Details of Drug Off-Target (DOT)

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

• DOT Name: Transcription factor SOX-9 (SOX9)
• Gene Name: SOX9
• Related Disease:
  46,XY disorder of sex development
  Campomelic dysplasia
  Lung adenocarcinoma
  Advanced cancer
  Autism spectrum disorder
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Chondrosarcoma
  Chromosomal disorder
  Clubfoot
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Gastric cancer
  Hypospadias
  Intellectual disability
  Intervertebral disc degeneration
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Major depressive disorder
  Melanoma
  Metastatic malignant neoplasm
  Non-small-cell lung cancer
  Nonsyndromic congenital nail disorder 4
  Osteoporosis
  Osteosarcoma
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Squamous cell carcinoma
  Stomach cancer
  Medulloblastoma
  Megalencephaly
  46,XX ovotesticular disorder of sex development
  46,XY complete gonadal dysgenesis
  46,XY partial gonadal dysgenesis
  Isolated Pierre-Robin syndrome
  Obsolete 46,XX sex reversal 1
  Undifferentiated carcinoma
  Adult glioblastoma
  Breast neoplasm
  Cooks syndrome
  Matthew-Wood syndrome
  Pancreatic cancer
  Pancreatic ductal carcinoma
• UniProt ID: SOX9_HUMAN
• PDB ID: 4EUW
• Pfam ID: PF00505 ; PF12444
• Sequence:
  MNLLDPFMKMTDEQEKGLSGAPSPTMSEDSAGSPCPSGSGSDTENTRPQENTFPKGEPDL
  KKESEEDKFPVCIREAVSQVLKGYDWTLVPMPVRVNGSSKNKPHVKRPMNAFMVWAQAAR
  RKLADQYPHLHNAELSKTLGKLWRLLNESEKRPFVEEAERLRVQHKKDHPDYKYQPRRRK
  SVKNGQAEAEEATEQTHISPNAIFKALQADSPHSSSGMSEVHSPGEHSGQSQGPPTPPTT
  PKTDVQPGKADLKREGRPLPEGGRQPPIDFRDVDIGELSSDVISNIETFDVNEFDQYLPP
  NGHPGVPATHGQVTYTGSYGISSTAATPASAGHVWMSKQQAPPPPPQQPPQAPPAPQAPP
  QPQAAPPQQPAAPPQQPQAHTLTTLSSEPGQSQRTHIKTEQLSPSHYSEQQQHSPQQIAY
  SPFNLPHYSPSYPPITRSQYDYTDHQNSSSYYSHAAGQGTGLYSTFTYMNPAQRPMYTPI
  ADTSGVPSIPQTHSPQHWEQPVYTQLTRP
• Function: Transcription factor that plays a key role in chondrocytes differentiation and skeletal development. Specifically binds the 5'-ACAAAG-3' DNA motif present in enhancers and super-enhancers and promotes expression of genes important for chondrogenesis, including cartilage matrix protein-coding genes COL2A1, COL4A2, COL9A1, COL11A2 and ACAN, SOX5 and SOX6. Also binds to some promoter regions. Plays a central role in successive steps of chondrocyte differentiation. Absolutely required for precartilaginous condensation, the first step in chondrogenesis during which skeletal progenitors differentiate into prechondrocytes. Together with SOX5 and SOX6, required for overt chondrogenesis when condensed prechondrocytes differentiate into early stage chondrocytes, the second step in chondrogenesis. Later, required to direct hypertrophic maturation and block osteoblast differentiation of growth plate chondrocytes: maintains chondrocyte columnar proliferation, delays prehypertrophy and then prevents osteoblastic differentiation of chondrocytes by lowering beta-catenin (CTNNB1) signaling and RUNX2 expression. Also required for chondrocyte hypertrophy, both indirectly, by keeping the lineage fate of chondrocytes, and directly, by remaining present in upper hypertrophic cells and transactivating COL10A1 along with MEF2C. Low lipid levels are the main nutritional determinant for chondrogenic commitment of skeletal progenitor cells: when lipids levels are low, FOXO (FOXO1 and FOXO3) transcription factors promote expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation. Mechanistically, helps, but is not required, to remove epigenetic signatures of transcriptional repression and deposit active promoter and enhancer marks at chondrocyte-specific genes. Acts in cooperation with the Hedgehog pathway-dependent GLI (GLI1 and GLI3) transcription factors. In addition to cartilage development, also acts as a regulator of proliferation and differentiation in epithelial stem/progenitor cells: involved in the lung epithelium during branching morphogenesis, by balancing proliferation and differentiation and regulating the extracellular matrix. Controls epithelial branching during kidney development.
• KEGG Pathway: cAMP sig.ling pathway (hsa04024)
• Reactome Pathway:
  Transcriptional regulation by RUNX2 (R-HSA-8878166)
  Transcriptional regulation of testis differentiation (R-HSA-9690406)
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
46,XY disorder of sex development	DIS78CGG	Definitive	Genetic Variation	[1]
Campomelic dysplasia	DISVTW53	Definitive	Autosomal dominant	[2]
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[5]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[7]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[7]
Carcinoma	DISH9F1N	Strong	Biomarker	[8]
Cervical cancer	DISFSHPF	Strong	Genetic Variation	[9]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[10]
Chondrosarcoma	DIS4I7JB	Strong	Altered Expression	[11]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[12]
Clubfoot	DISLXT4S	Strong	Altered Expression	[13]
Colon cancer	DISVC52G	Strong	Altered Expression	[14]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[14]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[15]
Gastric cancer	DISXGOUK	Strong	Biomarker	[16]
Hypospadias	DIS48CCP	Strong	Biomarker	[17]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[18]
Intervertebral disc degeneration	DISG3AIM	Strong	Posttranslational Modification	[19]
Lung cancer	DISCM4YA	Strong	Altered Expression	[4]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[4]
Lung neoplasm	DISVARNB	Strong	Biomarker	[20]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[21]
Melanoma	DIS1RRCY	Strong	Altered Expression	[22]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[23]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[4]
Nonsyndromic congenital nail disorder 4	DISTNU8N	Strong	Biomarker	[24]
Osteoporosis	DISF2JE0	Strong	Biomarker	[25]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[6]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[23]
Prostate cancer	DISF190Y	Strong	Biomarker	[26]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[26]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[27]
Stomach cancer	DISKIJSX	Strong	Biomarker	[16]
Medulloblastoma	DISZD2ZL	moderate	Altered Expression	[28]
Megalencephaly	DISYW5SV	moderate	Genetic Variation	[29]
46,XX ovotesticular disorder of sex development	DISQO3XF	Supportive	Autosomal dominant	[30]
46,XY complete gonadal dysgenesis	DISLF3LT	Supportive	Autosomal dominant	[30]
46,XY partial gonadal dysgenesis	DISMNH0C	Supportive	Autosomal dominant	[30]
Isolated Pierre-Robin syndrome	DISVEHG7	Supportive	Autosomal dominant	[31]
Obsolete 46,XX sex reversal 1	DIS79VJ6	Supportive	Autosomal dominant	[32]
Undifferentiated carcinoma	DISIAZST	Disputed	Biomarker	[33]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[34]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[35]
Cooks syndrome	DISRZF9H	Limited	Autosomal dominant	[2]
Matthew-Wood syndrome	DISA7HR7	Limited	Altered Expression	[36]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[37]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Transcription factor SOX-9 (SOX9) decreases the response to substance of Arsenic.	[84]
DTI-015	DMXZRW0	Approved	Transcription factor SOX-9 (SOX9) affects the response to substance of DTI-015.	[85]

