Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9ITT3P)

• DOT Name: Proline-rich membrane anchor 1 (PRIMA1)
• Synonyms: PRiMA
• Gene Name: PRIMA1
• Related Disease:
  Acute myelogenous leukaemia
  Follicular lymphoma
  Glioblastoma multiforme
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  Alzheimer disease
  Bladder cancer
  Breast neoplasm
  Cholangiocarcinoma
  Congenital contractural arachnodactyly
  Congestive heart failure
  EEC syndrome
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Ewing sarcoma
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Myelodysplastic syndrome
  Non-small-cell lung cancer
  Pancreatic cancer
  Precancerous condition
  Small-cell lung cancer
  Trigeminal neuralgia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Adult glioblastoma
  Recessive X-linked ichthyosis
  Sarcoma
  Small lymphocytic lymphoma
  Soft tissue sarcoma
  Neuroblastoma
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Breast cancer
  Breast carcinoma
  Melanoma
  Muscular dystrophy
  Plasma cell myeloma
  Waldenstrom macroglobulinemia
• UniProt ID: PRIMA_HUMAN
• Pfam ID: PF16101
• Sequence:
  MLLRDLVLRRGCCWSSLLLHCALHPLWGFVQVTHGEPQKSCSKVTDSCRHVCQCRPPPPL
  PPPPPPPPPPRLLSAPAPNSTSCPTEESWWSGLVIIIAVCCASLVFLTVLVIICYKAIKR
  KPLRKDENGTSVAEYPMSASQSNKGVDVNNAVV
• Function: Required to anchor acetylcholinesterase (ACHE) to the basal lamina of the neuromuscular junction and to the membrane of neuronal synapses in brain. Also able to organize ACHE into tetramers.

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Genetic Variation	[1]
Follicular lymphoma	DISVEUR6	Definitive	Biomarker	[2]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[3]
Prostate cancer	DISF190Y	Definitive	Genetic Variation	[4]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Bladder cancer	DISUHNM0	Strong	Biomarker	[7]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[8]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[9]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Biomarker	[9]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[10]
EEC syndrome	DISIYS7L	Strong	Genetic Variation	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[12]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[13]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[15]
Lung cancer	DISCM4YA	Strong	Biomarker	[16]
Lung carcinoma	DISTR26C	Strong	Biomarker	[16]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[17]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[18]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[19]
Precancerous condition	DISV06FL	Strong	Biomarker	[20]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[21]
Trigeminal neuralgia	DIS31ZY6	Strong	Genetic Variation	[22]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[7]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[7]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[3]
Recessive X-linked ichthyosis	DISZY56W	moderate	Altered Expression	[23]
Sarcoma	DISZDG3U	moderate	Biomarker	[23]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[24]
Soft tissue sarcoma	DISSN8XB	moderate	Biomarker	[23]
Neuroblastoma	DISVZBI4	Disputed	Biomarker	[25]
Thyroid cancer	DIS3VLDH	Disputed	Posttranslational Modification	[26]
Thyroid gland carcinoma	DISMNGZ0	Disputed	Posttranslational Modification	[26]
Thyroid tumor	DISLVKMD	Disputed	Posttranslational Modification	[26]
Breast cancer	DIS7DPX1	Limited	Biomarker	[27]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[27]
Melanoma	DIS1RRCY	Limited	Genetic Variation	[28]
Muscular dystrophy	DISJD6P7	Limited	Biomarker	[29]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[30]
Waldenstrom macroglobulinemia	DIS9O23I	Limited	Biomarker	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Proline-rich membrane anchor 1 (PRIMA1) increases the Insomnia ADR of Chlorothiazide.	[44]

15 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 Proline-rich membrane anchor 1 (PRIMA1).	[32]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Proline-rich membrane anchor 1 (PRIMA1).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Proline-rich membrane anchor 1 (PRIMA1).	[34]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Proline-rich membrane anchor 1 (PRIMA1).	[35]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Proline-rich membrane anchor 1 (PRIMA1).	[36]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Proline-rich membrane anchor 1 (PRIMA1).	[35]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Proline-rich membrane anchor 1 (PRIMA1).	[37]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Proline-rich membrane anchor 1 (PRIMA1).	[38]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Proline-rich membrane anchor 1 (PRIMA1).	[39]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Proline-rich membrane anchor 1 (PRIMA1).	[40]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Proline-rich membrane anchor 1 (PRIMA1).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Proline-rich membrane anchor 1 (PRIMA1).	[41]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Proline-rich membrane anchor 1 (PRIMA1).	[42]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Proline-rich membrane anchor 1 (PRIMA1).	[43]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Proline-rich membrane anchor 1 (PRIMA1).	[32]

