Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2EPIVZ)

• DOT Name: Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3)
• Synonyms: SH3 domain-containing protein 6511
• Gene Name: PACSIN3
• UniProt ID: PACN3_HUMAN
• Pfam ID: PF00611 ; PF14604
• Sequence:
  MAPEEDAGGEALGGSFWEAGNYRRTVQRVEDGHRLCGDLVSCFQERARIEKAYAQQLADW
  ARKWRGTVEKGPQYGTLEKAWHAFFTAAERLSALHLEVREKLQGQDSERVRAWQRGAFHR
  PVLGGFRESRAAEDGFRKAQKPWLKRLKEVEASKKSYHAARKDEKTAQTRESHAKADSAV
  SQEQLRKLQERVERCAKEAEKTKAQYEQTLAELHRYTPRYMEDMEQAFETCQAAERQRLL
  FFKDMLLTLHQHLDLSSSEKFHELHRDLHQGIEAASDEEDLRWWRSTHGPGMAMNWPQFE
  EWSLDTQRTISRKEKGGRSPDEVTLTSIVPTRDGTAPPPQSPGSPGTGQDEEWSDEESPR
  KAATGVRVRALYDYAGQEADELSFRAGEELLKMSEEDEQGWCQGQLQSGRIGLYPANYVE
  CVGA
• Function: Plays a role in endocytosis and regulates internalization of plasma membrane proteins. Overexpression impairs internalization of SLC2A1/GLUT1 and TRPV4 and increases the levels of SLC2A1/GLUT1 and TRPV4 at the cell membrane. Inhibits the TRPV4 calcium channel activity.
• Tissue Specificity: Widely expressed, with highest levels in heart and skeletal muscle, intermediate levels in placenta, liver and pancreas, and very low levels in brain, lung and kidney.
• Reactome Pathway: Clathrin-mediated endocytosis (R-HSA-8856828)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[7]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[14]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Protein kinase C and casein kinase substrate in neurons protein 3 (PACSIN3).	[15]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [13] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [14] 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.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.