Details of Drug Off-Target (DOT)

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

• DOT Name: Transcription factor SOX-2 (SOX2)
• Gene Name: SOX2
• Related Disease:
  Anophthalmia/microphthalmia-esophageal atresia syndrome
  Isolated anophthalmia-microphthalmia syndrome
  Septooptic dysplasia
• UniProt ID: SOX2_HUMAN
• PDB ID: 1O4X; 2LE4; 6T7B; 6T90; 6WX7; 6WX8; 6WX9; 6YOV
• Pfam ID: PF00505 ; PF12336
• Sequence:
  MYNMMETELKPPGPQQTSGGGGGNSTAAAAGGNQKNSPDRVKRPMNAFMVWSRGQRRKMA
  QENPKMHNSEISKRLGAEWKLLSETEKRPFIDEAKRLRALHMKEHPDYKYRPRRKTKTLM
  KKDKYTLPGGLLAPGGNSMASGVGVGAGLGAGVNQRMDSYAHMNGWSNGSYSMMQDQLGY
  PQHPGLNAHGAAQMQPMHRYDVSALQYNSMTSSQTYMNGSPTYSMSYSQQGTPGMALGSM
  GSVVKSEASSSPPVVTSSSHSRAPCQAGDLRDMISMYLPGAEVPEPAAPSRLHMSQHYQS
  GPVPGTAINGTLPLSHM
• Function: Transcription factor that forms a trimeric complex with OCT4 on DNA and controls the expression of a number of genes involved in embryonic development such as YES1, FGF4, UTF1 and ZFP206. Binds to the proximal enhancer region of NANOG. Critical for early embryogenesis and for embryonic stem cell pluripotency. Downstream SRRT target that mediates the promotion of neural stem cell self-renewal. Keeps neural cells undifferentiated by counteracting the activity of proneural proteins and suppresses neuronal differentiation. May function as a switch in neuronal development.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway:
  POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation (R-HSA-2892247)
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)
  Transcriptional regulation of pluripotent stem cells (R-HSA-452723)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Transcriptional Regulation by MECP2 (R-HSA-8986944)
  Germ layer formation at gastrulation (R-HSA-9754189)
  Formation of the anterior neural plate (R-HSA-9823739)
  Formation of the posterior neural plate (R-HSA-9832991)
  POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation (R-HSA-2892245)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anophthalmia/microphthalmia-esophageal atresia syndrome	DISFZF5X	Definitive	Autosomal dominant	[1]
Isolated anophthalmia-microphthalmia syndrome	DISA55ZA	Supportive	Autosomal dominant	[2]
Septooptic dysplasia	DISXYR1H	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Transcription factor SOX-2 (SOX2).	[4]

