Details of Drug Off-Target (DOT)

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

• DOT Name: Gastrin/cholecystokinin type B receptor (CCKBR)
• Synonyms: CCK-B receptor; CCK-BR; Cholecystokinin-2 receptor; CCK2-R
• Gene Name: CCKBR
• UniProt ID: GASR_HUMAN
• PDB ID: 1L4T; 7F8V; 7F8W; 7XOW; 8IA7
• Pfam ID: PF00001
• Sequence:
  MELLKLNRSVQGTGPGPGASLCRPGAPLLNSSSVGNLSCEPPRIRGAGTRELELAIRITL
  YAVIFLMSVGGNMLIIVVLGLSRRLRTVTNAFLLSLAVSDLLLAVACMPFTLLPNLMGTF
  IFGTVICKAVSYLMGVSVSVSTLSLVAIALERYSAICRPLQARVWQTRSHAARVIVATWL
  LSGLLMVPYPVYTVVQPVGPRVLQCVHRWPSARVRQTWSVLLLLLLFFIPGVVMAVAYGL
  ISRELYLGLRFDGDSDSDSQSRVRNQGGLPGAVHQNGRCRPETGAVGEDSDGCYVQLPRS
  RPALELTALTAPGPGSGSRPTQAKLLAKKRVVRMLLVIVVLFFLCWLPVYSANTWRAFDG
  PGAHRALSGAPISFIHLLSYASACVNPLVYCFMHRRFRQACLETCARCCPRPPRARPRAL
  PDEDPPTPSIASLSRLSYTTISTLGPG
• Function: Receptor for gastrin and cholecystokinin. The CCK-B receptors occur throughout the central nervous system where they modulate anxiety, analgesia, arousal, and neuroleptic activity. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.; Isoform 2 is constitutively activated and may regulate cancer cell proliferation via a gastrin-independent mechanism.
• Tissue Specificity: Isoform 1 is expressed in brain, pancreas, stomach, the colon cancer cell line LoVo and the T-lymphoblastoma Jurkat, but not in heart, placenta, liver, lung, skeletal muscle, kidney or the stomach cancer cell line AGS. Expressed at high levels in the small cell lung cancer cell line NCI-H510, at lower levels in NCI-H345, NCI-H69 and GLC-28 cell lines, not expressed in GLC-19 cell line. Within the stomach, expressed at high levels in the mucosa of the gastric fundus and at low levels in the antrum and duodenum. Isoform 2 is present in pancreatic cancer cells and colorectal cancer cells, but not in normal pancreas or colonic mucosa. Isoform 3 is expressed in brain, pancreas, stomach, the stomach cancer cell line AGS and the colon cancer cell line LoVo.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
  Gastric acid secretion (hsa04971)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Gastrin-CREB signalling pathway via PKC and MAPK (R-HSA-881907)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paricalcitol	DMYBV3G	Approved	Gastrin/cholecystokinin type B receptor (CCKBR) increases the Electrolyte imbalance ADR of Paricalcitol.	[8]

10 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 Gastrin/cholecystokinin type B receptor (CCKBR).	[1]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Gastrin/cholecystokinin type B receptor (CCKBR).	[2]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Gastrin/cholecystokinin type B receptor (CCKBR).	[3]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Gastrin/cholecystokinin type B receptor (CCKBR).	[3]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Gastrin/cholecystokinin type B receptor (CCKBR).	[4]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Gastrin/cholecystokinin type B receptor (CCKBR).	[5]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Gastrin/cholecystokinin type B receptor (CCKBR).	[3]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Gastrin/cholecystokinin type B receptor (CCKBR).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Gastrin/cholecystokinin type B receptor (CCKBR).	[2]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Gastrin/cholecystokinin type B receptor (CCKBR).	[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 decreases the methylation of Gastrin/cholecystokinin type B receptor (CCKBR).	[6]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [3] 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.
• [4] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [5] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [6] 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.
• [7] 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.
• [8] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.