Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXXE208)

• DOT Name: Protein smoothened (SMO)
• Synonyms: Protein Gx
• Gene Name: SMO
• Related Disease:
  Curry-Jones syndrome
  Congenital hypothalamic hamartoma syndrome
  Hirschsprung disease
  Medulloblastoma
• UniProt ID: SMO_HUMAN
• PDB ID: 4JKV; 4N4W; 4O9R; 4QIM; 4QIN; 5L7D; 5L7I; 5V56; 5V57; 6OT0; 6XBJ; 6XBK; 6XBL; 6XBM; 7ZI0
• Pfam ID: PF01534 ; PF01392
• Sequence:
  MAAARPARGPELPLLGLLLLLLLGDPGRGAASSGNATGPGPRSAGGSARRSAAVTGPPPP
  LSHCGRAAPCEPLRYNVCLGSVLPYGATSTLLAGDSDSQEEAHGKLVLWSGLRNAPRCWA
  VIQPLLCAVYMPKCENDRVELPSRTLCQATRGPCAIVERERGWPDFLRCTPDRFPEGCTN
  EVQNIKFNSSGQCEVPLVRTDNPKSWYEDVEGCGIQCQNPLFTEAEHQDMHSYIAAFGAV
  TGLCTLFTLATFVADWRNSNRYPAVILFYVNACFFVGSIGWLAQFMDGARREIVCRADGT
  MRLGEPTSNETLSCVIIFVIVYYALMAGVVWFVVLTYAWHTSFKALGTTYQPLSGKTSYF
  HLLTWSLPFVLTVAILAVAQVDGDSVSGICFVGYKNYRYRAGFVLAPIGLVLIVGGYFLI
  RGVMTLFSIKSNHPGLLSEKAASKINETMLRLGIFGFLAFGFVLITFSCHFYDFFNQAEW
  ERSFRDYVLCQANVTIGLPTKQPIPDCEIKNRPSLLVEKINLFAMFGTGIAMSTWVWTKA
  TLLIWRRTWCRLTGQSDDEPKRIKKSKMIAKAFSKRHELLQNPGQELSFSMHTVSHDGPV
  AGLAFDLNEPSADVSSAWAQHVTKMVARRGAILPQDISVTPVATPVPPEEQANLWLVEAE
  ISPELQKRLGRKKKRRKRKKEVCPLAPPPELHPPAPAPSTIPRLPQLPRQKCLVAAGAWG
  AGDSCRQGAWTLVSNPFCPEPSPPQDPFLPSAPAPVAWAHGRRQGLGPIHSRTNLMDTEL
  MDADSDF
• Function: G protein-coupled receptor which associates with the patched protein (PTCH) to transduce hedgehog protein signaling. Binding of sonic hedgehog (SHH) to its receptor patched prevents inhibition of smoothened (SMO) by patched. When active, SMO binds to and sequesters protein kinase A catalytic subunit PRKACA at the cell membrane, preventing PRKACA-mediated phosphorylation of GLI transcription factors which releases the GLI proteins from PRKACA-mediated inhibition and allows for transcriptional activation of hedgehog pathway target genes. Required for the accumulation of KIF7, GLI2 and GLI3 in the cilia. Interacts with DLG5 at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation.
• KEGG Pathway:
  Hedgehog sig.ling pathway (hsa04340)
  Axon guidance (hsa04360)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Basal cell carcinoma (hsa05217)
• Reactome Pathway:
  Hedgehog 'off' state (R-HSA-5610787)
  BBSome-mediated cargo-targeting to cilium (R-HSA-5620922)
  Hedgehog 'on' state (R-HSA-5632684)
  Activation of SMO (R-HSA-5635838)
  Class B/2 (Secretin family receptors) (R-HSA-373080)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Curry-Jones syndrome	DISSIC47	Definitive	Somatic mosaicism	[1]
Congenital hypothalamic hamartoma syndrome	DISO1UQ2	Moderate	Autosomal recessive	[2]
Hirschsprung disease	DISUUSM1	Supportive	Autosomal dominant	[3]
Medulloblastoma	DISZD2ZL	Limited	Autosomal dominant	[4]

1 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 Protein smoothened (SMO).	[5]

20 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 Protein smoothened (SMO).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein smoothened (SMO).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein smoothened (SMO).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein smoothened (SMO).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein smoothened (SMO).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the activity of Protein smoothened (SMO).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein smoothened (SMO).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Protein smoothened (SMO).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Protein smoothened (SMO).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Protein smoothened (SMO).	[15]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Protein smoothened (SMO).	[16]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Protein smoothened (SMO).	[17]
Vismodegib	DM5IXKQ	Approved	Vismodegib decreases the expression of Protein smoothened (SMO).	[18]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Protein smoothened (SMO).	[19]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Protein smoothened (SMO).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein smoothened (SMO).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Protein smoothened (SMO).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein smoothened (SMO).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Protein smoothened (SMO).	[23]
CYCLOPAMINE	DMEM2SW	Investigative	CYCLOPAMINE increases the expression of Protein smoothened (SMO).	[24]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling. Am J Hum Genet. 2020 Jun 4;106(6):779-792. doi: 10.1016/j.ajhg.2020.04.010. Epub 2020 May 14.
• [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] 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.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Quercetin suppresses pancreatic ductal adenocarcinoma progression via inhibition of SHH and TGF-/Smad signaling pathways. Cell Biol Toxicol. 2021 Jun;37(3):479-496. doi: 10.1007/s10565-020-09562-0. Epub 2020 Oct 17.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Identification of recurrent SMO and BRAF mutations in ameloblastomas. Nat Genet. 2014 Jul;46(7):722-5. doi: 10.1038/ng.2986. Epub 2014 May 25.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] Down-regulation of Sonic hedgehog signaling pathway activity is involved in 5-fluorouracil-induced apoptosis and motility inhibition in Hep3B cells. Acta Biochim Biophys Sin (Shanghai). 2008 Sep;40(9):819-29.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [17] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [18] Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms. PLoS One. 2011;6(11):e27306. doi: 10.1371/journal.pone.0027306. Epub 2011 Nov 8.
• [19] Effect of resveratrol on proliferation and apoptosis of human pancreatic cancer MIA PaCa-2 cells may?involve inhibition of the Hedgehog signaling pathway. Mol Med Rep. 2014 Nov;10(5):2563-7. doi: 10.3892/mmr.2014.2511. Epub 2014 Aug 21.
• [20] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [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.
• [23] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [24] Mono-2-ethyhexyl phthalate advancing the progression of prostate cancer through activating the hedgehog pathway in LNCaP cells. Toxicol In Vitro. 2016 Apr;32:86-91. doi: 10.1016/j.tiv.2015.12.012. Epub 2015 Dec 19.