38 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-2 (SOX2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transcription factor SOX-2 (SOX2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transcription factor SOX-2 (SOX2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transcription factor SOX-2 (SOX2).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Transcription factor SOX-2 (SOX2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Transcription factor SOX-2 (SOX2).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Transcription factor SOX-2 (SOX2).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transcription factor SOX-2 (SOX2).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transcription factor SOX-2 (SOX2).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Transcription factor SOX-2 (SOX2).	[14]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Transcription factor SOX-2 (SOX2).	[13]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Transcription factor SOX-2 (SOX2).	[15]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Transcription factor SOX-2 (SOX2).	[16]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Transcription factor SOX-2 (SOX2).	[17]
Vitamin C	DMXJ7O8	Approved	Vitamin C increases the expression of Transcription factor SOX-2 (SOX2).	[18]
Ciprofloxacin XR	DM2NLS9	Approved	Ciprofloxacin XR decreases the expression of Transcription factor SOX-2 (SOX2).	[19]
Pantothenic acid	DM091H2	Approved	Pantothenic acid decreases the expression of Transcription factor SOX-2 (SOX2).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transcription factor SOX-2 (SOX2).	[21]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Transcription factor SOX-2 (SOX2).	[22]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the expression of Transcription factor SOX-2 (SOX2).	[23]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Transcription factor SOX-2 (SOX2).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Transcription factor SOX-2 (SOX2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transcription factor SOX-2 (SOX2).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transcription factor SOX-2 (SOX2).	[25]
TAK-114	DMTXE19	Phase 1	TAK-114 decreases the expression of Transcription factor SOX-2 (SOX2).	[26]
CHIR-99021	DMB8MNU	Patented	CHIR-99021 decreases the expression of Transcription factor SOX-2 (SOX2).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Transcription factor SOX-2 (SOX2).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transcription factor SOX-2 (SOX2).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Transcription factor SOX-2 (SOX2).	[29]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Transcription factor SOX-2 (SOX2).	[30]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Transcription factor SOX-2 (SOX2).	[31]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Transcription factor SOX-2 (SOX2).	[32]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Transcription factor SOX-2 (SOX2).	[33]
Cordycepin	DM72Y01	Investigative	Cordycepin affects the expression of Transcription factor SOX-2 (SOX2).	[34]
Kaempferol	DMHEMUB	Investigative	Kaempferol decreases the expression of Transcription factor SOX-2 (SOX2).	[35]
Apigenin	DMI3491	Investigative	Apigenin decreases the expression of Transcription factor SOX-2 (SOX2).	[10]
Ginsenoside RG3	DMFN58T	Investigative	Ginsenoside RG3 decreases the expression of Transcription factor SOX-2 (SOX2).	[36]
Eckol	DMIVY0Q	Investigative	Eckol decreases the expression of Transcription factor SOX-2 (SOX2).	[37]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
UNC1215	DMWMRLS	Investigative	UNC1215 increases the degradation of Transcription factor SOX-2 (SOX2).	[38]

