Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC08PR5)

• DOT Name: Sal-like protein 4 (SALL4)
• Synonyms: Zinc finger protein 797; Zinc finger protein SALL4
• Gene Name: SALL4
• Related Disease:
  Duane-radial ray syndrome
  Breast neoplasm
  Carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Congenital deformities of limbs
  Congenital radioulnar synostosis
  Deafness
  Duane retraction syndrome 2
  Endometrial carcinoma
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Glioma
  Hepatitis B virus infection
  Isolated cleft lip
  leukaemia
  Leukemia
  Liver cancer
  Microphthalmia
  Myelodysplastic syndrome
  Otitis media
  Ovarian cancer
  Ovarian neoplasm
  Polydactyly of a biphalangeal thumb
  Wilms tumor
  Breast cancer
  Breast carcinoma
  Female hypogonadism
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Ventricular septal defect
  Duane retraction syndrome
  IVIC syndrome
  Prostate cancer
  Prostate carcinoma
  Acute myelogenous leukaemia
  Adult glioblastoma
  Gastric cancer
  Germ cell tumor
  Stomach cancer
• UniProt ID: SALL4_HUMAN
• PDB ID: 5XWR; 6UML; 7BQU; 7BQV; 7Y3I; 7Y3K; 7Y3M; 8CUC
• Pfam ID: PF00096
• Sequence:
  MSRRKQAKPQHINSEEDQGEQQPQQQTPEFADAAPAAPAAGELGAPVNHPGNDEVASEDE
  ATVKRLRREETHVCEKCCAEFFSISEFLEHKKNCTKNPPVLIMNDSEGPVPSEDFSGAVL
  SHQPTSPGSKDCHRENGGSSEDMKEKPDAESVVYLKTETALPPTPQDISYLAKGKVANTN
  VTLQALRGTKVAVNQRSADALPAPVPGANSIPWVLEQILCLQQQQLQQIQLTEQIRIQVN
  MWASHALHSSGAGADTLKTLGSHMSQQVSAAVALLSQKAGSQGLSLDALKQAKLPHANIP
  SATSSLSPGLAPFTLKPDGTRVLPNVMSRLPSALLPQAPGSVLFQSPFSTVALDTSKKGK
  GKPPNISAVDVKPKDEAALYKHKCKYCSKVFGTDSSLQIHLRSHTGERPFVCSVCGHRFT
  TKGNLKVHFHRHPQVKANPQLFAEFQDKVAAGNGIPYALSVPDPIDEPSLSLDSKPVLVT
  TSVGLPQNLSSGTNPKDLTGGSLPGDLQPGPSPESEGGPTLPGVGPNYNSPRAGGFQGSG
  TPEPGSETLKLQQLVENIDKATTDPNECLICHRVLSCQSSLKMHYRTHTGERPFQCKICG
  RAFSTKGNLKTHLGVHRTNTSIKTQHSCPICQKKFTNAVMLQQHIRMHMGGQIPNTPLPE
  NPCDFTGSEPMTVGENGSTGAICHDDVIESIDVEEVSSQEAPSSSSKVPTPLPSIHSASP
  TLGFAMMASLDAPGKVGPAPFNLQRQGSRENGSVESDGLTNDSSSLMGDQEYQSRSPDIL
  ETTSFQALSPANSQAESIKSKSPDAGSKAESSENSRTEMEGRSSLPSTFIRAPPTYVKVE
  VPGTFVGPSTLSPGMTPLLAAQPRRQAKQHGCTRCGKNFSSASALQIHERTHTGEKPFVC
  NICGRAFTTKGNLKVHYMTHGANNNSARRGRKLAIENTMALLGTDGKRVSEIFPKEILAP
  SVNVDPVVWNQYTSMLNGGLAVKTNEISVIQSGGVPTLPVSLGATSVVNNATVSKMDGSQ
  SGISADVEKPSATDGVPKHQFPHFLEENKIAVS
• Function: Transcription factor with a key role in the maintenance and self-renewal of embryonic and hematopoietic stem cells.
• Tissue Specificity: Expressed in testis. Constitutively expressed in acute myeloid leukemia (AML).
