Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1CRCOB)

• DOT Name: Transcription factor SOX-3 (SOX3)
• Gene Name: SOX3
• Related Disease:
  46,XX sex reversal 3
  Hypoparathyroidism
  Intellectual disability, X-linked, with panhypopituitarism
  46,XX testicular disorder of sex development
  Adult glioblastoma
  Alzheimer disease
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Congenital hypothyroidism
  Disorder of sexual differentiation
  Endometrial cancer
  Endometrial carcinoma
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Herpes simplex infection
  Hypopituitarism
  Intellectual disability
  Kallmann syndrome
  Male infertility
  Neural tube defect
  Obesity
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Panhypopituitarism, X-linked
  Pituitary dwarfism
  Pituitary gland disorder
  Pituitary stalk interruption syndrome
  Pseudohypoparathyroidism
  Pseudohypoparathyroidism type 1A
  Pseudopseudohypoparathyroidism
  Small-cell lung cancer
  Turner syndrome
  X-linked intellectual disability
  Beckwith-Wiedemann syndrome
  SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder
  Obsolete 46,XX sex reversal 1
  Panhypopituitarism
  Septooptic dysplasia
  X-linked congenital generalized hypertrichosis
  X-linked intellectual disability with isolated growth hormone deficiency
  Autism spectrum disorder
  Brachydactyly
  Neoplasm
  Neurodevelopmental disorder
  Rett syndrome
• UniProt ID: SOX3_HUMAN
• Pfam ID: PF00505 ; PF12336
• Sequence:
  MRPVRENSSGARSPRVPADLARSILISLPFPPDSLAHRPPSSAPTESQGLFTVAAPAPGA
  PSPPATLAHLLPAPAMYSLLETELKNPVGTPTQAAGTGGPAAPGGAGKSSANAAGGANSG
  GGSSGGASGGGGGTDQDRVKRPMNAFMVWSRGQRRKMALENPKMHNSEISKRLGADWKLL
  TDAEKRPFIDEAKRLRAVHMKEYPDYKYRPRRKTKTLLKKDKYSLPSGLLPPGAAAAAAA
  AAAAAAAASSPVGVGQRLDTYTHVNGWANGAYSLVQEQLGYAQPPSMSSPPPPPALPPMH
  RYDMAGLQYSPMMPPGAQSYMNVAAAAAAASGYGGMAPSATAAAAAAYGQQPATAAAAAA
  AAAAMSLGPMGSVVKSEPSSPPPAIASHSQRACLGDLRDMISMYLPPGGDAADAASPLPG
  GRLHGVHQHYQGAGTAVNGTVPLTHI
• Function: Transcription factor required during the formation of the hypothalamo-pituitary axis. May function as a switch in neuronal development. Keeps neural cells undifferentiated by counteracting the activity of proneural proteins and suppresses neuronal differentiation. Required also within the pharyngeal epithelia for craniofacial morphogenesis. Controls a genetic switch in male development. Is necessary for initiating male sex determination by directing the development of supporting cell precursors (pre-Sertoli cells) as Sertoli rather than granulosa cells.
• Reactome Pathway: Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
46,XX sex reversal 3	DISNEDPX	Definitive	X-linked dominant	[1]
Hypoparathyroidism	DISICS0V	Definitive	Biomarker	[2]
Intellectual disability, X-linked, with panhypopituitarism	DIS124N3	Definitive	X-linked recessive	[3]
46,XX testicular disorder of sex development	DISTZBTV	Strong	Altered Expression	[4]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[6]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[8]
Congenital hypothyroidism	DISL5XVU	Strong	Genetic Variation	[9]
Disorder of sexual differentiation	DISRMAEZ	Strong	Biomarker	[10]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[11]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[12]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[13]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[5]
Herpes simplex infection	DISL1SAV	Strong	Altered Expression	[14]
Hypopituitarism	DIS1QT3G	Strong	Biomarker	[15]
Intellectual disability	DISMBNXP	Strong	Biomarker	[15]
Kallmann syndrome	DISO3HDG	Strong	GermlineCausalMutation	[16]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[17]
Neural tube defect	DIS5J95E	Strong	Biomarker	[15]
Obesity	DIS47Y1K	Strong	Biomarker	[18]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[12]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[12]
Panhypopituitarism, X-linked	DISWNWZZ	Strong	X-linked	[19]
Pituitary dwarfism	DISI019B	Strong	Genetic Variation	[20]
Pituitary gland disorder	DIS7XB48	Strong	Biomarker	[21]
Pituitary stalk interruption syndrome	DISGSN5T	Strong	Biomarker	[22]
Pseudohypoparathyroidism	DIS183OJ	Strong	Biomarker	[18]
Pseudohypoparathyroidism type 1A	DISSOR3M	Strong	Genetic Variation	[23]
Pseudopseudohypoparathyroidism	DISRRO5I	Strong	Genetic Variation	[24]
Small-cell lung cancer	DISK3LZD	Strong	Altered Expression	[25]
