Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFM133C)

• DOT Name: Pericentriolar material 1 protein (PCM1)
• Synonyms: PCM-1; hPCM-1
• Gene Name: PCM1
• Related Disease:
  Acute leukaemia
  Bardet biedl syndrome
  Carcinoma
  Chronic obstructive pulmonary disease
  Ciliopathy
  Epithelial ovarian cancer
  Haematological malignancy
  Huntington disease
  Hydrocephalus
  Myeloproliferative neoplasm
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Plasma cell myeloma
  Plasma cell neoplasm
  Refractory chronic myeloid leukaemia
  Scleroderma
  Systemic sclerosis
  Thyroid gland papillary carcinoma
  Zika virus infection
  Childhood myelodysplastic syndrome
  Chronic eosinophilic leukemia
  Leukemia
  Lymphoma
  Myelodysplastic syndrome
  Primary cutaneous T-cell lymphoma
  Thyroid tumor
  Toxic epidermal necrolysis
• UniProt ID: PCM1_HUMAN
• PDB ID: 6HYL; 6HYM; 7Q46
• Pfam ID: PF15717
• Sequence:
  MATGGGPFEDGMNDQDLPNWSNENVDDRLNNMDWGAQQKKANRSSEKNKKKFGVESDKRV
  TNDISPESSPGVGRRRTKTPHTFPHSRYMSQMSVPEQAELEKLKQRINFSDLDQRSIGSD
  SQGRATAANNKRQLSENRKPFNFLPMQINTNKSKDASTNPPNRETIGSAQCKELFASALS
  NDLLQNCQVSEEDGRGEPAMESSQIVSRLVQIRDYITKASSMREDLVEKNERSANVERLT
  HLIDHLKEQEKSYMKFLKKILARDPQQEPMEEIENLKKQHDLLKRMLQQQEQLRALQGRQ
  AALLALQHKAEQAIAVMDDSVVAETAGSLSGVSITSELNEELNDLIQRFHNQLRDSQPPA
  VPDNRRQAESLSLTREVSQSRKPSASERLPDEKVELFSKMRVLQEKKQKMDKLLGELHTL
  RDQHLNNSSSSPQRSVDQRSTSAPSASVGLAPVVNGESNSLTSSVPYPTASLVSQNESEN
  EGHLNPSEKLQKLNEVRKRLNELRELVHYYEQTSDMMTDAVNENRKDEETEESEYDSEHE
  NSEPVTNIRNPQVASTWNEVNSHSNAQCVSNNRDGRTVNSNCEINNRSAANIRALNMPPS
  LDCRYNREGEQEIHVAQGEDDEEEEEEAEEEGVSGASLSSHRSSLVDEHPEDAEFEQKIN
  RLMAAKQKLRQLQDLVAMVQDDDAAQGVISASASNLDDFYPAEEDTKQNSNNTRGNANKT
  QKDTGVNEKAREKFYEAKLQQQQRELKQLQEERKKLIDIQEKIQALQTACPDLQLSAASV
  GNCPTKKYMPAVTSTPTVNQHETSTSKSVFEPEDSSIVDNELWSEMRRHEMLREELRQRR
  KQLEALMAEHQRRQGLAETASPVAVSLRSDGSENLCTPQQSRTEKTMATWGGSTQCALDE
  EGDEDGYLSEGIVRTDEEEEEEQDASSNDNFSVCPSNSVNHNSYNGKETKNRWKNNCPFS
  ADENYRPLAKTRQQNISMQRQENLRWVSELSYVEEKEQWQEQINQLKKQLDFSVSICQTL
  MQDQQTLSCLLQTLLTGPYSVMPSNVASPQVHFIMHQLNQCYTQLTWQQNNVQRLKQMLN
  ELMRQQNQHPEKPGGKERGSSASHPPSPSLFCPFSFPTQPVNLFNIPGFTNFSSFAPGMN
  FSPLFPSNFGDFSQNISTPSEQQQPLAQNSSGKTEYMAFPKPFESSSSIGAEKPRNKKLP
  EEEVESSRTPWLYEQEGEVEKPFIKTGFSVSVEKSTSSNRKNQLDTNGRRRQFDEESLES
  FSSMPDPVDPTTVTKTFKTRKASAQASLASKDKTPKSKSKKRNSTQLKSRVKNIRYESAS
  MSSTCEPCKSRNRHSAQTEEPVQAKVFSRKNHEQLEKIIKCNRSTEISSETGSDFSMFEA
  LRDTIYSEVATLISQNESRPHFLIELFHELQLLNTDYLRQRALYALQDIVSRHISESHEK
  GENVKSVNSGTWIASNSELTPSESLATTDDETFEKNFERETHKISEQNDADNASVLSVSS
  NFEPFATDDLGNTVIHLDQALARMREYERMKTEAESNSNMRCTCRIIEDGDGAGAGTTVN
  NLEETPVIENRSSQQPVSEVSTIPCPRIDTQQLDRQIKAIMKEVIPFLKEHMDEVCSSQL
  LTSVRRMVLTLTQQNDESKEFVKFFHKQLGSILQDSLAKFAGRKLKDCGEDLLVEISEVL
  FNELAFFKLMQDLDNNSITVKQRCKRKIEATGVIQSCAKEAKRILEDHGSPAGEIDDEDK
  DKDETETVKQTQTSEVYDGPKNVRSDISDQEEDEESEGCPVSINLSKAETQALTNYGSGE
  DENEDEEMEEFEEGPVDVQTSLQANTEATEENEHDEQVLQRDFKKTAESKNVPLEREATS
  KNDQNNCPVKPCYLNILEDEQPLNSAAHKESPPTVDSTQQPNPLPLRLPEMEPLVPRVKE
  VKSAQETPESSLAGSPDTESPVLVNDYEAESGNISQKSDEEDFVKVEDLPLKLTIYSEAD
  LRKKMVEEEQKNHLSGEICEMQTEELAGNSETLKEPETVGAQSI
• Function: Required for centrosome assembly and function. Essential for the correct localization of several centrosomal proteins including CEP250, CETN3, PCNT and NEK2. Required to anchor microtubules to the centrosome. Also involved in cilium biogenesis by recruiting the BBSome, a ciliary protein complex involved in cilium biogenesis, to the centriolar satellites. Recruits the tubulin polyglutamylase complex (TPGC) to centriolar satellites.
• Tissue Specificity: Expressed in blood, bone marrow, breast, lymph node, ovary and thyroid.
• Reactome Pathway:
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Strong	Biomarker	[1]
Bardet biedl syndrome	DISTBNZW	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	Strong	Biomarker	[3]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[4]