• Reactome Pathway:
  Transcriptional regulation of pluripotent stem cells (R-HSA-452723)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation (R-HSA-2892247)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Duane-radial ray syndrome	DISGTEBP	Definitive	Autosomal dominant	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Carcinoma	DISH9F1N	Strong	Biomarker	[3]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[6]
Congenital deformities of limbs	DISP4N1Q	Strong	Biomarker	[7]
Congenital radioulnar synostosis	DISF96QX	Strong	Genetic Variation	[8]
Deafness	DISKCLH4	Strong	Genetic Variation	[9]
Duane retraction syndrome 2	DISE6LRF	Strong	Biomarker	[7]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[10]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[11]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[12]
Glioma	DIS5RPEH	Strong	Biomarker	[13]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[14]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[15]
leukaemia	DISS7D1V	Strong	Altered Expression	[16]
Leukemia	DISNAKFL	Strong	Altered Expression	[16]
Liver cancer	DISDE4BI	Strong	Altered Expression	[4]
Microphthalmia	DISGEBES	Strong	Genetic Variation	[17]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[18]
Otitis media	DISGZDUO	Strong	Biomarker	[19]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[11]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[2]
Polydactyly of a biphalangeal thumb	DISX46OZ	Strong	Biomarker	[20]
Wilms tumor	DISB6T16	Strong	Biomarker	[21]
Breast cancer	DIS7DPX1	moderate	Biomarker	[22]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[22]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[23]
Lung cancer	DISCM4YA	moderate	Biomarker	[24]
Lung carcinoma	DISTR26C	moderate	Biomarker	[24]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[25]
Ventricular septal defect	DISICO41	moderate	Biomarker	[7]
Duane retraction syndrome	DISOEBK2	Supportive	Autosomal dominant	[26]
IVIC syndrome	DIS4G2ZE	Supportive	Autosomal dominant	[9]
Prostate cancer	DISF190Y	Disputed	Biomarker	[27]
Prostate carcinoma	DISMJPLE	Disputed	Biomarker	[27]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[28]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[29]
Gastric cancer	DISXGOUK	Limited	Biomarker	[30]
Germ cell tumor	DIS62070	Limited	Altered Expression	[2]
Stomach cancer	DISKIJSX	Limited	Biomarker	[30]

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 Sal-like protein 4 (SALL4).	[31]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sal-like protein 4 (SALL4).	[32]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sal-like protein 4 (SALL4).	[33]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sal-like protein 4 (SALL4).	[34]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sal-like protein 4 (SALL4).	[35]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Sal-like protein 4 (SALL4).	[36]
Thalidomide	DM70BU5	Approved	Thalidomide increases the expression of Sal-like protein 4 (SALL4).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sal-like protein 4 (SALL4).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sal-like protein 4 (SALL4).	[42]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Sal-like protein 4 (SALL4).	[43]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Sal-like protein 4 (SALL4).	[35]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Sal-like protein 4 (SALL4).	[44]
Ginsenoside RG3	DMFN58T	Investigative	Ginsenoside RG3 decreases the expression of Sal-like protein 4 (SALL4).	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Azacitidine	DMTA5OE	Approved	Azacitidine affects the methylation of Sal-like protein 4 (SALL4).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sal-like protein 4 (SALL4).	[39]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Sal-like protein 4 (SALL4).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Pomalidomide	DMTGBAX	Approved	Pomalidomide affects the binding of Sal-like protein 4 (SALL4).	[7]
Lenalidomide	DM6Q7U4	Approved	Lenalidomide affects the binding of Sal-like protein 4 (SALL4).	[7]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Functional and clinical significance of SALL4 in breast cancer.Tumour Biol. 2016 Sep;37(9):11701-11709. doi: 10.1007/s13277-016-5150-7. Epub 2016 Jul 21.
• [3] Expression of RNA-binding protein LIN28 in classic gastric hepatoid carcinomas, gastric fetal type gastrointestinal adenocarcinomas, and hepatocellular carcinomas: An immunohistochemical study with comparison to SALL4, alpha-fetoprotein, glypican-3, and Hep Par1.Pathol Res Pract. 2018 Oct;214(10):1707-1712. doi: 10.1016/j.prp.2018.07.037. Epub 2018 Aug 2.
• [4] New High-Throughput Screening Identifies Compounds That Reduce Viability Specifically in Liver Cancer Cells That Express High Levels of SALL4 by Inhibiting Oxidative Phosphorylation.Gastroenterology. 2019 Dec;157(6):1615-1629.e17. doi: 10.1053/j.gastro.2019.08.022. Epub 2019 Aug 22.
• [5] miR-219-5p plays a tumor suppressive role in colon cancer by targeting oncogene Sall4.Oncol Rep. 2015 Oct;34(4):1923-32. doi: 10.3892/or.2015.4168. Epub 2015 Aug 4.
• [6] Knockdown of Sal-like 4 expression by siRNA induces apoptosis in colorectal cancer.J Cell Biochem. 2019 Jul;120(7):11531-11538. doi: 10.1002/jcb.28433. Epub 2019 Feb 16.
• [7] Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. Elife. 2018 Aug 1;7:e38430. doi: 10.7554/eLife.38430.
• [8] An atypical 0.73 MB microduplication of 22q11.21 and a novel SALL4 missense mutation associated with thumb agenesis and radioulnar synostosis.Am J Med Genet A. 2015 Jul;167(7):1644-9. doi: 10.1002/ajmg.a.37066. Epub 2015 Mar 30.
• [9] IVIC syndrome is caused by a c.2607delA mutation in the SALL4 locus. Am J Med Genet A. 2007 Feb 15;143(4):326-32. doi: 10.1002/ajmg.a.31603.
• [10] High expression of SALL4 and fascin, and loss of E-cadherin expression in undifferentiated/dedifferentiated carcinomas of the endometrium: An immunohistochemical and clinicopathologic study.Medicine (Baltimore). 2017 Mar;96(10):e6248. doi: 10.1097/MD.0000000000006248.
