Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFN8JM1)

• DOT Name: Somatostatin receptor type 2 (SSTR2)
• Synonyms: SS-2-R; SS2-R; SS2R; SST2; SRIF-1
• Gene Name: SSTR2
• UniProt ID: SSR2_HUMAN
• PDB ID: 7T10; 7T11; 7UL5; 7WIC; 7WIG; 7WJ5; 7XAT; 7XAU; 7XAV; 7XMR; 7Y24; 7Y26; 7Y27; 7YAC; 7YAE
• Pfam ID: PF00001
• Sequence:
  MDMADEPLNGSHTWLSIPFDLNGSVVSTNTSNQTEPYYDLTSNAVLTFIYFVVCIIGLCG
  NTLVIYVILRYAKMKTITNIYILNLAIADELFMLGLPFLAMQVALVHWPFGKAICRVVMT
  VDGINQFTSIFCLTVMSIDRYLAVVHPIKSAKWRRPRTAKMITMAVWGVSLLVILPIMIY
  AGLRSNQWGRSSCTINWPGESGAWYTGFIIYTFILGFLVPLTIICLCYLFIIIKVKSSGI
  RVGSSKRKKSEKKVTRMVSIVVAVFIFCWLPFYIFNVSSVSMAISPTPALKGMFDFVVVL
  TYANSCANPILYAFLSDNFKKSFQNVLCLVKVSGTDDGERSDSKQDKSRLNETTETQRTL
  LNGDLQTSI
• Function: Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stimulates phosphotyrosine phosphatase and PLC via pertussis toxin insensitive as well as sensitive G proteins. Inhibits calcium entry by suppressing voltage-dependent calcium channels. Acts as the functionally dominant somatostatin receptor in pancreatic alpha- and beta-cells where it mediates the inhibitory effect of somatostatin-14 on hormone secretion. Inhibits cell growth through enhancement of MAPK1 and MAPK2 phosphorylation and subsequent up-regulation of CDKN1B. Stimulates neuronal migration and axon outgrowth and may participate in neuron development and maturation during brain development. Mediates negative regulation of insulin receptor signaling through PTPN6. Inactivates SSTR3 receptor function following heterodimerization.
• Tissue Specificity: Expressed in both pancreatic alpha- and beta-cells (at protein level). Expressed at higher levels in the pancreas than other somatostatin receptors. Also expressed in the cerebrum and kidney and, in lesser amounts, in the jejunum, colon and liver. In the developing nervous system, expressed in the cortex where it is located in the preplate at early stages and is enriched in the outer part of the germinal zone at later stages. In the cerebellum, expressed in the deep part of the external granular layer at gestational week 19. This pattern persists until birth but disappears at adulthood.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Growth hormone synthesis, secretion and action (hsa04935)
  Gastric acid secretion (hsa04971)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

9 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 Somatostatin receptor type 2 (SSTR2).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Somatostatin receptor type 2 (SSTR2).	[2]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Somatostatin receptor type 2 (SSTR2).	[3]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Somatostatin receptor type 2 (SSTR2).	[4]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Somatostatin receptor type 2 (SSTR2).	[4]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Somatostatin receptor type 2 (SSTR2).	[6]
PMID26394986-Compound-22	DM43Z1G	Patented	PMID26394986-Compound-22 increases the expression of Somatostatin receptor type 2 (SSTR2).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Somatostatin receptor type 2 (SSTR2).	[10]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Somatostatin receptor type 2 (SSTR2).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Pasireotide	DMHM7JS	Approved	Pasireotide affects the binding of Somatostatin receptor type 2 (SSTR2).	[5]
Edotreotide	DMQ08AJ	Phase 2	Edotreotide affects the binding of Somatostatin receptor type 2 (SSTR2).	[7]

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 increases the methylation of Somatostatin receptor type 2 (SSTR2).	[8]

References

• [1] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [2] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] 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.
• [4] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [5] Medicinal chemistry of somatostatin analogs leading to the DTPA and DOTA conjugates of the multi-receptor-ligand SOM230. J Endocrinol Invest. 2005;28(11 Suppl International):15-20.
• [6] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [7] Locoregional regulatory peptide receptor targeting with the diffusible somatostatin analogue 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC): a pilot study in human gliomas. Clin Cancer Res. 1999 May;5(5):1025-33.
• [8] 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.
• [9] Preoperative growth inhibition of human gastric adenocarcinoma treated with a combination of celecoxib and octreotide. Acta Pharmacol Sin. 2007 Nov;28(11):1842-50. doi: 10.1111/j.1745-7254.2007.00652.x.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] 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.