Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT40G45S)

• DOT Name: Angiomotin-like protein 1 (AMOTL1)
• Gene Name: AMOTL1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Splenic marginal zone lymphoma
  Chronic obstructive pulmonary disease
  Pulmonary emphysema
  Neoplasm
  Advanced cancer
  Cardiomyopathy
• UniProt ID: AMOL1_HUMAN
• Pfam ID: PF12240
• Sequence:
  MWRAKLRRGTCEPAVKGSPSACYSPSSPVQVLEDSTYFSPDFQLYSGRHETSALTVEATS
  SIREKVVEDPLCNFHSPNFLRISEVEMRGSEDAAAGTVLQRLIQEQLRYGTPTENMNLLA
  IQHQATGSAGPAHPTNNFSSTENLTQEDPQMVYQSARQEPQGQEHQVDNTVMEKQVRSTQ
  PQQNNEELPTYEEAKAQSQFFRGQQQQQQQQGAVGHGYYMAGGTSQKSRTEGRPTVNRAN
  SGQAHKDEALKELKQGHVRSLSERIMQLSLERNGAKQHLPGSGNGKGFKVGGGPSPAQPA
  GKVLDPRGPPPEYPFKTKQMMSPVSKTQEHGLFYGDQHPGMLHEMVKPYPAPQPVRTDVA
  VLRYQPPPEYGVTSRPCQLPFPSTMQQHSPMSSQTSSASGPLHSVSLPLPLPMALGAPQP
  PPAASPSQQLGPDAFAIVERAQQMVEILTEENRVLHQELQGYYDNADKLHKFEKELQRIS
  EAYESLVKSTTKRESLDKAMRNKLEGEIRRLHDFNRDLRDRLETANRQLSSREYEGHEDK
  AAEGHYASQNKEFLKEKEKLEMELAAVRTASEDHRRHIEILDQALSNAQARVIKLEEELR
  EKQAYVEKVEKLQQALTQLQSACEKREQMERRLRTWLERELDALRTQQKHGNGQPANMPE
  YNAPALLELVREKEERILALEADMTKWEQKYLEESTIRHFAMNAAATAAAERDTTIINHS
  RNGSYGESSLEAHIWQEEEEVVQANRRCQDMEYTIKNLHAKIIEKDAMIKVLQQRSRKDA
  GKTDSSSLRPARSVPSIAAATGTHSRQTSLTSSQLAEEKKEEKTWKGSIGLLLGKEHHEH
  ASAPLLPPPPTSALSSIASTTAASSAHAKTGSKDSSTQTDKSAELFWPSMASLPSRGRLS
  TTPAHSPVLKHPAAKGTAEKLENSPGHGKSPDHRGRVSSLLHKPEFPDGEMMEVLI
• Function: Inhibits the Wnt/beta-catenin signaling pathway, probably by recruiting CTNNB1 to recycling endosomes and hence preventing its translocation to the nucleus.
• KEGG Pathway: Tight junction (hsa04530)
• Reactome Pathway: Signaling by Hippo (R-HSA-2028269)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Cervical cancer	DISFSHPF	Strong	Biomarker	[2]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[4]
Splenic marginal zone lymphoma	DISCGTZY	Strong	Genetic Variation	[5]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[6]
Pulmonary emphysema	DIS5M7HZ	moderate	Biomarker	[6]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[7]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[8]
Cardiomyopathy	DISUPZRG	Limited	Altered Expression	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Angiomotin-like protein 1 (AMOTL1) affects the response to substance of Mitoxantrone.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Angiomotin-like protein 1 (AMOTL1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Angiomotin-like protein 1 (AMOTL1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Angiomotin-like protein 1 (AMOTL1).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Angiomotin-like protein 1 (AMOTL1).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Angiomotin-like protein 1 (AMOTL1).	[14]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Angiomotin-like protein 1 (AMOTL1).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Angiomotin-like protein 1 (AMOTL1).	[16]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Angiomotin-like protein 1 (AMOTL1).	[17]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Angiomotin-like protein 1 (AMOTL1).	[18]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Angiomotin-like protein 1 (AMOTL1).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Angiomotin-like protein 1 (AMOTL1).	[21]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Angiomotin-like protein 1 (AMOTL1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Angiomotin-like protein 1 (AMOTL1).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Angiomotin-like protein 1 (AMOTL1).	[22]

References

• [1] AMOTL1 Promotes Breast Cancer Progression and Is Antagonized by Merlin.Neoplasia. 2016 Jan;18(1):10-24. doi: 10.1016/j.neo.2015.11.010.
• [2] circAMOTL1 Motivates AMOTL1 Expression to Facilitate Cervical Cancer Growth.Mol Ther Nucleic Acids. 2020 Mar 6;19:50-60. doi: 10.1016/j.omtn.2019.09.022. Epub 2019 Sep 30.
• [3] Dysregulation of p53-RBM25-mediated circAMOTL1L biogenesis contributes to prostate cancer progression through the circAMOTL1L-miR-193a-5p-Pcdha pathway.Oncogene. 2019 Apr;38(14):2516-2532. doi: 10.1038/s41388-018-0602-8. Epub 2018 Dec 7.
• [4] Multifaceted genomic risk for brain function in schizophrenia.Neuroimage. 2012 Jul 16;61(4):866-75. doi: 10.1016/j.neuroimage.2012.03.022. Epub 2012 Mar 13.
• [5] A study of the mutational landscape of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma.Mod Pathol. 2016 Oct;29(10):1212-20. doi: 10.1038/modpathol.2016.102. Epub 2016 Jun 24.
• [6] The role of tumor necrosis factor- and interferon- in regulating angiomotin-like protein 1 expression in lung microvascular endothelial cells.Allergol Int. 2013 Sep;62(3):309-22. doi: 10.2332/allergolint.12-OA-0528. Epub 2013 Jun 25.
• [7] Angiomotin and angiomotin like proteins, their expression and correlation with angiogenesis and clinical outcome in human breast cancer.BMC Cancer. 2006 Jan 23;6:16. doi: 10.1186/1471-2407-6-16.
• [8] A circular RNA promotes tumorigenesis by inducing c-myc nuclear translocation.Cell Death Differ. 2017 Sep;24(9):1609-1620. doi: 10.1038/cdd.2017.86. Epub 2017 Jun 16.
• [9] A Circular RNA Binds To and Activates AKT Phosphorylation and Nuclear Localization Reducing Apoptosis and Enhancing Cardiac Repair.Theranostics. 2017 Aug 29;7(16):3842-3855. doi: 10.7150/thno.19764. eCollection 2017.
• [10] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] 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.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] Up-regulation of endothelial nitric oxide synthase (eNOS), silent mating type information regulation 2 homologue 1 (SIRT1) and autophagy-related genes by repeated treatments with resveratrol in human umbilical vein endothelial cells. Br J Nutr. 2013 Dec;110(12):2150-5.
• [18] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [19] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [20] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [23] 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.
• [24] Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. Oncogene. 2005 Nov 17;24(51):7542-51. doi: 10.1038/sj.onc.1208908.