Ciliopathy	DIS10G4I	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[6]
Haematological malignancy	DISCDP7W	Strong	Genetic Variation	[7]
Huntington disease	DISQPLA4	Strong	Biomarker	[8]
Hydrocephalus	DISIZUF7	Strong	Genetic Variation	[8]
Myeloproliferative neoplasm	DIS5KAPA	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[7]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[6]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[6]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[9]
Plasma cell neoplasm	DIS2PJJM	Strong	Genetic Variation	[9]
Refractory chronic myeloid leukaemia	DIS40YPP	Strong	Genetic Variation	[10]
Scleroderma	DISVQ342	Strong	Biomarker	[11]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[11]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Biomarker	[12]
Zika virus infection	DISQUCTY	Strong	Altered Expression	[13]
Childhood myelodysplastic syndrome	DISMN80I	Limited	Biomarker	[14]
Chronic eosinophilic leukemia	DISAJOUO	Limited	Genetic Variation	[15]
Leukemia	DISNAKFL	Limited	Biomarker	[14]
Lymphoma	DISN6V4S	Limited	Biomarker	[14]
Myelodysplastic syndrome	DISYHNUI	Limited	Biomarker	[14]
Primary cutaneous T-cell lymphoma	DIS35WVW	Limited	Genetic Variation	[15]
Thyroid tumor	DISLVKMD	Limited	Altered Expression	[12]
Toxic epidermal necrolysis	DISIWPFR	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	Pericentriolar material 1 protein (PCM1) affects the response to substance of Josamycin.	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Pericentriolar material 1 protein (PCM1).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pericentriolar material 1 protein (PCM1).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Pericentriolar material 1 protein (PCM1).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pericentriolar material 1 protein (PCM1).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Pericentriolar material 1 protein (PCM1).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pericentriolar material 1 protein (PCM1).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Pericentriolar material 1 protein (PCM1).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Pericentriolar material 1 protein (PCM1).	[23]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Pericentriolar material 1 protein (PCM1).	[24]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Pericentriolar material 1 protein (PCM1).	[25]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Pericentriolar material 1 protein (PCM1).	[26]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Pericentriolar material 1 protein (PCM1).	[27]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Pericentriolar material 1 protein (PCM1).	[28]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Pericentriolar material 1 protein (PCM1).	[29]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Pericentriolar material 1 protein (PCM1).	[30]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Pericentriolar material 1 protein (PCM1).	[31]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Pericentriolar material 1 protein (PCM1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Pericentriolar material 1 protein (PCM1).	[32]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Pericentriolar material 1 protein (PCM1).	[34]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Pericentriolar material 1 protein (PCM1).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Pericentriolar material 1 protein (PCM1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Pericentriolar material 1 protein (PCM1).	[33]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Pericentriolar material 1 protein (PCM1).	[33]

References

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• [2] The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression.Nat Genet. 2004 May;36(5):462-70. doi: 10.1038/ng1352. Epub 2004 Apr 25.