2 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-9 (SOX9).	[38]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Transcription factor SOX-9 (SOX9).	[73]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transcription factor SOX-9 (SOX9).	[39]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transcription factor SOX-9 (SOX9).	[40]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcription factor SOX-9 (SOX9).	[41]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transcription factor SOX-9 (SOX9).	[42]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transcription factor SOX-9 (SOX9).	[43]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transcription factor SOX-9 (SOX9).	[44]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Transcription factor SOX-9 (SOX9).	[45]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Transcription factor SOX-9 (SOX9).	[46]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Transcription factor SOX-9 (SOX9).	[47]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Transcription factor SOX-9 (SOX9).	[48]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Transcription factor SOX-9 (SOX9).	[49]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Transcription factor SOX-9 (SOX9).	[50]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Transcription factor SOX-9 (SOX9).	[51]
Marinol	DM70IK5	Approved	Marinol increases the expression of Transcription factor SOX-9 (SOX9).	[52]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Transcription factor SOX-9 (SOX9).	[53]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Transcription factor SOX-9 (SOX9).	[54]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Transcription factor SOX-9 (SOX9).	[55]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Transcription factor SOX-9 (SOX9).	[47]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Transcription factor SOX-9 (SOX9).	[56]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Transcription factor SOX-9 (SOX9).	[57]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Transcription factor SOX-9 (SOX9).	[58]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Transcription factor SOX-9 (SOX9).	[59]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Transcription factor SOX-9 (SOX9).	[60]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Transcription factor SOX-9 (SOX9).	[61]
Nicotinamide	DMUPE07	Approved	Nicotinamide decreases the expression of Transcription factor SOX-9 (SOX9).	[62]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transcription factor SOX-9 (SOX9).	[63]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Transcription factor SOX-9 (SOX9).	[64]
Berberine	DMC5Q8X	Phase 4	Berberine decreases the expression of Transcription factor SOX-9 (SOX9).	[65]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Transcription factor SOX-9 (SOX9).	[66]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Transcription factor SOX-9 (SOX9).	[66]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Transcription factor SOX-9 (SOX9).	[54]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Transcription factor SOX-9 (SOX9).	[67]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Transcription factor SOX-9 (SOX9).	[68]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Transcription factor SOX-9 (SOX9).	[69]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transcription factor SOX-9 (SOX9).	[70]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Transcription factor SOX-9 (SOX9).	[71]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transcription factor SOX-9 (SOX9).	[72]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transcription factor SOX-9 (SOX9).	[74]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transcription factor SOX-9 (SOX9).	[75]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Transcription factor SOX-9 (SOX9).	[76]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Transcription factor SOX-9 (SOX9).	[77]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Transcription factor SOX-9 (SOX9).	[44]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Transcription factor SOX-9 (SOX9).	[78]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Transcription factor SOX-9 (SOX9).	[79]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Transcription factor SOX-9 (SOX9).	[80]
CH-223191	DMMJZYC	Investigative	CH-223191 increases the expression of Transcription factor SOX-9 (SOX9).	[81]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone increases the expression of Transcription factor SOX-9 (SOX9).	[82]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid decreases the expression of Transcription factor SOX-9 (SOX9).	[83]

References

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