Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQMLEE1)

• DOT Name: Proline-rich nuclear receptor coactivator 1 (PNRC1)
• Synonyms: Proline-rich protein 2; Protein B4-2
• Gene Name: PNRC1
• Related Disease:
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Neoplasm
  Orofacial cleft
  Otofaciocervical syndrome 1
• UniProt ID: PNRC1_HUMAN
• Pfam ID: PF15365
• Sequence:
  MTVVSVPQREPLVLGGRLAPLGFSSRGYFGALPMVTTAPPPLPRIPDPRALPPTLFLPHF
  LGGDGPCLTPQPRAPAALPNRSLAVAGGTPRAAPKKRRKKKVRASPAGQLPSRFHQYQQH
  RPSLEGGRSPATGPSGAQEVPGPAAALAPSPAAAAGTEGASPDLAPLRPAAPGQTPLRKE
  VLKSKMGKSEKIALPHGQLVHGIHLYEQPKINRQKSKYNLPLTKITSAKRNENNFWQDSV
  SSDRIQKQEKKPFKNTENIKNSHLKKSAFLTEVSQKENYAGAKFSDPPSPSVLPKPPSHW
  MGSTVENSNQNRELMAVHLKTLLKVQT
• Function: Nuclear receptor coactivator. May play a role in signal transduction.
• Tissue Specificity: Expressed in liver, lung, fat and NK/T cells.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Orofacial cleft	DIST1HG6	Strong	Genetic Variation	[3]
Otofaciocervical syndrome 1	DISZJB3G	Strong	Genetic Variation	[3]

24 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 Proline-rich nuclear receptor coactivator 1 (PNRC1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[15]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[16]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[17]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[18]
Bexarotene	DMOBIKY	Approved	Bexarotene increases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[10]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[25]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[18]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[26]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug increases the expression of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Proline-rich nuclear receptor coactivator 1 (PNRC1).	[24]

References

• [1] MRNA expression of genes altered by 5-azacytidine treatment in cancer cell lines is associated with clinicopathological parameters of human cancers.J Cancer Res Clin Oncol. 2001 Dec;127(12):697-706. doi: 10.1007/s004320100284.
• [2] Tumor suppressor PNRC1 blocks rRNA maturation by recruiting the decapping complex to the nucleolus.EMBO J. 2018 Dec 3;37(23):e99179. doi: 10.15252/embj.201899179. Epub 2018 Oct 29.
• [3] Association analysis of the poliovirus receptor related-2 gene in patients with nonsyndromic cleft lip with or without cleft palate.DNA Cell Biol. 2010 Nov;29(11):681-5. doi: 10.1089/dna.2010.1061. Epub 2010 Jul 27.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [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] 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.
• [15] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [16] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [17] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [18] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [19] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [22] BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin Cancer Res. 2014 Feb 15;20(4):912-25.
• [23] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [24] 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.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [26] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.