• [3] Candidate tumor-suppressor genes on chromosome arm 8p in early-onset and high-grade breast cancers.Oncogene. 2004 Jul 22;23(33):5697-702. doi: 10.1038/sj.onc.1207740.
• [4] A genome-wide analysis of the response to inhaled 2-agonists in chronic obstructive pulmonary disease.Pharmacogenomics J. 2016 Aug;16(4):326-35. doi: 10.1038/tpj.2015.65. Epub 2015 Oct 27.
• [5] The centriolar satellite proteins Cep72 and Cep290 interact and are required for recruitment of BBS proteins to the cilium.Mol Biol Cell. 2012 Sep;23(17):3322-35. doi: 10.1091/mbc.E12-02-0134. Epub 2012 Jul 5.
• [6] Targeted resequencing of the microRNAome and 3'UTRome reveals functional germline DNA variants with altered prevalence in epithelial ovarian cancer.Oncogene. 2015 Apr 16;34(16):2125-37. doi: 10.1038/onc.2014.117. Epub 2014 Jun 9.
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• [8] Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease.J Clin Invest. 2011 Nov;121(11):4372-82. doi: 10.1172/JCI57552. Epub 2011 Oct 10.
• [9] Biphenotypic plasma cell myeloma: two cases of plasma cell neoplasm with a coexpression of kappa and lambda light chains.Int J Clin Exp Pathol. 2015 Jul 1;8(7):8536-44. eCollection 2015.
• [10] The t(8;9)(p22;p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1-JAK2 fusion gene.Oncogene. 2005 Nov 3;24(48):7248-52. doi: 10.1038/sj.onc.1208850.
• [11] Localization of autoepitopes on the PCM-1 autoantigen using scleroderma sera with autoantibodies against the centrosome.Mol Biol Rep. 1998 Mar;25(2):111-9. doi: 10.1023/a:1006814217037.
• [12] RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma.Oncogene. 2000 Aug 31;19(37):4236-42. doi: 10.1038/sj.onc.1203772.
• [13] Zika virus increases mind bomb 1 levels, causing degradation of pericentriolar material 1 (PCM1) and dispersion of PCM1-containing granules from the centrosome.J Biol Chem. 2019 Dec 6;294(49):18742-18755. doi: 10.1074/jbc.RA119.010973. Epub 2019 Oct 30.
• [14] Myeloid neoplasms with eosinophilia.Blood. 2017 Feb 9;129(6):704-714. doi: 10.1182/blood-2016-10-695973. Epub 2016 Dec 27.
• [15] t(8;9)(p22;p24)/PCM1-JAK2 activates SOCS2 and SOCS3 via STAT5.PLoS One. 2013;8(1):e53767. doi: 10.1371/journal.pone.0053767. Epub 2013 Jan 23.
• [16] 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.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] 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.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] 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.
• [23] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [24] 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.
• [25] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [26] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [28] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [29] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [30] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [31] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [32] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [33] 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.
• [34] 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.
• [35] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [36] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.