Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD7XNLL)

• DOT Name: Platelet glycoprotein Ib beta chain (GP1BB)
• Synonyms: GP-Ib beta; GPIb-beta; GPIbB; Antigen CD42b-beta; CD antigen CD42c
• Gene Name: GP1BB
• Related Disease:
  Bernard-Soulier syndrome
  Barber-Say syndrome
  Brooke-Spiegler syndrome
  DiGeorge syndrome
  Inherited bleeding disorder, platelet-type
  Juvenile idiopathic arthritis
  Polycystic ovarian syndrome
  Thrombocytopenia
  Thrombocytopenic purpura
  Autosomal dominant macrothrombocytopenia
• UniProt ID: GP1BB_HUMAN
• PDB ID: 3REZ; 3RFE
• Sequence:
  MGSGPRGALSLLLLLLAPPSRPAAGCPAPCSCAGTLVDCGRRGLTWASLPTAFPVDTTEL
  VLTGNNLTALPPGLLDALPALRTAHLGANPWRCDCRLVPLRAWLAGRPERAPYRDLRCVA
  PPALRGRLLPYLAEDELRAACAPGPLCWGALAAQLALLGLGLLHALLLVLLLCRLRRLRA
  RARARAAARLSLTDPLVAERAGTDES
• Function: Gp-Ib, a surface membrane protein of platelets, participates in the formation of platelet plugs by binding to von Willebrand factor, which is already bound to the subendothelium.
• Tissue Specificity: Expressed in heart and brain.
• KEGG Pathway:
  ECM-receptor interaction (hsa04512)
  Platelet activation (hsa04611)
  Hematopoietic cell lineage (hsa04640)
• Reactome Pathway:
  GP1b-IX-V activation signalling (R-HSA-430116)
  Platelet Adhesion to exposed collagen (R-HSA-75892)
  Platelet Aggregation (Plug Formation) (R-HSA-76009)
  Defective F9 activation (R-HSA-9673221)
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bernard-Soulier syndrome	DISLD1FU	Definitive	Autosomal recessive	[1]
Barber-Say syndrome	DISW5MTJ	Strong	Biomarker	[2]
Brooke-Spiegler syndrome	DIS36OT6	Strong	Biomarker	[2]
DiGeorge syndrome	DIST1RKO	Strong	Biomarker	[3]
Inherited bleeding disorder, platelet-type	DISIUNXT	Strong	Genetic Variation	[4]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[5]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[6]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[7]
Thrombocytopenic purpura	DISZI5Z8	Strong	Genetic Variation	[8]
Autosomal dominant macrothrombocytopenia	DISUTMSW	Supportive	Autosomal dominant	[4]

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 Platelet glycoprotein Ib beta chain (GP1BB).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Platelet glycoprotein Ib beta chain (GP1BB).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Platelet glycoprotein Ib beta chain (GP1BB).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Platelet glycoprotein Ib beta chain (GP1BB).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Platelet glycoprotein Ib beta chain (GP1BB).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Platelet glycoprotein Ib beta chain (GP1BB).	[13]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Platelet glycoprotein Ib beta chain (GP1BB).	[14]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Platelet glycoprotein Ib beta chain (GP1BB).	[15]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Platelet glycoprotein Ib beta chain (GP1BB).	[16]
APR-246	DMNFADH	Phase 2	APR-246 increases the expression of Platelet glycoprotein Ib beta chain (GP1BB).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Platelet glycoprotein Ib beta chain (GP1BB).	[19]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Bernard-Soulier syndrome.Haematologica. 2011 Mar;96(3):355-9. doi: 10.3324/haematol.2010.039883.
• [3] Heterozygous loss of platelet glycoprotein (GP) Ib-V-IX variably affects platelet function in velocardiofacial syndrome (VCFS) patients.Thromb Haemost. 2007 Dec;98(6):1298-308.
• [4] Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia. Blood. 2017 Jan 26;129(4):520-524. doi: 10.1182/blood-2016-08-732248. Epub 2016 Nov 14.
• [5] Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
• [6] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [7] Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.Blood. 2019 Dec 5;134(23):2082-2091. doi: 10.1182/blood.2018891192.
• [8] Low prevalence of a polymorphism of platelet membrane glycoprotein Ib beta associated with neonatal alloimmune thrombocytopenic purpura in Asian populations.Int J Hematol. 1999 Jan;69(1):54-6.
• [9] 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.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [12] Fetal-sex dependent genomic responses in the circulating lymphocytes of arsenic-exposed pregnant women in New Hampshire. Reprod Toxicol. 2017 Oct;73:184-195. doi: 10.1016/j.reprotox.2017.07.023. Epub 2017 Aug 6.
• [13] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [14] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [15] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [16] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [17] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [18] 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.
• [19] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.