Details of Drug Off-Target (DOT)

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

• DOT Name: SH3 and PX domain-containing protein 2B (SH3PXD2B)
• Synonyms: Adapter protein HOFI; Factor for adipocyte differentiation 49; Tyrosine kinase substrate with four SH3 domains
• Gene Name: SH3PXD2B
• Related Disease:
  Frank-Ter Haar syndrome
  Acute otitis media
  Axenfeld-Rieger syndrome
  Bone development disease
  Colon cancer
  Colon carcinoma
  Congenital glaucoma
  Glaucoma/ocular hypertension
  OPTN-related open angle glaucoma
  Osteochondrodysplasia
  Osteoporosis
  Otitis media
  Primary congenital glaucoma
  Pseudotumor cerebri
  Skeletal dysplasia
  Advanced cancer
  Deafness
• UniProt ID: SPD2B_HUMAN
• Pfam ID: PF00787 ; PF00018 ; PF07653
• Sequence:
  MPPRRSIVEVKVLDVQKRRVPNKHYVYIIRVTWSSGSTEAIYRRYSKFFDLQMQMLDKFP
  MEGGQKDPKQRIIPFLPGKILFRRSHIRDVAVKRLIPIDEYCKALIQLPPYISQCDEVLQ
  FFETRPEDLNPPKEEHIGKKKSGGDQTSVDPMVLEQYVVVANYQKQESSEISLSVGQVVD
  IIEKNESGWWFVSTAEEQGWVPATCLEGQDGVQDEFSLQPEEEEKYTVIYPYTARDQDEM
  NLERGAVVEVIQKNLEGWWKIRYQGKEGWAPASYLKKNSGEPLPPKPGPGSPSHPGALDL
  DGVSRQQNAVGREKELLSSQRDGRFEGRPVPDGDAKQRSPKMRQRPPPRRDMTIPRGLNL
  PKPPIPPQVEEEYYTIAEFQTTIPDGISFQAGLKVEVIEKNLSGWWYIQIEDKEGWAPAT
  FIDKYKKTSNASRPNFLAPLPHEVTQLRLGEAAALENNTGSEATGPSRPLPDAPHGVMDS
  GLPWSKDWKGSKDVLRKASSDMSASAGYEEISDPDMEEKPSLPPRKESIIKSEGELLERE
  RERQRTEQLRGPTPKPPGVILPMMPAKHIPPARDSRRPEPKPDKSRLFQLKNDMGLECGH
  KVLAKEVKKPNLRPISKSKTDLPEEKPDATPQNPFLKSRPQVRPKPAPSPKTEPPQGEDQ
  VDICNLRSKLRPAKSQDKSLLDGEGPQAVGGQDVAFSRSFLPGEGPGRAQDRTGKQDGLS
  PKEISCRAPPRPAKTTDPVSKSVPVPLQEAPQQRPVVPPRRPPPPKKTSSSSRPLPEVRG
  PQCEGHESRAAPTPGRALLVPPKAKPFLSNSLGGQDDTRGKGSLGPWGTGKIGENREKAA
  AASVPNADGLKDSLYVAVADFEGDKDTSSFQEGTVFEVREKNSSGWWFCQVLSGAPSWEG
  WIPSNYLRKKP
• Function: Adapter protein involved in invadopodia and podosome formation and extracellular matrix degradation. Binds matrix metalloproteinases (ADAMs), NADPH oxidases (NOXs) and phosphoinositides. Acts as an organizer protein that allows NOX1- or NOX3-dependent reactive oxygen species (ROS) generation and ROS localization. Plays a role in mitotic clonal expansion during the immediate early stage of adipocyte differentiation.
• Tissue Specificity: Expressed in fibroblasts.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Frank-Ter Haar syndrome	DIS75OSO	Definitive	Autosomal recessive	[1]
Acute otitis media	DISL8D8G	Strong	Genetic Variation	[2]
Axenfeld-Rieger syndrome	DIS6XY4L	Strong	Biomarker	[3]
Bone development disease	DISVKAZS	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Congenital glaucoma	DISHN3GO	Strong	Genetic Variation	[6]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Genetic Variation	[3]
OPTN-related open angle glaucoma	DISDR98A	Strong	Genetic Variation	[3]
Osteochondrodysplasia	DIS9SPWW	Strong	Biomarker	[7]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[8]
Otitis media	DISGZDUO	Strong	Biomarker	[9]
Primary congenital glaucoma	DISY7HN4	Strong	Biomarker	[3]
Pseudotumor cerebri	DISLLY7S	Strong	Genetic Variation	[10]
Skeletal dysplasia	DIS5Z8U6	Strong	Biomarker	[7]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[11]
Deafness	DISKCLH4	Limited	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of SH3 and PX domain-containing protein 2B (SH3PXD2B).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of SH3 and PX domain-containing protein 2B (SH3PXD2B).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SH3 and PX domain-containing protein 2B (SH3PXD2B).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of SH3 and PX domain-containing protein 2B (SH3PXD2B).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of SH3 and PX domain-containing protein 2B (SH3PXD2B).	[16]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of SH3 and PX domain-containing protein 2B (SH3PXD2B).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of SH3 and PX domain-containing protein 2B (SH3PXD2B).	[19]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of SH3 and PX domain-containing protein 2B (SH3PXD2B).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of SH3 and PX domain-containing protein 2B (SH3PXD2B).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of SH3 and PX domain-containing protein 2B (SH3PXD2B).	[23]

