Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT07Z2RQ)

• DOT Name: Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1)
• Synonyms: Syndapin-1
• Gene Name: PACSIN1
• Related Disease:
  Huntington disease
  Varicose veins
• UniProt ID: PACN1_HUMAN
• PDB ID: 3HAH; 3HAI; 3Q84; 3QNI
• Pfam ID: PF00611 ; PF14604
• Sequence:
  MSSSYDEASLAPEETTDSFWEVGNYKRTVKRIDDGHRLCNDLMNCVQERAKIEKAYGQQL
  TDWAKRWRQLIEKGPQYGSLERAWGAIMTEADKVSELHQEVKNNLLNEDLEKVKNWQKDA
  YHKQIMGGFKETKEAEDGFRKAQKPWAKKMKELEAAKKAYHLACKEEKLAMTREMNSKTE
  QSVTPEQQKKLQDKVDKCKQDVQKTQEKYEKVLEDVGKTTPQYMENMEQVFEQCQQFEEK
  RLVFLKEVLLDIKRHLNLAENSSYIHVYRELEQAIRGADAQEDLRWFRSTSGPGMPMNWP
  QFEEWNPDLPHTTTKKEKQPKKAEGVALTNATGAVESTSQAGDRGSVSSYDRGQPYATEW
  SDDESGNPFGGSETNGGANPFEDDSKGVRVRALYDYDGQEQDELSFKAGDELTKLGEEDE
  QGWCRGRLDSGQLGLYPANYVEAI
• Function: Plays a role in the reorganization of the microtubule cytoskeleton via its interaction with MAPT; this decreases microtubule stability and inhibits MAPT-induced microtubule polymerization. Plays a role in cellular transport processes by recruiting DNM1, DNM2 and DNM3 to membranes. Plays a role in the reorganization of the actin cytoskeleton and in neuron morphogenesis via its interaction with COBL and WASL, and by recruiting COBL to the cell cortex. Plays a role in the regulation of neurite formation, neurite branching and the regulation of neurite length. Required for normal synaptic vesicle endocytosis; this process retrieves previously released neurotransmitters to accommodate multiple cycles of neurotransmission. Required for normal excitatory and inhibitory synaptic transmission. Binds to membranes via its F-BAR domain and mediates membrane tubulation.
• Tissue Specificity: Highly expressed in brain and, at much lower levels, in heart and pancreas.
• Reactome Pathway: Clathrin-mediated endocytosis (R-HSA-8856828)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Huntington disease	DISQPLA4	Strong	Biomarker	[1]
Varicose veins	DISIMBN2	Strong	Biomarker	[1]

3 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 Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1).	[15]

References

• [1] PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington's disease brains.Hum Mol Genet. 2002 Oct 1;11(21):2547-58. doi: 10.1093/hmg/11.21.2547.
• [2] 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.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] 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.
• [5] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] 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.
• [13] 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.
• [14] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [15] 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.