Details of Drug Off-Target (DOT)

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

• DOT Name: Single-minded homolog 1 (SIM1)
• Synonyms: Class E basic helix-loop-helix protein 14; bHLHe14
• Gene Name: SIM1
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cervical cancer
  Cervical carcinoma
  Complex neurodevelopmental disorder
  Depression
  Hypopituitarism
  Language disorder
  Lung adenocarcinoma
  Lung squamous cell carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Inherited obesity
  Obesity due to SIM1 deficiency
  Erectile dysfunction
  Intellectual disability
  Prader-Willi syndrome
• UniProt ID: SIM1_HUMAN
• Pfam ID: PF00010 ; PF00989 ; PF08447 ; PF06621
• Sequence:
  MKEKSKNAARTRREKENSEFYELAKLLPLPSAITSQLDKASIIRLTTSYLKMRVVFPEGL
  GEAWGHSSRTSPLDNVGRELGSHLLQTLDGFIFVVAPDGKIMYISETASVHLGLSQVELT
  GNSIYEYIHPADHDEMTAVLTAHQPYHSHFVQEYEIERSFFLRMKCVLAKRNAGLTCGGY
  KVIHCSGYLKIRQYSLDMSPFDGCYQNVGLVAVGHSLPPSAVTEIKLHSNMFMFRASLDM
  KLIFLDSRVAELTGYEPQDLIEKTLYHHVHGCDTFHLRCAHHLLLVKGQVTTKYYRFLAK
  HGGWVWVQSYATIVHNSRSSRPHCIVSVNYVLTDTEYKGLQLSLDQISASKPAFSYTSSS
  TPTMTDNRKGAKSRLSSSKSKSRTSPYPQYSGFHTERSESDHDSQWGGSPLTDTASPQLL
  DPADRPGSQHDASCAYRQFSDRSSLCYGFALDHSRLVEERHFHTQACEGGRCEAGRYFLG
  TPQAGREPWWGSRAALPLTKASPESREAYENSMPHIASVHRIHGRGHWDEDSVVSSPDPG
  SASESGDRYRTEQYQSSPHEPSKIETLIRATQQMIKEEENRLQLRKAPSDQLASINGAGK
  KHSLCFANYQQPPPTGEVCHGSALANTSPCDHIQQREGKMLSPHENDYDNSPTALSRISS
  PNSDRISKSSLILAKDYLHSDISPHQTAGDHPTVSPNCFGSHRQYFDKHAYTLTGYALEH
  LYDSETIRNYSLGCNGSHFDVTSHLRMQPDPAQGHKGTSVIITNGS
• Function: Transcriptional factor that may have pleiotropic effects during embryogenesis and in the adult.

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Cervical cancer	DISFSHPF	Strong	Posttranslational Modification	[1]
Cervical carcinoma	DIST4S00	Strong	Posttranslational Modification	[1]
Complex neurodevelopmental disorder	DISB9AFI	Strong	Autosomal dominant	[4]
Depression	DIS3XJ69	Strong	Genetic Variation	[5]
Hypopituitarism	DIS1QT3G	Strong	Biomarker	[6]
Language disorder	DISTLKP7	Strong	Genetic Variation	[7]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[8]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[1]
Inherited obesity	DISVH4OT	moderate	Biomarker	[11]
Obesity due to SIM1 deficiency	DISQXLQ5	Supportive	Autosomal recessive	[12]
Erectile dysfunction	DISD8MTH	Limited	Biomarker	[13]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[14]
Prader-Willi syndrome	DISYWMLU	Limited	Biomarker	[14]

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 Single-minded homolog 1 (SIM1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Single-minded homolog 1 (SIM1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Single-minded homolog 1 (SIM1).	[16]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Single-minded homolog 1 (SIM1).	[17]

References

• [1] Aberrant single-minded homolog 1 methylation as a potential biomarker for cervical cancer.Diagn Cytopathol. 2018 Jan;46(1):15-21. doi: 10.1002/dc.23838. Epub 2017 Oct 24.
• [2] DNA methylation marker to estimate the breast cancer cell fraction in DNA samples.Med Oncol. 2018 Sep 14;35(11):147. doi: 10.1007/s12032-018-1207-3.
• [3] Identification of 20 genes aberrantly methylated in human breast cancers.Int J Cancer. 2005 Sep 1;116(3):407-14. doi: 10.1002/ijc.21054.
• [4] 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.
• [5] Gene expression signature of antidepressant treatment response/non-response in Flinders Sensitive Line rats subjected to maternal separation.Eur Neuropsychopharmacol. 2020 Feb;31:69-85. doi: 10.1016/j.euroneuro.2019.11.004. Epub 2019 Dec 6.
• [6] Endocrine phenotype of 6q16.1-q21 deletion involving SIM1 and Prader-Willi syndrome-like features.Am J Med Genet A. 2013 Dec;161A(12):3137-43. doi: 10.1002/ajmg.a.36149. Epub 2013 Aug 16.
• [7] Associations between oxytocin-related genes and autistic-like traits.Soc Neurosci. 2014;9(4):378-86. doi: 10.1080/17470919.2014.897995. Epub 2014 Mar 17.
• [8] Identification and validation of candidate epigenetic biomarkers in lung adenocarcinoma.Sci Rep. 2016 Oct 26;6:35807. doi: 10.1038/srep35807.
• [9] Predicting the Lung Squamous Cell Carcinoma Diagnosis and Prognosis Markers by Unique DNA Methylation and Gene Expression Profiles.J Comput Biol. 2020 Jul;27(7):1041-1054. doi: 10.1089/cmb.2019.0138. Epub 2019 Nov 11.
• [10] Genome-wide methylation screen in low-grade breast cancer identifies novel epigenetically altered genes as potential biomarkers for tumor diagnosis.FASEB J. 2012 Dec;26(12):4937-50. doi: 10.1096/fj.12-209502. Epub 2012 Aug 28.
• [11] Common variation in SIM1 is reproducibly associated with BMI in Pima Indians.Diabetes. 2009 Jul;58(7):1682-9. doi: 10.2337/db09-0028. Epub 2009 Apr 28.
• [12] Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features. J Clin Invest. 2013 Jul;123(7):3037-41. doi: 10.1172/JCI68035. Epub 2013 Jun 17.
• [13] GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology.Am J Hum Genet. 2019 Jan 3;104(1):157-163. doi: 10.1016/j.ajhg.2018.11.004. Epub 2018 Dec 21.
• [14] Obesity with associated developmental delay and/or learning disability in patients exhibiting additional features: report of novel pathogenic copy number variants.Am J Med Genet A. 2013 Mar;161A(3):479-86. doi: 10.1002/ajmg.a.35761. Epub 2013 Feb 7.
• [15] 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.
• [16] 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.
• [17] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [18] 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.