Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC3U0YH)

• DOT Name: Synaptopodin-2 (SYNPO2)
• Synonyms: Genethonin-2; Myopodin
• Gene Name: SYNPO2
• Related Disease:
  Lung cancer
  Lung carcinoma
  Cardiovascular disease
  Epithelial ovarian cancer
  Neoplasm
  Triple negative breast cancer
  Vascular disease
  Asthma
  Breast cancer
  Breast carcinoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: SYNP2_HUMAN
• Pfam ID: PF00595
• Sequence:
  MGTGDFICISMTGGAPWGFRLQGGKEQKQPLQVAKIRNQSKASGSGLCEGDEVVSINGNP
  CADLTYPEVIKLMESITDSLQMLIKRPSSGISEALISENENKNLEHLTHGGYVESTTLQI
  RPATKTQCTEFFLAPVKTEVPLAENQRSGPDCAGSLKEETGPSYQRAPQMPDSQRGRVAE
  ELILREKVEAVQPGPVVELQLSLSQERHKGASGPLVALPGAEKSKSPDPDPNLSHDRIVH
  INSIPTNEKADPFLRSSKIIQISSGRELRVIQESEAGDAGLPRVEVILDCSDRQKTEGCR
  LQAGKECVDSPVEGGQSEAPPSLVSFAVSSEGTEQGEDPRSEKDHSRPHKHRARHARLRR
  SESLSEKQVKEAKSKCKSIALLLTDAPNPNSKGVLMFKKRRRRARKYTLVSYGTGELERE
  ADEEEEGDKEDTCEVAFLGASESEVDEELLSDVDDNTQVVNFDWDSGLVDIEKKLNRGDK
  MEMLPDTTGKGALMFAKRRERMDQITAQKEEDKVGGTPSREQDAAQTDGLRTTTSYQRKE
  EESVRTQSSVSKSYIEVSHGLGHVPQQNGFSGTSETANIQRMVPMNRTAKPFPGSVNQPA
  TPFSPTRNMTSPIADFPAPPPYSAVTPPPDAFSRGVSSPIAGPAQPPPWPQPAPWSQPAF
  YDSSERIASRDERISVPAKRTGILQEAKRRSTTKPMFTFKEPKVSPNPELLSLLQNSEGK
  RGTGAGGDSGPEEDYLSLGAEACNFMQSSSAKQKTPPPVAPKPAVKSSSSQPVTPVSPVW
  SPGVAPTQPPAFPTSNPSKGTVVSSIKIAQPSYPPARPASTLNVAGPFKGPQAAVASQNY
  TPKPTVSTPTVNAVQPGAVGPSNELPGMSGRGAQLFAKRQSRMEKYVVDSDTVQAHAARA
  QSPTPSLPASWKYSSNVRAPPPVAYNPIHSPSYPLAALKSQPSAAQPSKMGKKKGKKPLN
  ALDVMKHQPYQLNASLFTFQPPDAKDGLPQKSSVKVNSALAMKQALPPRPVNAASPTNVQ
  ASSVYSVPAYTSPPSFFAEASSPVSASPVPVGIPTSPKQESASSSYFVAPRPKFSAKKSG
  VTIQVWKPSVVEE
• Function: Has an actin-binding and actin-bundling activity. Can induce the formation of F-actin networks in an isoform-specific manner. At the sarcomeric Z lines is proposed to act as adapter protein that links nascent myofibers to the sarcolemma via ZYX and may play a role in early assembly and stabilization of the Z lines. Involved in autophagosome formation. May play a role in chaperone-assisted selective autophagy (CASA) involved in Z lines maintenance in striated muscle under mechanical tension; may link the client-processing CASA chaperone machinery to a membrane-tethering and fusion complex providing autophagosome membranes. Involved in regulation of cell migration. May be a tumor suppressor ; [Isoform 1]: Involved in regulation of cell migration. Can induce formation of thick, irregular actin bundles in the cell body; [Isoform 2]: Involved in regulation of cell migration. Can induce long, well-organized actin bundles frequently orientated in parallel along the long axis of the cell showing characteristics of contractile ventral stress fibers; [Isoform 3]: Involved in regulation of cell migration. Can induce an amorphous actin meshwork throughout the cell body containing a mixture of long and short, randomly organized thick and thin actin bundles; [Isoform 4]: Can induce long, well-organized actin bundles frequently orientated in parallel along the long axis of the cell showing characteristics of contractile ventral stress fibers; [Isoform 5]: Involved in regulation of cell migration in part dependent on the Rho-ROCK cascade; can promote formation of nascent focal adhesions, actin bundles at the leading cell edge and lamellipodia. Can induce formation of thick, irregular actin bundles in the cell body; the induced actin network is associated with enhanced cell migration in vitro.
• Tissue Specificity: Expressed in heart muscle. Isoform 5 is specifically expressed in skeletal muscle.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Altered Expression	[1]
Lung carcinoma	DISTR26C	Definitive	Altered Expression	[1]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[4]
Vascular disease	DISVS67S	Strong	Biomarker	[5]
Asthma	DISW9QNS	Limited	Genetic Variation	[6]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Limited	Genetic Variation	[4]
Prostate cancer	DISF190Y	Limited	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[7]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Synaptopodin-2 (SYNPO2) affects the response to substance of Temozolomide.	[21]
DTI-015	DMXZRW0	Approved	Synaptopodin-2 (SYNPO2) affects the response to substance of DTI-015.	[21]