References

• [1] SOX2 anophthalmia syndrome. Am J Med Genet A. 2005 May 15;135(1):1-7; discussion 8. doi: 10.1002/ajmg.a.30642.
• [2] Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia. Clin Genet. 2014 Oct;86(4):326-34. doi: 10.1111/cge.12275. Epub 2013 Oct 7.
• [3] Genetics of septo-optic dysplasia. Pituitary. 2007;10(4):393-407. doi: 10.1007/s11102-007-0055-5.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [8] Ivermectin as an inhibitor of cancer stem?like cells. Mol Med Rep. 2018 Feb;17(2):3397-3403. doi: 10.3892/mmr.2017.8231. Epub 2017 Dec 8.
• [9] Arsenic promotes the COX2/PGE2-SOX2 axis to increase the malignant stemness properties of urothelial cells. Int J Cancer. 2018 Jul 1;143(1):113-126.
• [10] Apigenin Inhibits Cancer Stem Cell-Like Phenotypes in Human Glioblastoma Cells via Suppression of c-Met Signaling. Phytother Res. 2016 Nov;30(11):1833-1840. doi: 10.1002/ptr.5689. Epub 2016 Jul 29.
• [11] 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.
• [12] Arsenic trioxide inhibits Hedgehog, Notch and stem cell properties in glioblastoma neurospheres. Acta Neuropathol Commun. 2014 Mar 31;2:31. doi: 10.1186/2051-5960-2-31.
• [13] 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.
• [14] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [15] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [16] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [17] Effects of all-trans and 9-cis retinoic acid on differentiating human neural stem cells in vitro. Toxicology. 2023 Mar 15;487:153461. doi: 10.1016/j.tox.2023.153461. Epub 2023 Feb 16.
• [18] Ascorbic acid induces in vitro proliferation of human subcutaneous adipose tissue derived mesenchymal stem cells with upregulation of embryonic stem cell pluripotency markers Oct4 and SOX 2. Hum Cell. 2010 Nov;23(4):152-5. doi: 10.1111/j.1749-0774.2010.00095.x.
• [19] Ciprofloxacin mediates cancer stem cell phenotypes in lung cancer cells through caveolin-1-dependent mechanism. Chem Biol Interact. 2016 Apr 25;250:1-11.
• [20] Calcium pantothenate modulates gene expression in proliferating human dermal fibroblasts. Exp Dermatol. 2009 Nov;18(11):969-78. doi: 10.1111/j.1600-0625.2009.00884.x. Epub 2009 Apr 8.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Resveratrol inhibits pancreatic cancer stem cell characteristics in human and KrasG12D transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. PLoS One. 2011 Jan 31;6(1):e16530. doi: 10.1371/journal.pone.0016530.
• [23] The antipsychotic chlorpromazine suppresses YAP signaling, stemness properties, and drug resistance in breast cancer cells. Chem Biol Interact. 2019 Apr 1;302:28-35. doi: 10.1016/j.cbi.2019.01.033. Epub 2019 Jan 28.
• [24] A human embryonic stem cell-based model for benzo[a]pyrene-induced embryotoxicity. Reprod Toxicol. 2019 Apr;85:26-33. doi: 10.1016/j.reprotox.2019.01.008. Epub 2019 Jan 16.
• [25] Activation of SOX2 expression by BRD4-NUT oncogenic fusion drives neoplastic transformation in NUT midline carcinoma. Cancer Res. 2014 Jun 15;74(12):3332-43. doi: 10.1158/0008-5472.CAN-13-2658. Epub 2014 Apr 15.
• [26] Methylisoindigo preferentially kills cancer stem cells by interfering cell metabolism via inhibition of LKB1 and activation of AMPK in PDACs. Mol Oncol. 2016 Jun;10(6):806-24. doi: 10.1016/j.molonc.2016.01.008. Epub 2016 Feb 4.
• [27] Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells. Reprod Toxicol. 2020 Jan;91:74-91. doi: 10.1016/j.reprotox.2019.10.004. Epub 2019 Nov 8.
• [28] 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.
• [29] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [30] Methylparaben stimulates tumor initiating cells in ER+ breast cancer models. J Appl Toxicol. 2017 Apr;37(4):417-425. doi: 10.1002/jat.3374. Epub 2016 Sep 1.
• [31] Cancer stem-like cells accumulated in nickel-induced malignant transformation. Toxicol Sci. 2016 Jun;151(2):376-87.
• [32] Aspartame induces cancer stem cell enrichment through p21, NICD and GLI1 in human PANC-1 pancreas adenocarcinoma cells. Food Chem Toxicol. 2021 Jul;153:112264. doi: 10.1016/j.fct.2021.112264. Epub 2021 May 14.
• [33] Phenolic-rich extract of avocado Persea americana (var. Colinred) peel blunts paraquat/maneb-induced apoptosis through blocking phosphorylation of LRRK2 kinase in human nerve-like cells. Environ Toxicol. 2022 Mar;37(3):660-676. doi: 10.1002/tox.23433. Epub 2021 Dec 12.
• [34] Cordycepin Enhances SIRT1 Expression and Maintains Stemness of Human Mesenchymal Stem Cells. In Vivo. 2023 Mar-Apr;37(2):596-610. doi: 10.21873/invivo.13118.
• [35] Deregulation of the CD44-NANOG-MDR1 associated chemoresistance pathways of breast cancer stem cells potentiates the anti-cancer effect of Kaempferol in synergism with Verapamil. Toxicol Appl Pharmacol. 2022 Feb 15;437:115887. doi: 10.1016/j.taap.2022.115887. Epub 2022 Jan 19.
• [36] Ginsenoside Rg3 attenuates the osimertinib resistance by reducing the stemness of non-small cell lung cancer cells. Environ Toxicol. 2020 Jun;35(6):643-651. doi: 10.1002/tox.22899. Epub 2020 Jan 9.
• [37] Eckol suppresses maintenance of stemness and malignancies in glioma stem-like cells. Toxicol Appl Pharmacol. 2011 Jul 1;254(1):32-40. doi: 10.1016/j.taap.2011.04.006. Epub 2011 Apr 14.
• [38] PHF20L1 antagonizes SOX2 proteolysis triggered by the MLL1/WDR5 complexes. Lab Invest. 2018 Dec;98(12):1627-1641. doi: 10.1038/s41374-018-0106-8. Epub 2018 Aug 8.