04510)
  Adherens junction (hsa04520)
  .tural killer cell mediated cytotoxicity (hsa04650)
  B cell receptor sig.ling pathway (hsa04662)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Regulation of actin cytoskeleton (hsa04810)
  Yersinia infection (hsa05135)
  Human cytomegalovirus infection (hsa05163)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
  Colorectal cancer (hsa05210)
  Pancreatic cancer (hsa05212)
  Choline metabolism in cancer (hsa05231)
  Viral myocarditis (hsa05416)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  RAC3 GTPase cycle (R-HSA-9013423)
  PCP/CE pathway (R-HSA-4086400)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies	DISY4LCH	Strong	Autosomal dominant	[1]

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 Ras-related C3 botulinum toxin substrate 3 (RAC3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[14]

13 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-related C3 botulinum toxin substrate 3 (RAC3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[8]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[9]
Isoflavone	DM7U58J	Phase 4	Isoflavone decreases the expression of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[16]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[17]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[18]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Simvastatin	DM30SGU	Approved	Simvastatin affects the localization of Ras-related C3 botulinum toxin substrate 3 (RAC3).	[10]

References

• [1] WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome. Am J Hum Genet. 2018 Jan 4;102(1):27-43. doi: 10.1016/j.ajhg.2017.10.002. Epub 2017 Dec 21.
• [2] 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.
• [3] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] 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.
• [9] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [10] Statin-triggered cell death in primary human lung mesenchymal cells involves p53-PUMA and release of Smac and Omi but not cytochrome c. Biochim Biophys Acta. 2010 Apr;1803(4):452-67. doi: 10.1016/j.bbamcr.2009.12.005. Epub 2010 Jan 4.
• [11] Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells. J Nutr. 2007 Apr;137(4):964-72.
• [12] The effect of resveratrol on a cell model of human aging. Ann N Y Acad Sci. 2007 Oct;1114:407-18. doi: 10.1196/annals.1396.001. Epub 2007 Sep 5.
• [13] 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.
• [14] 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.
• [15] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [16] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [17] 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.
• [18] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.