References

• [1] Synergistic effects of PRIMA-1(Met) (APR-246) and 5-azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia.Haematologica. 2020 Jun;105(6):1539-1551. doi: 10.3324/haematol.2019.218453. Epub 2019 Sep 5.
• [2] Impact of age on clinical risk scores in follicular lymphoma.Blood Adv. 2019 Apr 9;3(7):1033-1038. doi: 10.1182/bloodadvances.2019032136.
• [3] Sensitivity to PRIMA-1MET is associated with decreased MGMT in human glioblastoma cells and glioblastoma stem cells irrespective of p53 status.Oncotarget. 2016 Sep 13;7(37):60245-60269. doi: 10.18632/oncotarget.11197.
• [4] Silencing of CD24 Enhances the PRIMA-1-Induced Restoration of Mutant p53 in Prostate Cancer Cells.Clin Cancer Res. 2016 May 15;22(10):2545-54. doi: 10.1158/1078-0432.CCR-15-1927. Epub 2015 Dec 28.
• [5] PRIMA-1MET induces apoptosis through accumulation of intracellular reactive oxygen species irrespective of p53 status and chemo-sensitivity in epithelial ovarian cancer cells.Oncol Rep. 2016 May;35(5):2543-52. doi: 10.3892/or.2016.4653. Epub 2016 Mar 3.
• [6] Increased Expression of Readthrough Acetylcholinesterase Variants in the Brains of Alzheimer's Disease Patients.J Alzheimers Dis. 2016 May 30;53(3):831-41. doi: 10.3233/JAD-160220.
• [7] Prima-1 induces apoptosis in bladder cancer cell lines by activating p53.Clinics (Sao Paulo). 2013;68(3):297-303. doi: 10.6061/clinics/2013(03)oa03.
• [8] PRIMA-1 inhibits growth of breast cancer cells by re-activating mutant p53 protein.Int J Oncol. 2009 Nov;35(5):1015-23. doi: 10.3892/ijo_00000416.
• [9] PRIMA-1(MET) Induces Cellular Senescence and Apoptotic Cell Death in Cholangiocarcinoma Cells.Cancer Genomics Proteomics. 2019 Nov-Dec;16(6):543-552. doi: 10.21873/cgp.20156.
• [10] NT-proBNP (N-Terminal pro-B-Type Natriuretic Peptide)-Guided Therapy in Acute Decompensated Heart Failure: PRIMA II Randomized Controlled Trial (Can NT-ProBNP-Guided Therapy During Hospital Admission for Acute Decompensated Heart Failure Reduce Mortality and Readmissions?).Circulation. 2018 Apr 17;137(16):1671-1683. doi: 10.1161/CIRCULATIONAHA.117.029882. Epub 2017 Dec 14.
• [11] APR-246/PRIMA-1(MET) rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations.Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2157-62. doi: 10.1073/pnas.1201993110. Epub 2013 Jan 25.
• [12] PRIMA-1 induces p53-mediated apoptosis by upregulating Noxa in esophageal squamous cell carcinoma with TP53 missense mutation.Cancer Sci. 2018 Feb;109(2):412-421. doi: 10.1111/cas.13454. Epub 2017 Dec 28.
• [13] Variability in functional p53 reactivation by PRIMA-1(Met)/APR-246 in Ewing sarcoma.Br J Cancer. 2013 Nov 12;109(10):2696-704. doi: 10.1038/bjc.2013.635. Epub 2013 Oct 15.
• [14] Dysregulated cholinergic network as a novel biomarker of poor prognostic in patients with head and neck squamous cell carcinoma.BMC Cancer. 2015 May 10;15:385. doi: 10.1186/s12885-015-1402-y.
• [15] In vitro and in vivo cytotoxic effects of PRIMA-1 on hepatocellular carcinoma cells expressing mutant p53ser249.Carcinogenesis. 2008 Jul;29(7):1428-34. doi: 10.1093/carcin/bgm266. Epub 2007 Nov 28.
• [16] MicroRNA-34a is an important component of PRIMA-1-induced apoptotic network in human lung cancer cells.Int J Cancer. 2010 Jul 15;127(2):313-20. doi: 10.1002/ijc.25049.
• [17] Genome-wide DNA methylation scan in major depressive disorder.PLoS One. 2012;7(4):e34451. doi: 10.1371/journal.pone.0034451. Epub 2012 Apr 12.
