Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFSKXG9)

• DOT Name: Rho guanine nucleotide exchange factor 40 (ARHGEF40)
• Synonyms: Protein SOLO
• Gene Name: ARHGEF40
• Related Disease:
  Advanced cancer
  High blood pressure
  Thrombocytopenia
  Endocarditis
  Atopic dermatitis
• UniProt ID: ARH40_HUMAN
• Pfam ID: PF00621
• Sequence:
  MEPEPVEDCVQSTLAALYPPFEATAPTLLGQVFQVVERTYREDALRYTLDFLVPAKHLLA
  KVQQEACAQYSGFLFFHEGWPLCLHEQVVVQLAALPWQLLRPGDFYLQVVPSAAQAPRLA
  LKCLAPGGGRVQEVPVPNEACAYLFTPEWLQGINKDRPTGRLSTCLLSAPSGIQRLPWAE
  LICPRFVHKEGLMVGHQPSTLPPELPSGPPGLPSPPLPEEALGTRSPGDGHNAPVEGPEG
  EYVELLEVTLPVRGSPTDAEGSPGLSRVRTVPTRKGAGGKGRHRRHRAWMHQKGLGPRGQ
  DGARPPGEGSSTGASPESPPGAEAVPEAAVLEVSEPPAEAVGEASGSCPLRPGELRGGGG
  GGQGAEGPPGTPRRTGKGNRRKKRAAGRGALSRGGDSAPLSPGDKEDASHQEALGNLPSP
  SEHKLPECHLVKEEYEGSGKPESEPKELKTAGEKEPQLSEACGPTEEGAGERELEGPGLL
  CMAGHTGPEGPLSDTPTPPLETVQEGKGDNIPEEALAVSVSDHPDVAWDLMASGFLILTG
  GVDQSGRALLTITPPCPPEEPPPSRDTLNTTLHYLHSLLRPDLQTLGLSVLLDLRQAPPL
  PPALIPALSQLQDSGDPPLVQRLLILIHDDLPTELCGFQGAEVLSENDLKRVAKPEELQW
  ELGGHRDPSPSHWVEIHQEVVRLCRLCQGVLGSVRQAIEELEGAAEPEEEEAVGMPKPLQ
  KVLADPRLTALQRDGGAILMRLRSTPSSKLEGQGPATLYQEVDEAIHQLVRLSNLHVQQQ
  EQRQCLRRLQQVLQWLSGPGEEQLASFAMPGDTLSALQETELRFRAFSAEVQERLAQARE
  ALALEENATSQKVLDIFEQRLEQVESGLHRALRLQRFFQQAHEWVDEGFARLAGAGPGRE
  AVLAALALRRAPEPSAGTFQEMRALALDLGSPAALREWGRCQARCQELERRIQQHVGEEA
  SPRGYRRRRADGASSGGAQWGPRSPSPSLSSLLLPSSPGPRPAPSHCSLAPCGEDYEEEG
  PELAPEAEGRPPRAVLIRGLEVTSTEVVDRTCSPREHVLLGRARGPDGPWGVGTPRMERK
  RSISAQQRLVSELIACEQDYVATLSEPVPPPGPELTPELRGTWAAALSARERLRSFHRTH
  FLRELQGCATHPLRIGACFLRHGDQFSLYAQYVKHRHKLENGLAALSPLSKGSMEAGPYL
  PRALQQPLEQLTRYGRLLEELLREAGPELSSECRALGAAVQLLREQEARGRDLLAVEAVR
  GCEIDLKEQGQLLHRDPFTVICGRKKCLRHVFLFEHLLLFSKLKGPEGGSEMFVYKQAFK
  TADMGLTENIGDSGLCFELWFRRRRAREAYTLQATSPEIKLKWTSSIAQLLWRQAAHNKE
  LRVQQMVSMGIGNKPFLDIKALGERTLSALLTGRAARTRASVAVSSFEHAGPSLPGLSPG
  ACSLPARVEEEAWDLDVKQISLAPETLDSSGDVSPGPRNSPSLQPPHPGSSTPTLASRGI
  LGLSRQSHARALSDPTTPL
• Function: May act as a guanine nucleotide exchange factor (GEF).
• Tissue Specificity: Expressed at higher level in the central nervous system and skeletal muscle and greater abundance in fetal than adult brain (at protein level).
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOC GTPase cycle (R-HSA-9013106)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
High blood pressure	DISY2OHH	Strong	Biomarker	[2]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[3]
Endocarditis	DISBU610	Disputed	Genetic Variation	[4]
Atopic dermatitis	DISTCP41	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Rho guanine nucleotide exchange factor 40 (ARHGEF40).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Rho guanine nucleotide exchange factor 40 (ARHGEF40).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rho guanine nucleotide exchange factor 40 (ARHGEF40).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rho guanine nucleotide exchange factor 40 (ARHGEF40).	[9]
Marinol	DM70IK5	Approved	Marinol increases the expression of Rho guanine nucleotide exchange factor 40 (ARHGEF40).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Rho guanine nucleotide exchange factor 40 (ARHGEF40).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho guanine nucleotide exchange factor 40 (ARHGEF40).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rho guanine nucleotide exchange factor 40 (ARHGEF40).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Rho guanine nucleotide exchange factor 40 (ARHGEF40).	[14]

References

• [1] Paradoxical expression of anti-apoptotic and MRP genes on cancer stem-like cell isolated from TJ905 glioblastoma multiforme cell line.Cancer Invest. 2008 May;26(4):338-43. doi: 10.1080/07357900701788064.
• [2] Six-Month Results of Treatment-Blinded Medication Titration for Hypertension Control After Randomization to Endovascular Ultrasound Renal Denervation or a Sham Procedure in the RADIANCE-HTN SOLO Trial.Circulation. 2019 May 28;139(22):2542-2553. doi: 10.1161/CIRCULATIONAHA.119.040451. Epub 2019 Mar 17.
• [3] Freedom SOLO-Associated Thrombocytopaenia is Valve-Dependent and Not Due to In Vitro Pseudothrombocytopaenia.Heart Lung Circ. 2017 Mar;26(3):268-275. doi: 10.1016/j.hlc.2016.07.002. Epub 2016 Aug 16.
• [4] Is the Freedom SOLO Stentless Bioprosthesis a Useful Tool for Patients with Aortic Endocarditis and Aortic Annular Destruction?.Thorac Cardiovasc Surg. 2019 Dec;67(8):644-651. doi: 10.1055/s-0038-1668134. Epub 2018 Aug 16.
• [5] Dupilumab improves patient-reported symptoms of atopic dermatitis, symptoms of anxiety and depression, and health-related quality of life in moderate-to-severe atopic dermatitis: analysis of pooled data from the randomized trials SOLO 1 and SOLO 2.J Dermatolog Treat. 2020 Sep;31(6):606-614. doi: 10.1080/09546634.2019.1612836. Epub 2019 Jun 9.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [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] 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.