Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX8GUC4)

• DOT Name: Syntaxin-binding protein 2 (STXBP2)
• Synonyms: Protein unc-18 homolog 2; Unc18-2; Protein unc-18 homolog B; Unc-18B
• Gene Name: STXBP2
• Related Disease:
  Familial hemophagocytic lymphohistiocytosis 5
  Adult lymphoma
  Autoimmune hepatitis
  Coagulation defect
  Inborn error of immunity
  Intestinal disorder
  Juvenile idiopathic arthritis
  Lymphoma
  Myocardial infarction
  Pediatric lymphoma
  Thrombocytopenia
  Hereditary hemophagocytic lymphohistiocytosis
  Chronic diarrhoea
  Epstein barr virus infection
  Microvillus inclusion disease
• UniProt ID: STXB2_HUMAN
• PDB ID: 4CCA
• Pfam ID: PF00995
• Sequence:
  MAPSGLKAVVGEKILSGVIRSVKKDGEWKVLIMDHPSMRILSSCCKMSDILAEGITIVED
  INKRREPIPSLEAIYLLSPTEKSVQALIKDFQGTPTFTYKAAHIFFTDTCPEPLFSELGR
  SRLAKVVKTLKEIHLAFLPYEAQVFSLDAPHSTYNLYCPFRAEERTRQLEVLAQQIATLC
  ATLQEYPAIRYRKGPEDTAQLAHAVLAKLNAFKADTPSLGEGPEKTRSQLLIMDRAADPV
  SPLLHELTFQAMAYDLLDIEQDTYRYETTGLSEAREKAVLLDEDDDLWVELRHMHIADVS
  KKVTELLRTFCESKRLTTDKANIKDLSQILKKMPQYQKELNKYSTHLHLADDCMKHFKGS
  VEKLCSVEQDLAMGSDAEGEKIKDSMKLIVPVLLDAAVPAYDKIRVLLLYILLRNGVSEE
  NLAKLIQHANVQAHSSLIRNLEQLGGTVTNPGGSGTSSRLEPRERMEPTYQLSRWTPVIK
  DVMEDAVEDRLDRNLWPFVSDPAPTASSQAAVSARFGHWHKNKAGIEARAGPRLIVYVMG
  GVAMSEMRAAYEVTRATEGKWEVLIGSSHILTPTRFLDDLKALDKKLEDIALP
• Function: Involved in intracellular vesicle trafficking and vesicle fusion with membranes. Contributes to the granule exocytosis machinery through interaction with soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins that regulate membrane fusion. Regulates cytotoxic granule exocytosis in natural killer (NK) cells.
• Tissue Specificity: Placenta, lung, liver, kidney and pancreas, as well as in peripheral blood lymphocytes.
• Reactome Pathway:
  Other interleukin signaling (R-HSA-449836)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial hemophagocytic lymphohistiocytosis 5	DISCWVFW	Definitive	Autosomal recessive	[1]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[2]
Autoimmune hepatitis	DISOX03Q	Strong	Genetic Variation	[3]
Coagulation defect	DIS9X3H6	Strong	Altered Expression	[4]
Inborn error of immunity	DISNGCMN	Strong	Genetic Variation	[5]
Intestinal disorder	DISGPMUQ	Strong	Genetic Variation	[6]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[7]
Lymphoma	DISN6V4S	Strong	Biomarker	[2]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[8]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[2]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[9]
Hereditary hemophagocytic lymphohistiocytosis	DISQP21Z	Supportive	Autosomal recessive	[10]
Chronic diarrhoea	DISH3PX3	Limited	Genetic Variation	[11]
Epstein barr virus infection	DISOO0WT	Limited	Genetic Variation	[12]
Microvillus inclusion disease	DIS6L4RW	Limited	Autosomal recessive	[13]

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 Syntaxin-binding protein 2 (STXBP2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Syntaxin-binding protein 2 (STXBP2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Syntaxin-binding protein 2 (STXBP2).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Syntaxin-binding protein 2 (STXBP2).	[16]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Syntaxin-binding protein 2 (STXBP2).	[17]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Syntaxin-binding protein 2 (STXBP2).	[18]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Syntaxin-binding protein 2 (STXBP2).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Syntaxin-binding protein 2 (STXBP2).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Syntaxin-binding protein 2 (STXBP2).	[22]

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] Development of classical Hodgkin's lymphoma in an adult with biallelic STXBP2 mutations.Haematologica. 2013 May;98(5):760-4. doi: 10.3324/haematol.2012.073098. Epub 2012 Oct 25.
• [3] Novel Patient with Late-Onset Familial Hemophagocytic Lymphohistiocytosis with STXBP2 Mutations Presenting with Autoimmune Hepatitis, Neurological Manifestations and Infections Associated with Hypogammaglobulinemia.J Clin Immunol. 2015 Jan;35(1):22-5. doi: 10.1007/s10875-014-0119-z. Epub 2014 Dec 10.
• [4] Persistent defective membrane trafficking in epithelial cells of patients with familial hemophagocytic lymphohistiocytosis type 5 due to STXBP2/MUNC18-2 mutations.Pediatr Blood Cancer. 2013 Jul;60(7):1215-22. doi: 10.1002/pbc.24475. Epub 2013 Feb 4.
• [5] Munc18-2 is required for Syntaxin 11 Localization on the Plasma Membrane in Cytotoxic T-Lymphocytes.Traffic. 2015 Dec;16(12):1330-41. doi: 10.1111/tra.12337. Epub 2015 Nov 2.
• [6] Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations.JCI Insight. 2017 Jul 20;2(14):e94564. doi: 10.1172/jci.insight.94564. eCollection 2017 Jul 20.
• [7] Whole-exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis.Arthritis Rheumatol. 2014 Dec;66(12):3486-95. doi: 10.1002/art.38793.
• [8] Identification of STXBP2 as a novel susceptibility locus for myocardial infarction in Japanese individuals by an exome-wide association study.Oncotarget. 2017 May 16;8(20):33527-33535. doi: 10.18632/oncotarget.16536.
• [9] Benefit of Anakinra in Treating Pediatric Secondary Hemophagocytic Lymphohistiocytosis.Arthritis Rheumatol. 2020 Feb;72(2):326-334. doi: 10.1002/art.41103. Epub 2019 Dec 26.
• [10] Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. Am J Hum Genet. 2001 Mar;68(3):590-7. doi: 10.1086/318796. Epub 2001 Feb 6.
• [11] Type 5 Familial Hemophagocytic Lymphohistiocytosis in a Seven-year-old Girl Post Second Bone Marrow Transplantation with Failure to Thrive: STXBP2 Novel Mutation.Cureus. 2019 Nov 27;11(11):e6246. doi: 10.7759/cureus.6246.
• [12] Novel mutations of STXBP2 and LYST associated with adult haemophagocytic lymphohistiocytosis with Epstein-Barr virus infection: a case report.BMC Med Genet. 2019 Feb 19;20(1):34. doi: 10.1186/s12881-019-0765-3.
• [13] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [14] 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.
• [15] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [16] 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.
• [17] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [18] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [19] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [20] 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.
• [21] 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.
• [22] 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.