Turner syndrome	DIS2035C	Strong	Biomarker	[26]
X-linked intellectual disability	DISYJBY3	Strong	Biomarker	[20]
Beckwith-Wiedemann syndrome	DISH15GR	moderate	Biomarker	[27]
SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder	DIS4JPRT	Moderate	X-linked	[28]
Obsolete 46,XX sex reversal 1	DIS79VJ6	Supportive	Autosomal dominant	[29]
Panhypopituitarism	DISAKJ4T	Supportive	Autosomal recessive	[30]
Septooptic dysplasia	DISXYR1H	Supportive	Autosomal dominant	[31]
X-linked congenital generalized hypertrichosis	DISVL46B	Supportive	X-linked	[32]
X-linked intellectual disability with isolated growth hormone deficiency	DISYTZA8	Supportive	X-linked	[19]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[33]
Brachydactyly	DIS2533F	Limited	Biomarker	[18]
Neoplasm	DISZKGEW	Limited	Biomarker	[34]
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[33]
Rett syndrome	DISGG5UV	Limited	Genetic Variation	[35]

4 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 Transcription factor SOX-3 (SOX3).	[36]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Transcription factor SOX-3 (SOX3).	[37]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the methylation of Transcription factor SOX-3 (SOX3).	[44]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transcription factor SOX-3 (SOX3).	[45]

8 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 Transcription factor SOX-3 (SOX3).	[38]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transcription factor SOX-3 (SOX3).	[39]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Transcription factor SOX-3 (SOX3).	[40]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Transcription factor SOX-3 (SOX3).	[41]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Transcription factor SOX-3 (SOX3).	[42]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Transcription factor SOX-3 (SOX3).	[43]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Transcription factor SOX-3 (SOX3).	[42]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transcription factor SOX-3 (SOX3).	[46]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Bone Mineral Density and Its Serial Changes Are Associated With PTH Levels in Pseudohypoparathyroidism Type 1B Patients.J Bone Miner Res. 2018 Apr;33(4):743-752. doi: 10.1002/jbmr.3360. Epub 2018 Jan 3.
• [3] Familial X-linked mental retardation and isolated growth hormone deficiency: clinical and molecular findings. Am J Med Genet. 1996 Jul 12;64(1):35-41. doi: 10.1002/(SICI)1096-8628(19960712)64:1<35::AID-AJMG5>3.0.CO;2-Q.
• [4] Gene expression profile during testicular development in patients with SRY-negative 46,XX testicular disorder of sex development.Urology. 2013 Dec;82(6):1453.e1-7. doi: 10.1016/j.urology.2013.08.040. Epub 2013 Oct 19.
• [5] SOX3 can promote the malignant behavior of glioblastoma cells.Cell Oncol (Dordr). 2019 Feb;42(1):41-54. doi: 10.1007/s13402-018-0405-5. Epub 2018 Sep 12.
• [6] Early Impairments of Hippocampal Neurogenesis in 5xFAD Mouse Model of Alzheimer's Disease Are Associated with Altered Expression of SOXB Transcription Factors.J Alzheimers Dis. 2018;65(3):963-976. doi: 10.3233/JAD-180277.
• [7] Downregulation of SOX3 leads to the inhibition of the proliferation, migration and invasion of osteosarcoma cells.Int J Oncol. 2018 Apr;52(4):1277-1284. doi: 10.3892/ijo.2018.4278. Epub 2018 Feb 20.
• [8] MiR-483 suppresses cell proliferation and promotes cell apoptosis by targeting SOX3 in breast cancer.Eur Rev Med Pharmacol Sci. 2019 Mar;23(5):2069-2074. doi: 10.26355/eurrev_201903_17248.
• [9] A novel mutation causing pseudohypoparathyroidism 1A with congenital hypothyroidism and osteoma cutis.J Clin Res Pediatr Endocrinol. 2009;1(5):244-7. doi: 10.4274/jcrpe.v1i5.244. Epub 2009 Aug 6.
• [10] Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3.Eur J Hum Genet. 2015 Aug;23(8):1025-32. doi: 10.1038/ejhg.2014.237. Epub 2014 Nov 5.
• [11] Overexpression of microRNA-194 suppresses the epithelial-mesenchymal transition in targeting stem cell transcription factor Sox3 in endometrial carcinoma stem cells.Tumour Biol. 2017 Jun;39(6):1010428317706217. doi: 10.1177/1010428317706217.
• [12] Sex-determining region Y-box3 (SOX3) functions as an oncogene in promoting epithelial ovarian cancer by targeting Src kinase.Tumour Biol. 2016 Sep;37(9):12263-12271. doi: 10.1007/s13277-016-5095-x. Epub 2016 Jun 1.
