Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKDOE94)

• DOT Name: Transcriptional activator GLI3 (GLI3)
• Synonyms: GLI3 form of 190 kDa; GLI3-190; GLI3 full-length protein; GLI3FL
• Gene Name: GLI3
• Related Disease:
  Greig cephalopolysyndactyly syndrome
  Hereditary hemochromatosis
  Pallister-Hall syndrome
  Polydactyly, postaxial, type A1
  Acute myelogenous leukaemia
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Colorectal carcinoma
  Congenital hypothalamic hamartoma syndrome
  Corpus callosum, agenesis of
  Gastric neoplasm
  Gastrointestinal stromal tumour
  Glioblastoma multiforme
  Hamartoma
  Hepatocellular carcinoma
  Hereditary diffuse gastric adenocarcinoma
  Hypopigmentation of the skin
  Hypospadias
  Intellectual disability
  Neoplasm
  Neural tube defect
  Polydactyly
  Primary biliary cholangitis
  Clubfoot
  Polydactyly of a biphalangeal thumb
  Polysyndactyly 4
  Preaxial polydactyly of fingers
  Syndactyly
  Acrocallosal syndrome
  Postaxial polydactyly type A
  Tibial hemimelia
  Advanced cancer
  Gastric cancer
  Holoprosencephaly
  Postaxial polydactyly
  Pyoderma gangrenosum
• UniProt ID: GLI3_HUMAN
• PDB ID: 4BLD
• Pfam ID: PF00096
• Sequence:
  MEAQSHSSTTTEKKKVENSIVKCSTRTDVSEKAVASSTTSNEDESPGQTYHRERRNAITM
  QPQNVQGLSKVSEEPSTSSDERASLIKKEIHGSLPHVAEPSVPYRGTVFAMDPRNGYMEP
  HYHPPHLFPAFHPPVPIDARHHEGRYHYDPSPIPPLHMTSALSSSPTYPDLPFIRISPHR
  NPTAASESPFSPPHPYINPYMDYIRSLHSSPSLSMISATRGLSPTDAPHAGVSPAEYYHQ
  MALLTGQRSPYADIIPSAATAGTGAIHMEYLHAMDSTRFSSPRLSARPSRKRTLSISPLS
  DHSFDLQTMIRTSPNSLVTILNNSRSSSSASGSYGHLSASAISPALSFTYSSAPVSLHMH
  QQILSRQQSLGSAFGHSPPLIHPAPTFPTQRPIPGIPTVLNPVQVSSGPSESSQNKPTSE
  SAVSSTGDPMHNKRSKIKPDEDLPSPGARGQQEQPEGTTLVKEEGDKDESKQEPEVIYET
  NCHWEGCAREFDTQEQLVHHINNDHIHGEKKEFVCRWLDCSREQKPFKAQYMLVVHMRRH
  TGEKPHKCTFEGCTKAYSRLENLKTHLRSHTGEKPYVCEHEGCNKAFSNASDRAKHQNRT
  HSNEKPYVCKIPGCTKRYTDPSSLRKHVKTVHGPEAHVTKKQRGDIHPRPPPPRDSGSHS
  QSRSPGRPTQGALGEQQDLSNTTSKREECLQVKTVKAEKPMTSQPSPGGQSSCSSQQSPI
  SNYSNSGLELPLTDGGSIGDLSAIDETPIMDSTISTATTALALQARRNPAGTKWMEHVKL
  ERLKQVNGMFPRLNPILPPKAPAVSPLIGNGTQSNNTCSLGGPMTLLPGRSDLSGVDVTM
  LNMLNRRDSSASTISSAYLSSRRSSGISPCFSSRRSSEASQAEGRPQNVSVADSYDPIST
  DASRRSSEASQSDGLPSLLSLTPAQQYRLKAKYAAATGGPPPTPLPNMERMSLKTRLALL
  GDALEPGVALPPVHAPRRCSDGGAHGYGRRHLQPHDAPGHGVRRASDPVRTGSEGLALPR
  VPRFSSLSSCNPPAMATSAEKRSLVLQNYTRPEGGQSRNFHSSPCPPSITENVTLESLTM
  DADANLNDEDFLPDDVVQYLNSQNQAGYEQHFPSALPDDSKVPHGPGDFDAPGLPDSHAG
  QQFHALEQPCPEGSKTDLPIQWNEVSSGSADLSSSKLKCGPRPAVPQTRAFGFCNGMVVH
  PQNPLRSGPAGGYQTLGENSNPYGGPEHLMLHNSPGSGTSGNAFHEQPCKAPQYGNCLNR
  QPVAPGALDGACGAGIQASKLKSTPMQGSGGQLNFGLPVAPNESAGSMVNGMQNQDPVGQ
  GYLAHQLLGDSMQHPGAGRPGQQMLGQISATSHINIYQGPESCLPGAHGMGSQPSSLAVV
  RGYQPCASFGGSRRQAMPRDSLALQSGQLSDTSQTCRVNGIKMEMKGQPHPLCSNLQNYS
  GQFYDQTVGFSQQDTKAGSFSISDASCLLQGTSAKNSELLSPGANQVTSTVDSLDSHDLE
  GVQIDFDAIIDDGDHSSLMSGALSPSIIQNLSHSSSRLTTPRASLPFPALSMSTTNMAIG
  DMSSLLTSLAEESKFLAVMQ
• Function: Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development. The full-length GLI3 form (GLI3FL) after phosphorylation and nuclear translocation, acts as an activator (GLI3A) while GLI3R, its C-terminally truncated form, acts as a repressor. A proper balance between the GLI3 activator and the repressor GLI3R, rather than the repressor gradient itself or the activator/repressor ratio gradient, specifies limb digit number and identity. In concert with TRPS1, plays a role in regulating the size of the zone of distal chondrocytes, in restricting the zone of PTHLH expression in distal cells and in activating chondrocyte proliferation. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'.
• Tissue Specificity: Is expressed in a wide variety of normal adult tissues, including lung, colon, spleen, placenta, testis, and myometrium.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Hedgehog sig.ling pathway (hsa04340)
  Pathways in cancer (hsa05200)
  Basal cell carcinoma (hsa05217)
• Reactome Pathway:
  Hedgehog 'off' state (R-HSA-5610787)
  Hedgehog 'on' state (R-HSA-5632684)
  GLI proteins bind promoters of Hh responsive genes to promote transcription (R-HSA-5635851)
  RUNX2 regulates osteoblast differentiation (R-HSA-8940973)
  GLI3 is processed to GLI3R by the proteasome (R-HSA-5610785)