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 decreases the methylation of SH3 and PX domain-containing protein 2B (SH3PXD2B).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of SH3 and PX domain-containing protein 2B (SH3PXD2B).	[20]

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] Sh3pxd2b mice are a model for craniofacial dysmorphology and otitis media.PLoS One. 2011;6(7):e22622. doi: 10.1371/journal.pone.0022622. Epub 2011 Jul 27.
• [3] Localization of SH3PXD2B in human eyes and detection of rare variants in patients with anterior segment diseases and glaucoma.Mol Vis. 2012;18:705-13. Epub 2012 Mar 26.
• [4] The podosomal-adaptor protein SH3PXD2B is essential for normal postnatal development.Mamm Genome. 2009 Aug;20(8):462-75. doi: 10.1007/s00335-009-9210-9. Epub 2009 Aug 8.
• [5] Absence of the Tks4 Scaffold Protein Induces Epithelial-Mesenchymal Transition-Like Changes in Human Colon Cancer Cells.Cells. 2019 Oct 29;8(11):1343. doi: 10.3390/cells8111343.
• [6] Effect of ocular hypertension on the pattern of retinal ganglion cell subtype loss in a mouse model of early-onset glaucoma.Exp Eye Res. 2019 Aug;185:107703. doi: 10.1016/j.exer.2019.107703. Epub 2019 Jun 15.
• [7] Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome. Am J Hum Genet. 2010 Feb 12;86(2):254-61. doi: 10.1016/j.ajhg.2010.01.009. Epub 2010 Feb 4.
• [8] Significance of the Tks4 scaffold protein in bone tissue homeostasis.Sci Rep. 2019 Apr 8;9(1):5781. doi: 10.1038/s41598-019-42250-6.
• [9] Anterior segment dysgenesis and early-onset glaucoma in nee mice with mutation of Sh3pxd2b.Invest Ophthalmol Vis Sci. 2011 Apr 1;52(5):2679-88. doi: 10.1167/iovs.10-5993. Print 2011 Apr.
• [10] Ophthalmic findings in Frank-ter Haar syndrome: report of a sibling pair.J AAPOS. 2017 Dec;21(6):514-516. doi: 10.1016/j.jaapos.2017.07.216. Epub 2017 Oct 31.
• [11] Invadopodia are required for cancer cell extravasation and are a therapeutic target for metastasis.Cell Rep. 2014 Sep 11;8(5):1558-70. doi: 10.1016/j.celrep.2014.07.050. Epub 2014 Aug 28.
• [12] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [13] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [14] 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.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [17] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [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] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [20] 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.
• [21] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [22] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [23] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.