Details of Drug Off-Target (DOT)

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

• DOT Name: Transcription factor SOX-5 (SOX5)
• Gene Name: SOX5
• Related Disease:
  Lamb-Shaffer syndrome
  Developmental and speech delay due to SOX5 deficiency
• UniProt ID: SOX5_HUMAN
• Pfam ID: PF00505
• Sequence:
  MLTDPDLPQEFERMSSKRPASPYGEADGEVAMVTSRQKVEEEESDGLPAFHLPLHVSFPN
  KPHSEEFQPVSLLTQETCGHRTPTSQHNTMEVDGNKVMSSFAPHNSSTSPQKAEEGGRQS
  GESLSSTALGTPERRKGSLADVVDTLKQRKMEELIKNEPEETPSIEKLLSKDWKDKLLAM
  GSGNFGEIKGTPESLAEKERQLMGMINQLTSLREQLLAAHDEQKKLAASQIEKQRQQMEL
  AKQQQEQIARQQQQLLQQQHKINLLQQQIQVQGQLPPLMIPVFPPDQRTLAAAAQQGFLL
  PPGFSYKAGCSDPYPVQLIPTTMAAAAAATPGLGPLQLQQLYAAQLAAMQVSPGGKLPGI
  PQGNLGAAVSPTSIHTDKSTNSPPPKSKDEVAQPLNLSAKPKTSDGKSPTSPTSPHMPAL
  RINSGAGPLKASVPAALASPSARVSTIGYLNDHDAVTKAIQEARQMKEQLRREQQVLDGK
  VAVVNSLGLNNCRTEKEKTTLESLTQQLAVKQNEEGKFSHAMMDFNLSGDSDGSAGVSES
  RIYRESRGRGSNEPHIKRPMNAFMVWAKDERRKILQAFPDMHNSNISKILGSRWKAMTNL
  EKQPYYEEQARLSKQHLEKYPDYKYKPRPKRTCLVDGKKLRIGEYKAIMRNRRQEMRQYF
  NVGQQAQIPIATAGVVYPGAIAMAGMPSPHLPSEHSSVSSSPEPGMPVIQSTYGVKGEEP
  HIKEEIQAEDINGEIYDEYDEEEDDPDVDYGSDSENHIAGQAN
• Function: Transcription factor involved in chondrocytes differentiation and cartilage formation. Specifically binds the 5'-AACAAT-3' DNA motif present in enhancers and super-enhancers and promotes expression of genes important for chondrogenesis, including cartilage matrix protein-coding genes, such as COL2A1 and AGC1. Required for overt chondrogenesis when condensed prechondrocytes differentiate into early stage chondrocytes: SOX5 and SOX6 cooperatively bind with SOX9 on active enhancers and super-enhancers associated with cartilage-specific genes, and thereby potentiate SOX9's ability to transactivate. Not involved in precartilaginous condensation, the first step in chondrogenesis, during which skeletal progenitors differentiate into prechondrocytes. Together with SOX6, required to form and maintain a pool of highly proliferating chondroblasts between epiphyses and metaphyses, to form columnar chondroblasts, delay chondrocyte prehypertrophy but promote hypertrophy, and to delay terminal differentiation of chondrocytes on contact with ossification fronts. Binds to the proximal promoter region of the myelin protein MPZ gene.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lamb-Shaffer syndrome	DIS3UI0M	Definitive	Autosomal dominant	[1]
Developmental and speech delay due to SOX5 deficiency	DISCZE28	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Transcription factor SOX-5 (SOX5).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transcription factor SOX-5 (SOX5).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcription factor SOX-5 (SOX5).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcription factor SOX-5 (SOX5).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Transcription factor SOX-5 (SOX5).	[7]
Marinol	DM70IK5	Approved	Marinol increases the expression of Transcription factor SOX-5 (SOX5).	[8]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Transcription factor SOX-5 (SOX5).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Transcription factor SOX-5 (SOX5).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Transcription factor SOX-5 (SOX5).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transcription factor SOX-5 (SOX5).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Transcription factor SOX-5 (SOX5).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Transcription factor SOX-5 (SOX5).	[16]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Transcription factor SOX-5 (SOX5).	[17]

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 Transcription factor SOX-5 (SOX5).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Transcription factor SOX-5 (SOX5).	[15]

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] Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features. Hum Mutat. 2012 Apr;33(4):728-40. doi: 10.1002/humu.22037.
• [3] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [10] 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.
• [11] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [12] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] 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.
• [15] Bisphenol A Represses Dopaminergic Neuron Differentiation from Human Embryonic Stem Cells through Downregulating the Expression of Insulin-like Growth Factor 1. Mol Neurobiol. 2017 Jul;54(5):3798-3812. doi: 10.1007/s12035-016-9898-y. Epub 2016 Jun 7.
• [16] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [17] Deguelin inhibits growth of breast cancer cells by modulating the expression of key members of the Wnt signaling pathway. Cancer Prev Res (Phila). 2009 Nov;2(11):942-50. doi: 10.1158/1940-6207.CAPR-08-0232. Epub 2009 Oct 27.