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Greig cephalopolysyndactyly syndrome	DISBMUUT	Definitive	Autosomal dominant	[1]
Hereditary hemochromatosis	DISVG5MT	Definitive	Biomarker	[2]
Pallister-Hall syndrome	DISTYTPU	Definitive	Autosomal dominant	[1]
Polydactyly, postaxial, type A1	DISFMXAM	Definitive	Autosomal dominant	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[6]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[7]
Congenital hypothalamic hamartoma syndrome	DISO1UQ2	Strong	Genetic Variation	[8]
Corpus callosum, agenesis of	DISO9P40	Strong	Biomarker	[9]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[10]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[11]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[12]
Hamartoma	DIS0I87H	Strong	Genetic Variation	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[14]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[10]
Hypopigmentation of the skin	DIS39YKC	Strong	Biomarker	[15]
Hypospadias	DIS48CCP	Strong	Biomarker	[16]
Intellectual disability	DISMBNXP	Strong	Biomarker	[17]
Neoplasm	DISZKGEW	Strong	Altered Expression	[18]
Neural tube defect	DIS5J95E	Strong	Biomarker	[19]
Polydactyly	DIS25BMZ	Strong	Genetic Variation	[20]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[21]
Clubfoot	DISLXT4S	moderate	Biomarker	[22]
Polydactyly of a biphalangeal thumb	DISX46OZ	moderate	Genetic Variation	[23]
Polysyndactyly 4	DISD78QR	Moderate	Autosomal dominant	[24]
Preaxial polydactyly of fingers	DISXO6C9	moderate	Genetic Variation	[25]
Syndactyly	DISZK2BT	moderate	Genetic Variation	[26]
Acrocallosal syndrome	DISKMCG2	Supportive	Autosomal recessive	[27]
Postaxial polydactyly type A	DIS4IIPW	Supportive	Autosomal recessive	[28]
Tibial hemimelia	DISB31NE	Supportive	Autosomal dominant	[29]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[5]
Gastric cancer	DISXGOUK	Limited	Biomarker	[30]
Holoprosencephaly	DISR35EC	Limited	Genetic Variation	[31]
Postaxial polydactyly	DIS085OV	Limited	Genetic Variation	[32]
Pyoderma gangrenosum	DIS8QVTT	Limited	Biomarker	[33]

3 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 Transcriptional activator GLI3 (GLI3).	[34]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Transcriptional activator GLI3 (GLI3).	[45]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transcriptional activator GLI3 (GLI3).	[46]

13 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 Transcriptional activator GLI3 (GLI3).	[35]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transcriptional activator GLI3 (GLI3).	[36]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transcriptional activator GLI3 (GLI3).	[37]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transcriptional activator GLI3 (GLI3).	[38]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Transcriptional activator GLI3 (GLI3).	[39]
Marinol	DM70IK5	Approved	Marinol increases the expression of Transcriptional activator GLI3 (GLI3).	[40]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Transcriptional activator GLI3 (GLI3).	[41]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Transcriptional activator GLI3 (GLI3).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Transcriptional activator GLI3 (GLI3).	[43]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transcriptional activator GLI3 (GLI3).	[44]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transcriptional activator GLI3 (GLI3).	[47]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Transcriptional activator GLI3 (GLI3).	[48]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Transcriptional activator GLI3 (GLI3).	[49]

References

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