• [18] APR-246 (PRIMA-1(MET)) strongly synergizes with AZD2281 (olaparib) induced PARP inhibition to induce apoptosis in non-small cell lung cancer cell lines.Cancer Lett. 2016 Jun 1;375(2):313-322. doi: 10.1016/j.canlet.2016.03.017. Epub 2016 Mar 11.
• [19] PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines.Invest New Drugs. 2014 Oct;32(5):783-94. doi: 10.1007/s10637-014-0090-9. Epub 2014 May 20.
• [20] Selective induction of apoptosis in mutant p53 premalignant and malignant cancer cells by PRIMA-1 through the c-Jun-NH2-kinase pathway.Mol Cancer Ther. 2005 Jun;4(6):901-9. doi: 10.1158/1535-7163.MCT-04-0206.
• [21] PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53.Clin Cancer Res. 2011 May 1;17(9):2830-41. doi: 10.1158/1078-0432.CCR-10-3168. Epub 2011 Mar 17.
• [22] Mutant p53: a novel target for the treatment of patients with triple-negative breast cancer?.Int J Cancer. 2017 Jan 1;140(1):234-246. doi: 10.1002/ijc.30425. Epub 2016 Sep 24.
• [23] PRIMA-1(MET) induces death in soft-tissue sarcomas cell independent of p53.BMC Cancer. 2015 Oct 13;15:684. doi: 10.1186/s12885-015-1667-1.
• [24] Mutated and non-mutated TP53 as targets in the treatment of leukaemia.Br J Haematol. 2008 May;141(4):445-53. doi: 10.1111/j.1365-2141.2008.07046.x. Epub 2008 Mar 12.
• [25] PRIMA-1(MET)-induced neuroblastoma cell death is modulated by p53 and mycn through glutathione level.J Exp Clin Cancer Res. 2019 Feb 12;38(1):69. doi: 10.1186/s13046-019-1066-6.
• [26] PRIMA-1 selectively induces global DNA demethylation in p53 mutant-type thyroid cancer cells.J Biomed Nanotechnol. 2014 Jul;10(7):1249-58. doi: 10.1166/jbn.2014.1862.
• [27] p53 reactivation with induction of massive apoptosis-1 (PRIMA-1) inhibits amyloid aggregation of mutant p53 in cancer cells.J Biol Chem. 2019 Mar 8;294(10):3670-3682. doi: 10.1074/jbc.RA118.004671. Epub 2019 Jan 2.
• [28] p53 Reactivation by PRIMA-1(Met) (APR-246) sensitises (V600E/K)BRAF melanoma to vemurafenib.Eur J Cancer. 2016 Mar;55:98-110. doi: 10.1016/j.ejca.2015.12.002. Epub 2016 Jan 17.
• [29] The AChE membrane-binding tail PRiMA is down-regulated in muscle and nerve of mice with muscular dystrophy by merosin deficiency.Chem Biol Interact. 2013 Mar 25;203(1):330-4. doi: 10.1016/j.cbi.2012.08.001. Epub 2012 Aug 10.
• [30] MiRNA-29a as a tumor suppressor mediates PRIMA-1Met-induced anti-myeloma activity by targeting c-Myc.Oncotarget. 2016 Feb 9;7(6):7149-60. doi: 10.18632/oncotarget.6880.
• [31] PRIMA-1Met induces apoptosis in Waldenstrm's Macroglobulinemia cells independent of p53.Cancer Biol Ther. 2015;16(5):799-806. doi: 10.1080/15384047.2015.1026482.
• [32] 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.
• [33] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [34] 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.
• [35] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [36] 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.
• [37] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [38] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [39] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [40] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [41] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [42] 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.
• [43] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [44] A genome-wide association study of caffeine-related sleep disturbance: confirmation of a role for a common variant in the adenosine receptor. Sleep. 2012 Jul 1;35(7):967-75. doi: 10.5665/sleep.1962.