11 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 Synaptopodin-2 (SYNPO2).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Synaptopodin-2 (SYNPO2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Synaptopodin-2 (SYNPO2).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Synaptopodin-2 (SYNPO2).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Synaptopodin-2 (SYNPO2).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Synaptopodin-2 (SYNPO2).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Synaptopodin-2 (SYNPO2).	[14]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Synaptopodin-2 (SYNPO2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Synaptopodin-2 (SYNPO2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Synaptopodin-2 (SYNPO2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Synaptopodin-2 (SYNPO2).	[19]

2 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 affects the methylation of Synaptopodin-2 (SYNPO2).	[16]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the methylation of Synaptopodin-2 (SYNPO2).	[20]

References

• [1] Molecular Changes of Lung Malignancy in HIV Infection.Sci Rep. 2018 Sep 3;8(1):13128. doi: 10.1038/s41598-018-31572-6.
• [2] Phenotypic Modulation of Smooth Muscle Cells in Atherosclerosis Is Associated With Downregulation of LMOD1, SYNPO2, PDLIM7, PLN, and SYNM.Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):1947-61. doi: 10.1161/ATVBAHA.116.307893. Epub 2016 Jul 28.
• [3] Association of a common variant of SYNPO2 gene with increased risk of serous epithelial ovarian cancer.Tumour Biol. 2017 Feb;39(2):1010428317691185. doi: 10.1177/1010428317691185.
• [4] Synaptopodin-2 suppresses metastasis of triple-negative breast cancer via inhibition of YAP/TAZ activity.J Pathol. 2018 Jan;244(1):71-83. doi: 10.1002/path.4995.
• [5] Regulation of smooth muscle dystrophin and synaptopodin 2 expression by actin polymerization and vascular injury.Arterioscler Thromb Vasc Biol. 2015 Jun;35(6):1489-97. doi: 10.1161/ATVBAHA.114.305065. Epub 2015 Apr 9.
• [6] A genome-wide association study of total serum and mite-specific IgEs in asthma patients.PLoS One. 2013 Aug 13;8(8):e71958. doi: 10.1371/journal.pone.0071958. eCollection 2013.
• [7] Synaptopodin-2 induces assembly of peripheral actin bundles and immature focal adhesions to promote lamellipodia formation and prostate cancer cell migration.Oncotarget. 2015 May 10;6(13):11162-74. doi: 10.18632/oncotarget.3578.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] 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.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [12] Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [16] 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.
• [17] 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.
• [18] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [19] 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.
• [20] Association of Glyphosate Exposure with Blood DNA Methylation in a Cross-Sectional Study of Postmenopausal Women. Environ Health Perspect. 2022 Apr;130(4):47001. doi: 10.1289/EHP10174. Epub 2022 Apr 4.
• [21] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.