Details of Drug Off-Target (DOT)

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

• DOT Name: Beta-chimaerin (CHN2)
• Synonyms: Beta-chimerin; Rho GTPase-activating protein 3
• Gene Name: CHN2
• UniProt ID: CHIO_HUMAN
• PDB ID: 1XA6
• Pfam ID: PF00130 ; PF00620 ; PF00017
• Sequence:
  MAASSNSSLSGSSVSSDAEEYQPPIWKSYLYQLQQEAPRPKRIICPREVENRPKYYGREF
  HGIISREQADELLGGVEGAYILRESQRQPGCYTLALRFGNQTLNYRLFHDGKHFVGEKRF
  ESIHDLVTDGLITLYIETKAAEYISKMTTNPIYEHIGYATLLREKVSRRLSRSKNEPRKT
  NVTHEEHTAVEKISSLVRRAALTHNDNHFNYEKTHNFKVHTFRGPHWCEYCANFMWGLIA
  QGVRCSDCGLNVHKQCSKHVPNDCQPDLKRIKKVYCCDLTTLVKAHNTQRPMVVDICIRE
  IEARGLKSEGLYRVSGFTEHIEDVKMAFDRDGEKADISANVYPDINIITGALKLYFRDLP
  IPVITYDTYSKFIDAAKISNADERLEAVHEVLMLLPPAHYETLRYLMIHLKKVTMNEKDN
  FMNAENLGIVFGPTLMRPPEDSTLTTLHDMRYQKLIVQILIENEDVLF
• Function: GTPase-activating protein for p21-rac. Insufficient expression of beta-2 chimaerin is expected to lead to higher Rac activity and could therefore play a role in the progression from low-grade to high-grade tumors.
• Tissue Specificity: Highest levels in the brain and pancreas. Also expressed in the heart, placenta, and weakly in the kidney and liver. Expression is much reduced in the malignant gliomas, compared to normal brain or low-grade astrocytomas.
• Reactome Pathway: RAC1 GTPase cycle (R-HSA-9013149)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Beta-chimaerin (CHN2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Beta-chimaerin (CHN2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Beta-chimaerin (CHN2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Beta-chimaerin (CHN2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Beta-chimaerin (CHN2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Beta-chimaerin (CHN2).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Beta-chimaerin (CHN2).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Beta-chimaerin (CHN2).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Beta-chimaerin (CHN2).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Beta-chimaerin (CHN2).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Beta-chimaerin (CHN2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Beta-chimaerin (CHN2).	[2]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Beta-chimaerin (CHN2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Beta-chimaerin (CHN2).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Beta-chimaerin (CHN2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Beta-chimaerin (CHN2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Beta-chimaerin (CHN2).	[11]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] 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.
• [5] 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.
• [6] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [7] 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.
• [8] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.