• [13] The effect of high Sox3 expression on lymphangiogenesis and lymph node metastasis in esophageal squamous cell carcinoma.Am J Transl Res. 2017 Jun 15;9(6):2684-2693. eCollection 2017.
• [14] Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease.J Neurosci. 2002 Nov 15;22(22):9733-41. doi: 10.1523/JNEUROSCI.22-22-09733.2002.
• [15] Xq27.1 Duplication Encompassing SOX3: Variable Phenotype and Smallest Duplication Associated with Hypopituitarism to Date - A Large Case Series of Unrelated Patients and a Literature Review.Horm Res Paediatr. 2019;92(6):382-389. doi: 10.1159/000503784. Epub 2019 Nov 1.
• [16] New insights into septo-optic dysplasia.Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2014;35(1):123-7.
• [17] X-linked sex-determining region Y box 3 (SOX3) gene mutations are uncommon in men with idiopathic oligoazoospermic infertility.J Clin Endocrinol Metab. 2004 Aug;89(8):4146-8. doi: 10.1210/jc.2004-0191.
• [18] Pseudohypoparathyroidism vs. tricho-rhino-phalangeal syndrome: patient reclassification.J Pediatr Endocrinol Metab. 2014 Nov;27(11-12):1089-94. doi: 10.1515/jpem-2014-0020.
• [19] Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency. Am J Hum Genet. 2002 Dec;71(6):1450-5. doi: 10.1086/344661. Epub 2002 Nov 8.
• [20] A complex phenotype in a family with a pathogenic SOX3 missense variant.Eur J Med Genet. 2018 Mar;61(3):168-172. doi: 10.1016/j.ejmg.2017.11.012. Epub 2017 Nov 24.
• [21] Functional Equivalence of the SOX2 and SOX3 Transcription Factors in the Developing Mouse Brain and Testes.Genetics. 2017 Jul;206(3):1495-1503. doi: 10.1534/genetics.117.202549. Epub 2017 May 17.
• [22] Whole-exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome. J Clin Endocrinol Metab. 2015 Jan;100(1):E140-7. doi: 10.1210/jc.2014-1984.
• [23] Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity.J Bone Miner Res. 2018 Aug;33(8):1480-1488. doi: 10.1002/jbmr.3450. Epub 2018 Jun 7.
• [24] Pseudohypoparathyroidism Ia and hypercalcitoninemia.J Clin Endocrinol Metab. 2001 Jul;86(7):3091-6. doi: 10.1210/jcem.86.7.7690.
• [25] Serological identification of embryonic neural proteins as highly immunogenic tumor antigens in small cell lung cancer.Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4198-203. doi: 10.1073/pnas.97.8.4198.
• [26] Dermatoglyphic and radiographic findings in a mother and daughter with pseudohypoparathyroidism.Clin Genet. 1978 Apr;13(4):359-68. doi: 10.1111/j.1399-0004.1978.tb01193.x.
• [27] New mechanisms involved in paternal 20q disomy associated with pseudohypoparathyroidism.Eur J Endocrinol. 2010 Dec;163(6):953-62. doi: 10.1530/EJE-10-0435. Epub 2010 Sep 13.
• [28] 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.
• [29] Identification of SOX3 as an XX male sex reversal gene in mice and humans. J Clin Invest. 2011 Jan;121(1):328-41. doi: 10.1172/JCI42580. Epub 2010 Dec 22.
• [30] Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet. 2005 May;76(5):833-49. doi: 10.1086/430134. Epub 2005 Mar 30.
• [31] Genetics of septo-optic dysplasia. Pituitary. 2007;10(4):393-407. doi: 10.1007/s11102-007-0055-5.
• [32] X-linked congenital hypertrichosis syndrome is associated with interchromosomal insertions mediated by a human-specific palindrome near SOX3. Am J Hum Genet. 2011 Jun 10;88(6):819-826. doi: 10.1016/j.ajhg.2011.05.004.
• [33] Putative contributions of the sex chromosome proteins SOX3 and SRY to neurodevelopmental disorders.Am J Med Genet B Neuropsychiatr Genet. 2019 Sep;180(6):390-414. doi: 10.1002/ajmg.b.32704. Epub 2018 Dec 9.
• [34] Identification of genomic and molecular traits that present therapeutic vulnerability to HGF-targeted therapy in glioblastoma.Neuro Oncol. 2019 Feb 14;21(2):222-233. doi: 10.1093/neuonc/noy105.
• [35] Mutation screening in Rett syndrome patients.J Med Genet. 2000 Apr;37(4):250-5. doi: 10.1136/jmg.37.4.250.
• [36] 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.
• [37] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [38] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [39] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [40] 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.
• [41] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [42] 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.
• [43] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [44] Reduced camptothecin sensitivity of estrogen receptor-positive human breast cancer cells following exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes. Environ Toxicol. 2019 Apr;34(4):401-414.
• [45] 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.
• [46] 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.