Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQN35G2)

• DOT Name: Calsyntenin-1 (CLSTN1)
• Synonyms: Alcadein-alpha; Alc-alpha; Alzheimer-related cadherin-like protein; Non-classical cadherin XB31alpha
• Gene Name: CLSTN1
• Related Disease:
  Adult germ cell tumor
  Bacterial vaginosis
  Fragile X syndrome
  Germ cell tumor
  Germ cell tumour
  Lung adenocarcinoma
  Non-small-cell lung cancer
  Nongerminomatous germ cell tumor
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Testicular germ cell tumor
  Asthma
• UniProt ID: CSTN1_HUMAN
• Pfam ID: PF00028 ; PF19699 ; PF13385
• Sequence:
  MLRRPAPALAPAARLLLAGLLCGGGVWAARVNKHKPWLEPTYHGIVTENDNTVLLDPPLI
  ALDKDAPLRFAESFEVTVTKEGEICGFKIHGQNVPFDAVVVDKSTGEGVIRSKEKLDCEL
  QKDYSFTIQAYDCGKGPDGTNVKKSHKATVHIQVNDVNEYAPVFKEKSYKATVIEGKQYD
  SILRVEAVDADCSPQFSQICSYEIITPDVPFTVDKDGYIKNTEKLNYGKEHQYKLTVTAY
  DCGKKRATEDVLVKISIKPTCTPGWQGWNNRIEYEPGTGALAVFPNIHLETCDEPVASVQ
  ATVELETSHIGKGCDRDTYSEKSLHRLCGAAAGTAELLPSPSGSLNWTMGLPTDNGHDSD
  QVFEFNGTQAVRIPDGVVSVSPKEPFTISVWMRHGPFGRKKETILCSSDKTDMNRHHYSL
  YVHGCRLIFLFRQDPSEEKKYRPAEFHWKLNQVCDEEWHHYVLNVEFPSVTLYVDGTSHE
  PFSVTEDYPLHPSKIETQLVVGACWQEFSGVENDNETEPVTVASAGGDLHMTQFFRGNLA
  GLTLRSGKLADKKVIDCLYTCKEGLDLQVLEDSGRGVQIQAHPSQLVLTLEGEDLGELDK
  AMQHISYLNSRQFPTPGIRRLKITSTIKCFNEATCISVPPVDGYVMVLQPEEPKISLSGV
  HHFARAASEFESSEGVFLFPELRIISTITREVEPEGDGAEDPTVQESLVSEEIVHDLDTC
  EVTVEGEELNHEQESLEVDMARLQQKGIEVSSSELGMTFTGVDTMASYEEVLHLLRYRNW
  HARSLLDRKFKLICSELNGRYISNEFKVEVNVIHTANPMEHANHMAAQPQFVHPEHRSFV
  DLSGHNLANPHPFAVVPSTATVVIVVCVSFLVFMIILGVFRIRAAHRRTMRDQDTGKENE
  MDWDDSALTITVNPMETYEDQHSSEEEEEEEEEEESEDGEEEDDITSAESESSEEEEGEQ
  GDPQNATRQQQLEWDDSTLSY
• Function: Postsynaptic adhesion molecule that binds to presynaptic neurexins to mediate both excitatory and inhibitory synapse formation. Promotes synapse development by acting as a cell adhesion molecule at the postsynaptic membrane, which associates with neurexin-alpha at the presynaptic membrane. Also functions as a cargo in axonal anterograde transport by acting as a molecular adapter that promotes KLC1 association with vesicles. Complex formation with APBA2 and APP, stabilizes APP metabolism and enhances APBA2-mediated suppression of beta-APP40 secretion, due to the retardation of intracellular APP maturation ; [Soluble Alc-alpha]: As intracellular fragment AlcICD, suppresses APBB1-dependent transactivation stimulated by APP C-terminal intracellular fragment (AICD), most probably by competing with AICD for APBB1-binding ; [CTF1-alpha]: In complex with APBA2 and C99, a C-terminal APP fragment, abolishes C99 interaction with PSEN1 and thus APP C99 cleavage by gamma-secretase, most probably through stabilization of the direct interaction between APBA2 and APP.
• Tissue Specificity: Expressed in the brain and, a lower level, in the heart, skeletal muscle, kidney and placenta. Accumulates in dystrophic neurites around the amyloid core of Alzheimer disease senile plaques (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult germ cell tumor	DISJUCQ7	Strong	Biomarker	[1]
Bacterial vaginosis	DISK2MZ2	Strong	Biomarker	[2]
Fragile X syndrome	DISE8W3A	Strong	Biomarker	[3]
Germ cell tumor	DIS62070	Strong	Biomarker	[1]
Germ cell tumour	DISOF3TK	Strong	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[5]
Nongerminomatous germ cell tumor	DISQOQJU	Strong	Biomarker	[1]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[7]
Testicular germ cell tumor	DIS5RN24	Strong	Genetic Variation	[1]
Asthma	DISW9QNS	moderate	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Calsyntenin-1 (CLSTN1) affects the response to substance of Methotrexate.	[18]

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 Calsyntenin-1 (CLSTN1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Calsyntenin-1 (CLSTN1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Calsyntenin-1 (CLSTN1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Calsyntenin-1 (CLSTN1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Calsyntenin-1 (CLSTN1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Calsyntenin-1 (CLSTN1).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Calsyntenin-1 (CLSTN1).	[14]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Calsyntenin-1 (CLSTN1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Calsyntenin-1 (CLSTN1).	[15]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Calsyntenin-1 (CLSTN1).	[13]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Calsyntenin-1 (CLSTN1).	[17]

References

• [1] Economy of Standards: European Association of Urology Guideline Changes Influence Treatment Costs in Stage I Testicular Cancer Patients.Urol Int. 2018;100(3):279-287. doi: 10.1159/000486343. Epub 2018 Mar 7.
• [2] Factors associated with the composition and diversity of the cervical microbiota of reproductive-age Black South African women: a retrospective cross-sectional study.PeerJ. 2019 Aug 15;7:e7488. doi: 10.7717/peerj.7488. eCollection 2019.
• [3] Calsyntenin-1 Negatively Regulates ICAM5 Accumulation in Postsynaptic Membrane and Influences Dendritic Spine Maturation in a Mouse Model of Fragile X Syndrome.Front Neurosci. 2019 Oct 18;13:1098. doi: 10.3389/fnins.2019.01098. eCollection 2019.
• [4] Calsyntenin-1, clusterin and neutrophil gelatinase-associated lipocalin are candidate serological biomarkers for lung adenocarcinoma.Oncotarget. 2017 Nov 14;8(64):107964-107976. doi: 10.18632/oncotarget.22438. eCollection 2017 Dec 8.
• [5] Impact of Staging With Positron-emission Tomography (PET) and Comorbidities on Management and Survival of American Veterans With Stage I-III Non-Small Cell Lung Cancer.Am J Clin Oncol. 2018 May;41(5):513-518. doi: 10.1097/COC.0000000000000316.
• [6] Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma.Mol Cancer Ther. 2009 Sep;8(9):2616-24. doi: 10.1158/1535-7163.MCT-09-0483. Epub 2009 Sep 1.
• [7] Age-related DNA methylation changes in normal human prostate tissues.Clin Cancer Res. 2007 Jul 1;13(13):3796-802. doi: 10.1158/1078-0432.CCR-07-0085.
• [8] Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma.Toxicol Sci. 2015 Jul;146(1):192-201. doi: 10.1093/toxsci/kfv084. Epub 2015 Apr 26.
• [9] 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.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [14] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.
• [18] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.