Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0K99TO)

• DOT Name: Guanine nucleotide-binding protein subunit alpha-11 (GNA11)
• Synonyms: G alpha-11; G-protein subunit alpha-11; Guanine nucleotide-binding protein G(y) subunit alpha
• Gene Name: GNA11
• Related Disease:
  Autosomal dominant hypocalcemia 2
  Familial hypocalciuric hypercalcemia 2
  Autosomal dominant hypocalcemia
• UniProt ID: GNA11_HUMAN
• PDB ID: 6OIJ; 7RKF; 7TRY
• Pfam ID: PF00503
• Sequence:
  MTLESMMACCLSDEVKESKRINAEIEKQLRRDKRDARRELKLLLLGTGESGKSTFIKQMR
  IIHGAGYSEEDKRGFTKLVYQNIFTAMQAMIRAMETLKILYKYEQNKANALLIREVDVEK
  VTTFEHQYVSAIKTLWEDPGIQECYDRRREYQLSDSAKYYLTDVDRIATLGYLPTQQDVL
  RVRVPTTGIIEYPFDLENIIFRMVDVGGQRSERRKWIHCFENVTSIMFLVALSEYDQVLV
  ESDNENRMEESKALFRTIITYPWFQNSSVILFLNKKDLLEDKILYSHLVDYFPEFDGPQR
  DAQAAREFILKMFVDLNPDSDKIIYSHFTCATDTENIRFVFAAVKDTILQLNLKEYNLV
• Function: Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. Acts as an activator of phospholipase C. Transduces FFAR4 signaling in response to long-chain fatty acids (LCFAs). Together with GNAQ, required for heart development.
• Tissue Specificity: Expressed in testis.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Vascular smooth muscle contraction (hsa04270)
  Gap junction (hsa04540)
  Cholinergic sy.pse (hsa04725)
  Long-term depression (hsa04730)
  Insulin secretion (hsa04911)
  GnRH sig.ling pathway (hsa04912)
  Aldosterone synthesis and secretion (hsa04925)
  Cortisol synthesis and secretion (hsa04927)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  GnRH secretion (hsa04929)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Chagas disease (hsa05142)
  Amoebiasis (hsa05146)
  Human cytomegalovirus infection (hsa05163)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  G-protein activation (R-HSA-202040)
  Acetylcholine regulates insulin secretion (R-HSA-399997)
  G alpha (q) signalling events (R-HSA-416476)
  ADP signalling through P2Y purinoceptor 1 (R-HSA-418592)
  Thromboxane signalling through TP receptor (R-HSA-428930)
  Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion (R-HSA-434316)
  Thrombin signalling through proteinase activated receptors (PARs) (R-HSA-456926)
  Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding (R-HSA-6814122)
  PLC beta mediated events (R-HSA-112043)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant hypocalcemia 2	DISM33SF	Strong	Autosomal dominant	[1]
Familial hypocalciuric hypercalcemia 2	DISBQO80	Strong	Autosomal dominant	[2]
Autosomal dominant hypocalcemia	DISW4TUE	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Guanine nucleotide-binding protein subunit alpha-11 (GNA11) affects the response to substance of Methotrexate.	[12]
Trametinib	DM2JGQ3	Approved	Guanine nucleotide-binding protein subunit alpha-11 (GNA11) increases the response to substance of Trametinib.	[13]
(+)-JQ1	DM1CZSJ	Phase 1	Guanine nucleotide-binding protein subunit alpha-11 (GNA11) increases the response to substance of (+)-JQ1.	[14]

2 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 Guanine nucleotide-binding protein subunit alpha-11 (GNA11).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Guanine nucleotide-binding protein subunit alpha-11 (GNA11).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Guanine nucleotide-binding protein subunit alpha-11 (GNA11).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Guanine nucleotide-binding protein subunit alpha-11 (GNA11).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guanine nucleotide-binding protein subunit alpha-11 (GNA11).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Guanine nucleotide-binding protein subunit alpha-11 (GNA11).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Guanine nucleotide-binding protein subunit alpha-11 (GNA11).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Guanine nucleotide-binding protein subunit alpha-11 (GNA11).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Guanine nucleotide-binding protein subunit alpha-11 (GNA11).	[11]

References

• [1] Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat Genet. 2013 Jan;45(1):93-7. doi: 10.1038/ng.2492. Epub 2012 Dec 9.
• [2] Mutations affecting G-protein subunit 11 in hypercalcemia and hypocalcemia. N Engl J Med. 2013 Jun 27;368(26):2476-2486. doi: 10.1056/NEJMoa1300253.
• [3] 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.
• [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] 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.
• [7] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [8] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [12] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [13] Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent manner. Clin Cancer Res. 2012 Aug 15;18(16):4345-55. doi: 10.1158/1078-0432.CCR-11-3227. Epub 2012 Jun 25.
• [14] BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells. Oncotarget. 2015 Oct 20;6(32):33397-409. doi: 10.18632/oncotarget.5179.