Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOGF42G)

• DOT Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12)
• Synonyms: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12
• Gene Name: GNG12
• Related Disease:
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Epithelial ovarian cancer
• UniProt ID: GBG12_HUMAN
• Pfam ID: PF00631
• Sequence:
  MSSKTASTNNIAQARRTVQQLRLEASIERIKVSKASADLMSYCEEHARSDPLLIGIPTSE
  NPFKDKKTCIIL
• Function: Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Chemokine sig.ling pathway (hsa04062)
  PI3K-Akt sig.ling pathway (hsa04151)
  Apelin sig.ling pathway (hsa04371)
  Circadian entrainment (hsa04713)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  GABAergic sy.pse (hsa04727)
  Dopaminergic sy.pse (hsa04728)
  Regulation of actin cytoskeleton (hsa04810)
  Relaxin sig.ling pathway (hsa04926)
  Morphine addiction (hsa05032)
  Alcoholism (hsa05034)
  Human cytomegalovirus infection (hsa05163)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  Glucagon signaling in metabolic regulation (R-HSA-163359)
  G-protein activation (R-HSA-202040)
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)
  ADP signalling through P2Y purinoceptor 12 (R-HSA-392170)
  G beta (R-HSA-392451)
  Prostacyclin signalling through prostacyclin receptor (R-HSA-392851)
  Adrenaline,noradrenaline inhibits insulin secretion (R-HSA-400042)
  Ca2+ pathway (R-HSA-4086398)
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (12/13) signalling events (R-HSA-416482)
  G beta (R-HSA-418217)
  G alpha (s) signalling events (R-HSA-418555)
  ADP signalling through P2Y purinoceptor 1 (R-HSA-418592)
  G alpha (i) signalling events (R-HSA-418594)
  G alpha (z) signalling events (R-HSA-418597)
  Glucagon-type ligand receptors (R-HSA-420092)
  Thromboxane signalling through TP receptor (R-HSA-428930)
  Vasopressin regulates renal water homeostasis via Aquaporins (R-HSA-432040)
  Thrombin signalling through proteinase activated receptors (PARs) (R-HSA-456926)
  Presynaptic function of Kainate receptors (R-HSA-500657)
  Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding (R-HSA-6814122)
  G beta (R-HSA-8964315)
  G beta (R-HSA-8964616)
  Extra-nuclear estrogen signaling (R-HSA-9009391)
  GPER1 signaling (R-HSA-9634597)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits (R-HSA-997272)
  Activation of G protein gated Potassium channels (R-HSA-1296041)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon cancer	DISVC52G	Strong	Genetic Variation	[1]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[1]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[1]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[1]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[1]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[1]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]

14 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 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[8]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[11]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[12]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[15]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[16]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 (GNG12).	[10]

References

• [1] Bayesian and frequentist analysis of an Austrian genome-wide association study of colorectal cancer and advanced adenomas.Oncotarget. 2017 Oct 9;8(58):98623-98634. doi: 10.18632/oncotarget.21697. eCollection 2017 Nov 17.
• [2] Evaluation of core serous epithelial ovarian cancer genes as potential prognostic markers and indicators of the underlying molecular mechanisms using an integrated bioinformatics analysis.Oncol Lett. 2019 Nov;18(5):5508-5522. doi: 10.3892/ol.2019.10884. Epub 2019 Sep 19.
• [3] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors. Leuk Res. 2007 Nov;31(11):1511-20.
• [10] 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.
• [11] 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.
• [12] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [13] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [14] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [15] 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.
• [16] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [17] Identifying qualitative differences in PPAR signaling networks in human and rat hepatocytes and their significance for next generation chemical risk assessment methods. Toxicol In Vitro. 2020 Apr;64:104463. doi: 10.1016/j.tiv.2019.02.017. Epub 2019 Oct 15.