Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5YX0YB)

• DOT Name: CLIP-associating protein 2 (CLASP2)
• Synonyms: Cytoplasmic linker-associated protein 2; Protein Orbit homolog 2; hOrbit2
• Gene Name: CLASP2
• Related Disease:
  Bladder cancer
  Bladder transitional cell carcinoma
  Familial adenomatous polyposis
  Neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
  ACTH-independent macronodular adrenal hyperplasia 1
  Intellectual disability
• UniProt ID: CLAP2_HUMAN
• PDB ID: 3WOY; 5NR4
• Pfam ID: PF21040 ; PF12348
• Sequence:
  MAMGDDKSFDDEESVDGNRPSSAASAFKVPAPKTSGNPANSARKPGSAGGPKVGGASKEG
  GAGAVDEDDFIKAFTDVPSIQIYSSRELEETLNKIREILSDDKHDWDQRANALKKIRSLL
  VAGAAQYDCFFQHLRLLDGALKLSAKDLRSQVVREACITVAHLSTVLGNKFDHGAEAIVP
  TLFNLVPNSAKVMATSGCAAIRFIIRHTHVPRLIPLITSNCTSKSVPVRRRSFEFLDLLL
  QEWQTHSLERHAAVLVETIKKGIHDADAEARVEARKTYMGLRNHFPGEAETLYNSLEPSY
  QKSLQTYLKSSGSVASLPQSDRSSSSSQESLNRPFSSKWSTANPSTVAGRVSAGSSKASS
  LPGSLQRSRSDIDVNAAAGAKAHHAAGQSVRSGRLGAGALNAGSYASLEDTSDKLDGTAS
  EDGRVRAKLSAPLAGMGNAKADSRGRSRTKMVSQSQPGSRSGSPGRVLTTTALSTVSSGV
  QRVLVNSASAQKRSKIPRSQGCSREASPSRLSVARSSRIPRPSVSQGCSREASRESSRDT
  SPVRSFQPLASRHHSRSTGALYAPEVYGASGPGYGISQSSRLSSSVSAMRVLNTGSDVEE
  AVADALKKPARRRYESYGMHSDDDANSDASSACSERSYSSRNGSIPTYMRQTEDVAEVLN
  RCASSNWSERKEGLLGLQNLLKNQRTLSRVELKRLCEIFTRMFADPHGKRVFSMFLETLV
  DFIQVHKDDLQDWLFVLLTQLLKKMGADLLGSVQAKVQKALDVTRESFPNDLQFNILMRF
  TVDQTQTPSLKVKVAILKYIETLAKQMDPGDFINSSETRLAVSRVITWTTEPKSSDVRKA
  AQSVLISLFELNTPEFTMLLGALPKTFQDGATKLLHNHLRNTGNGTQSSMGSPLTRPTPR
  SPANWSSPLTSPTNTSQNTLSPSAFDYDTENMNSEDIYSSLRGVTEAIQNFSFRSQEDMN
  EPLKRDSKKDDGDSMCGGPGMSDPRAGGDATDSSQTALDNKASLLHSMPTHSSPRSRDYN
  PYNYSDSISPFNKSALKEAMFDDDADQFPDDLSLDHSDLVAELLKELSNHNERVEERKIA
  LYELMKLTQEESFSVWDEHFKTILLLLLETLGDKEPTIRALALKVLREILRHQPARFKNY
  AELTVMKTLEAHKDPHKEVVRSAEEAASVLATSISPEQCIKVLCPIIQTADYPINLAAIK
  MQTKVIERVSKETLNLLLPEIMPGLIQGYDNSESSVRKACVFCLVAVHAVIGDELKPHLS
  QLTGSKMKLLNLYIKRAQTGSGGADPTTDVSGQS
• Function: Microtubule plus-end tracking protein that promotes the stabilization of dynamic microtubules. Involved in the nucleation of noncentrosomal microtubules originating from the trans-Golgi network (TGN). Required for the polarization of the cytoplasmic microtubule arrays in migrating cells towards the leading edge of the cell. May act at the cell cortex to enhance the frequency of rescue of depolymerizing microtubules by attaching their plus-ends to cortical platforms composed of ERC1 and PHLDB2. This cortical microtubule stabilizing activity is regulated at least in part by phosphatidylinositol 3-kinase signaling. Also performs a similar stabilizing function at the kinetochore which is essential for the bipolar alignment of chromosomes on the mitotic spindle. Acts as a mediator of ERBB2-dependent stabilization of microtubules at the cell cortex.
• Tissue Specificity: Brain-specific.
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  Role of ABL in ROBO-SLIT signaling (R-HSA-428890)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Strong	Biomarker	[1]
Bladder transitional cell carcinoma	DISNL46A	Strong	Altered Expression	[2]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[1]
ACTH-independent macronodular adrenal hyperplasia 1	DISH2YV8	Limited	Biomarker	[4]
Intellectual disability	DISMBNXP	Limited	Biomarker	[5]

3 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 CLIP-associating protein 2 (CLASP2).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of CLIP-associating protein 2 (CLASP2).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of CLIP-associating protein 2 (CLASP2).	[16]

12 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 CLIP-associating protein 2 (CLASP2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CLIP-associating protein 2 (CLASP2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of CLIP-associating protein 2 (CLASP2).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CLIP-associating protein 2 (CLASP2).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of CLIP-associating protein 2 (CLASP2).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of CLIP-associating protein 2 (CLASP2).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of CLIP-associating protein 2 (CLASP2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of CLIP-associating protein 2 (CLASP2).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of CLIP-associating protein 2 (CLASP2).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of CLIP-associating protein 2 (CLASP2).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of CLIP-associating protein 2 (CLASP2).	[12]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of CLIP-associating protein 2 (CLASP2).	[18]

References

• [1] CLASP2 is involved in the EMT and early progression after transurethral resection of the bladder tumor.BMC Cancer. 2017 Feb 6;17(1):105. doi: 10.1186/s12885-017-3101-3.
• [2] Significance of CLASP2 expression in prognosis for muscle-invasive bladder cancer patients: A propensity score-based analysis.Urol Oncol. 2019 Oct;37(10):800-807. doi: 10.1016/j.urolonc.2019.05.003. Epub 2019 May 24.
• [3] ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells.Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18517-22. doi: 10.1073/pnas.1000975107. Epub 2010 Oct 11.
• [4] Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome.Science. 2014 May 23;344(6186):913-7. doi: 10.1126/science.1249480. Epub 2014 Apr 3.
• [5] Interstitial deletion of 3p22.3p22.2 encompassing ARPP21 and CLASP2 is a potential pathogenic factor for a syndromic form of intellectual disability: a co-morbidity model with additional copy number variations in a large family.Am J Med Genet A. 2013 Nov;161A(11):2890-3. doi: 10.1002/ajmg.a.36257. Epub 2013 Oct 11.
• [6] 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.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] 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.
• [9] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] 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.
• [16] 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.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.