Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV3XRE5)

• DOT Name: Son of sevenless homolog 2 (SOS2)
• Synonyms: SOS-2
• Gene Name: SOS2
• Related Disease:
  Noonan syndrome
  Noonan syndrome 9
  Alzheimer disease
  Cardiovascular disease
  Lung cancer
  Non-small-cell lung cancer
  Noonan syndrome 1
  Skin neoplasm
  Squamous cell carcinoma
  Turner syndrome
• UniProt ID: SOS2_HUMAN
• PDB ID: 6EIE
• Pfam ID: PF00169 ; PF00617 ; PF00618 ; PF00621
• Sequence:
  MQQAPQPYEFFSEENSPKWRGLLVSALRKVQEQVHPTLSANEESLYYIEELIFQLLNKLC
  MAQPRTVQDVEERVQKTFPHPIDKWAIADAQSAIEKRKRRNPLLLPVDKIHPSLKEVLGY
  KVDYHVSLYIVAVLEYISADILKLAGNYVFNIRHYEISQQDIKVSMCADKVLMDMFDQDD
  IGLVSLCEDEPSSSGELNYYDLVRTEIAEERQYLRELNMIIKVFREAFLSDRKLFKPSDI
  EKIFSNISDIHELTVKLLGLIEDTVEMTDESSPHPLAGSCFEDLAEEQAFDPYETLSQDI
  LSPEFHEHFNKLMARPAVALHFQSIADGFKEAVRYVLPRLMLVPVYHCWHYFELLKQLKA
  CSEEQEDRECLNQAITALMNLQGSMDRIYKQYSPRRRPGDPVCPFYSHQLRSKHLAIKKM
  NEIQKNIDGWEGKDIGQCCNEFIMEGPLTRIGAKHERHIFLFDGLMISCKPNHGQTRLPG
  YSSAEYRLKEKFVMRKIQICDKEDTCEHKHAFELVSKDENSIIFAAKSAEEKNNWMAALI
  SLHYRSTLDRMLDSVLLKEENEQPLRLPSPEVYRFVVKDSEENIVFEDNLQSRSGIPIIK
  GGTVVKLIERLTYHMYADPNFVRTFLTTYRSFCKPQELLSLLIERFEIPEPEPTDADKLA
  IEKGEQPISADLKRFRKEYVQPVQLRILNVFRHWVEHHFYDFERDLELLERLESFISSVR
  GKAMKKWVESIAKIIRRKKQAQANGVSHNITFESPPPPIEWHISKPGQFETFDLMTLHPI
  EIARQLTLLESDLYRKVQPSELVGSVWTKEDKEINSPNLLKMIRHTTNLTLWFEKCIVEA
  ENFEERVAVLSRIIEILQVFQDLNNFNGVLEIVSAVNSVSVYRLDHTFEALQERKRKILD
  EAVELSQDHFKKYLVKLKSINPPCVPFFGIYLTNILKTEEGNNDFLKKKGKDLINFSKRR
  KVAEITGEIQQYQNQPYCLRIEPDMRRFFENLNPMGSASEKEFTDYLFNKSLEIEPRNCK
  QPPRFPRKSTFSLKSPGIRPNTGRHGSTSGTLRGHPTPLEREPCKISFSRIAETELESTV
  SAPTSPNTPSTPPVSASSDLSVFLDVDLNSSCGSNSIFAPVLLPHSKSFFSSCGSLHKLS
  EEPLIPPPLPPRKKFDHDASNSKGNMKSDDDPPAIPPRQPPPPKVKPRVPVPTGAFDGPL
  HSPPPPPPRDPLPDTPPPVPLRPPEHFINCPFNLQPPPLGHLHRDSDWLRDISTCPNSPS
  TPPSTPSPRVPRRCYVLSSSQNNLAHPPAPPVPPRQNSSPHLPKLPPKTYKRELSHPPLY
  RLPLLENAETPQ
• Function: Promotes the exchange of Ras-bound GDP by GTP.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  Endocrine resistance (hsa01522)
  MAPK sig.ling pathway (hsa04010)
  ErbB sig.ling pathway (hsa04012)
  Ras sig.ling pathway (hsa04014)
  Chemokine sig.ling pathway (hsa04062)
  FoxO sig.ling pathway (hsa04068)
  Phospholipase D sig.ling pathway (hsa04072)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  Gap junction (hsa04540)
  JAK-STAT sig.ling pathway (hsa04630)
  .tural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor sig.ling pathway (hsa04660)
  B cell receptor sig.ling pathway (hsa04662)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Thermogenesis (hsa04714)
  Neurotrophin sig.ling pathway (hsa04722)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin sig.ling pathway (hsa04910)
  GnRH sig.ling pathway (hsa04912)
  Estrogen sig.ling pathway (hsa04915)
  Prolactin sig.ling pathway (hsa04917)
  Relaxin sig.ling pathway (hsa04926)
  Growth hormone synthesis, secretion and action (hsa04935)
  Alcoholism (hsa05034)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  MicroR.s in cancer (hsa05206)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Colorectal cancer (hsa05210)
  Re.l cell carcinoma (hsa05211)
  Endometrial cancer (hsa05213)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Chronic myeloid leukemia (hsa05220)
  Acute myeloid leukemia (hsa05221)
  Non-small cell lung cancer (hsa05223)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  Activation of RAC1 (R-HSA-428540)
  Interleukin-15 signaling (R-HSA-8983432)
  RAC1 GTPase cycle (R-HSA-9013149)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Noonan syndrome	DIS7Q7DN	Definitive	Autosomal dominant	[1]
Noonan syndrome 9	DISL30XH	Definitive	Autosomal dominant	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Noonan syndrome 1	DIS7M92N	Strong	Genetic Variation	[2]
Skin neoplasm	DIS16DDV	Strong	Biomarker	[7]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[8]
Turner syndrome	DIS2035C	Strong	Biomarker	[9]

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 Son of sevenless homolog 2 (SOS2).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Son of sevenless homolog 2 (SOS2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Son of sevenless homolog 2 (SOS2).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Son of sevenless homolog 2 (SOS2).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Son of sevenless homolog 2 (SOS2).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Son of sevenless homolog 2 (SOS2).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Son of sevenless homolog 2 (SOS2).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Son of sevenless homolog 2 (SOS2).	[16]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Son of sevenless homolog 2 (SOS2).	[17]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Son of sevenless homolog 2 (SOS2).	[16]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Son of sevenless homolog 2 (SOS2).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Son of sevenless homolog 2 (SOS2).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Son of sevenless homolog 2 (SOS2).	[15]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of Son of sevenless homolog 2 (SOS2).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Son of sevenless homolog 2 (SOS2).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Son of sevenless homolog 2 (SOS2).	[22]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Son of sevenless homolog 2 (SOS2).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Son of sevenless homolog 2 (SOS2).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Son of sevenless homolog 2 (SOS2).	[26]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Son of sevenless homolog 2 (SOS2).	[27]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid decreases the expression of Son of sevenless homolog 2 (SOS2).	[28]

References

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• [2] Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome. Hum Mutat. 2015 Nov;36(11):1080-7. doi: 10.1002/humu.22834. Epub 2015 Aug 3.
• [3] Candidate gene association study of insulin signaling genes and Alzheimer's disease: evidence for SOS2, PCK1, and PPARgamma as susceptibility loci.Am J Med Genet B Neuropsychiatr Genet. 2007 Jun 5;144B(4):508-16. doi: 10.1002/ajmg.b.30503.
• [4] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
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• [17] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
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• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
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• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] 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.
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