• [11] SALL4 is a marker of poor prognosis in serous ovarian carcinoma promoting invasion and metastasis.Oncol Rep. 2016 Mar;35(3):1796-806. doi: 10.3892/or.2016.4545. Epub 2016 Jan 5.
• [12] Correlation between SALL4 stemness marker and bone morphogenetic protein signaling genes in esophageal squamous cell carcinoma.J Biochem Mol Toxicol. 2019 Mar;33(3):e22262. doi: 10.1002/jbt.22262. Epub 2018 Nov 15.
• [13] Methylation-induced downregulation and tumor-suppressive role of microRNA-98 in glioma through targeting Sal-like protein 4.Int J Mol Med. 2018 May;41(5):2651-2659. doi: 10.3892/ijmm.2018.3464. Epub 2018 Feb 6.
• [14] Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion.Nat Commun. 2018 Mar 28;9(1):1241. doi: 10.1038/s41467-018-03584-3.
• [15] Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity.Nat Commun. 2017 Feb 24;8:14364. doi: 10.1038/ncomms14364.
• [16] The Study of SALL4 Gene and BMI-1 Gene Expression in Acute Myeloid Leukemia Patients.Lab Med. 2020 May 6;51(3):265-270. doi: 10.1093/labmed/lmz056.
• [17] Two missense mutations in SALL4 in a patient with microphthalmia, coloboma, and optic nerve hypoplasia.Ophthalmic Genet. 2017 Jul-Aug;38(4):371-375. doi: 10.1080/13816810.2016.1217550. Epub 2016 Sep 23.
• [18] Leukemic survival factor SALL4 contributes to defective DNA damage repair.Oncogene. 2016 Nov 24;35(47):6087-6095. doi: 10.1038/onc.2016.146. Epub 2016 May 2.
• [19] A Sall4 mutant mouse model useful for studying the role of Sall4 in early embryonic development and organogenesis.Genesis. 2007 Jan;45(1):51-8. doi: 10.1002/dvg.20264.
• [20] Fanconi anemia with concurrent thumb polydactyly and dorsal dimelia: a case report with discussion of embryology.Ann Plast Surg. 2013 Jan;70(1):116-8. doi: 10.1097/SAP.0b013e31822f9960.
• [21] Cystic metastasis of prostate cancer: A case report.Medicine (Baltimore). 2018 Dec;97(50):e13697. doi: 10.1097/MD.0000000000013697.
• [22] Knockdown of sal-like 4 expression by small interfering RNA induces apoptosis in breast cancer cells.J Cell Biochem. 2019 Jun;120(6):9392-9399. doi: 10.1002/jcb.28214. Epub 2018 Dec 5.
• [23] Whole-exome sequencing reveals SALL4 variants in premature ovarian insufficiency: an update on genotype-phenotype correlations.Hum Genet. 2019 Jan;138(1):83-92. doi: 10.1007/s00439-018-1962-4. Epub 2019 Jan 2.
• [24] Upregulation of SALL4 by EGFR activation regulates the stemness of CD44-positive lung cancer.Oncogenesis. 2018 Apr 25;7(4):36. doi: 10.1038/s41389-018-0045-7.
• [25] SALL4 as an Epithelial-Mesenchymal Transition and Drug Resistance Inducer through the Regulation of c-Myc in Endometrial Cancer.PLoS One. 2015 Sep 25;10(9):e0138515. doi: 10.1371/journal.pone.0138515. eCollection 2015.
• [26] Diversified clinical presentations associated with a novel sal-like 4 gene mutation in a Chinese pedigree with Duane retraction syndrome. Mol Vis. 2013 May 6;19:986-94. Print 2013.
• [27] Effects of siRNA-mediated silencing of Sal-like 4 expression on proliferation and apoptosis of prostate cancer C4-2 cells.Genet Mol Res. 2016 May 13;15(2). doi: 10.4238/gmr.15027885.
• [28] Expression pattern and prognostic implication of SALL4 gene in myeloid leukemias: a case-control study.Scand J Clin Lab Invest. 2019 Feb-Apr;79(1-2):65-70. doi: 10.1080/00365513.2018.1555854. Epub 2019 Jan 12.
• [29] Knockdown of SALL4 expression using RNA interference induces cell cycle arrest, enhances early apoptosis, inhibits invasion and increases chemosensitivity to temozolomide in U251 glioma cells.Oncol Lett. 2017 Oct;14(4):4263-4269. doi: 10.3892/ol.2017.6722. Epub 2017 Aug 4.
• [30] PGD2/PTGDR2 Signaling Restricts the Self-Renewal and Tumorigenesis of Gastric Cancer.Stem Cells. 2018 Jul;36(7):990-1003. doi: 10.1002/stem.2821. Epub 2018 Apr 4.
• [31] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [32] 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.
• [33] 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.
• [34] 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.
• [35] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [36] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [37] Novel approach for detecting global epigenetic alterations associated with tumor cell aneuploidy. Int J Cancer. 2007 Oct 1;121(7):1487-93. doi: 10.1002/ijc.22847.
• [38] Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. Elife. 2018 Aug 1;7:e38430. doi: 10.7554/eLife.38430.
• [39] 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.
• [40] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [41] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [42] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [43] 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.
• [44] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [45] 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.