Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIRCB6I)

• DOT Name: Pleckstrin homology-like domain family B member 1 (PHLDB1)
• Synonyms: Protein LL5-alpha
• Gene Name: PHLDB1
• Related Disease:
  Adult glioblastoma
  Breast cancer
  Breast carcinoma
  Central nervous system neoplasm
  Coeliac disease
  Glioma
  IgA nephropathy
  Nasopharyngeal carcinoma
  Primary sclerosing cholangitis
  Systemic lupus erythematosus
  Glioblastoma multiforme
  Malignant glioma
  Mixed glioma
• UniProt ID: PHLB1_HUMAN
• Pfam ID: PF00498 ; PF00169
• Sequence:
  MDALNRNQIGPGCQTQTMVQKGPLDLIETGKGLKVQTDKPHLVSLGSGRLSTAITLLPLE
  EGRTVIGSAARDISLQGPGLAPEHCYIENLRGTLTLYPCGNACTIDGLPVRQPTRLTQGC
  MLCLGQSTFLRFNHPAEAKWMKSMIPAGGRAPGPPYSPVPAESESLVNGNHTPQTATRGP
  SACASHSSLVSSIEKDLQEIMDSLVLEEPGAAGKKPAATSPLSPMANGGRYLLSPPTSPG
  AMSVGSSYENTSPAFSPLSSPASSGSCASHSPSGQEPGPSVPPLVPARSSSYHLALQPPQ
  SRPSGARSESPRLSRKGGHERPPSPGLRGLLTDSPAATVLAEARRATESPRLGGQLPVVA
  ISLSEYPASGALSQPTSIPGSPKFQPPVPAPRNKIGTLQDRPPSPFREPPGSERVLTTSP
  SRQLVGRTFSDGLATRTLQPPESPRLGRRGLDSMRELPPLSPSLSRRALSPLPTRTTPDP
  KLNREVAESPRPRRWAAHGASPEDFSLTLGARGRRTRSPSPTLGESLAPHKGSFSGRLSP
  AYSLGSLTGASPCQSPCVQRKLSSGDLRVPVTRERKNSITEISDNEDDLLEYHRRQRQER
  LREQEMERLERQRLETILNLCAEYSRADGGPEAGELPSIGEATAALALAGRRPSRGLAGA
  SGRSSEEPGVATQRLWESMERSDEENLKEECSSTESTQQEHEDAPSTKLQGEVLALEEER
  AQVLGHVEQLKVRVKELEQQLQESAREAEMERALLQGEREAERALLQKEQKAVDQLQEKL
  VALETGIQKERDKEAEALETETKLFEDLEFQQLERESRVEEERELAGQGLLRSKAELLRS
  IAKRKERLAILDSQAGQIRAQAVQESERLARDKNASLQLLQKEKEKLTVLERRYHSLTGG
  RPFPKTTSTLKEMEKLLLPAVDLEQWYQELMAGLGTGPAAASPHSSPPPLPAKASRQLQV
  YRSKMDGEATSPLPRTRSGPLPSSSGSSSSSSQLSVATLGRSPSPKSALLTQNGTGSLPR
  NLAATLQDIETKRQLALQQKGQQVIEEQRRRLAELKQKAAAEAQCQWDALHGAAPFPAGP
  SGFPPLMHHSILHHLPAGRERGEEGEHAYDTLSLESSDSMETSISTGGNSACSPDNMSSA
  SGLDMGKIEEMEKMLKEAHAEKNRLMESREREMELRRQALEEERRRREQVERRLQSESAR
  RQQLVEKEVKMREKQFSQARPLTRYLPIRKEDFDLKTHIESSGHGVDTCLHVVLSSKVCR
  GYLVKMGGKIKSWKKRWFVFDRLKRTLSYYVDKHETKLKGVIYFQAIEEVYYDHLRSAAK
  KRFFRFTMVTESPNPALTFCVKTHDRLYYMVAPSAEAMRIWMDVIVTGAEGYTQFMN

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 glioblastoma	DISVP4LU	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Central nervous system neoplasm	DISFC18W	Strong	Genetic Variation	[3]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[4]
Glioma	DIS5RPEH	Strong	Genetic Variation	[5]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[6]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[7]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Genetic Variation	[8]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[9]
Glioblastoma multiforme	DISK8246	Limited	Genetic Variation	[5]
Malignant glioma	DISFXKOV	Limited	Biomarker	[10]
Mixed glioma	DIS64UY3	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Pleckstrin homology-like domain family B member 1 (PHLDB1) increases the Metabolic disorder ADR of Chlorothiazide.	[21]

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 Pleckstrin homology-like domain family B member 1 (PHLDB1).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Pleckstrin homology-like domain family B member 1 (PHLDB1).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Pleckstrin homology-like domain family B member 1 (PHLDB1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Pleckstrin homology-like domain family B member 1 (PHLDB1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Pleckstrin homology-like domain family B member 1 (PHLDB1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pleckstrin homology-like domain family B member 1 (PHLDB1).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Pleckstrin homology-like domain family B member 1 (PHLDB1).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Pleckstrin homology-like domain family B member 1 (PHLDB1).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Pleckstrin homology-like domain family B member 1 (PHLDB1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Pleckstrin homology-like domain family B member 1 (PHLDB1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Pleckstrin homology-like domain family B member 1 (PHLDB1).	[20]

References

• [1] Association of sequence variants on chromosomes 20, 11, and 5 (20q13.33, 11q23.3, and 5p15.33) with glioma susceptibility in a Chinese population.Am J Epidemiol. 2011 Apr 15;173(8):915-22. doi: 10.1093/aje/kwq457. Epub 2011 Feb 24.
• [2] Role of Polymorphisms of FAM13A, PHLDB1, and CYP24A1 in Breast Cancer Risk.Curr Mol Med. 2019;19(8):579-588. doi: 10.2174/1566524019666190619125109.
• [3] Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors.Nat Genet. 2017 May;49(5):789-794. doi: 10.1038/ng.3823. Epub 2017 Mar 27.
• [4] Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci.Eur J Hum Genet. 2016 Feb;24(2):291-7. doi: 10.1038/ejhg.2015.87. Epub 2015 Apr 29.
• [5] Replication of GWAS identifies RTEL1, CDKN2A/B, and PHLDB1 SNPs as risk factors in Portuguese gliomas patients.Mol Biol Rep. 2020 Feb;47(2):877-886. doi: 10.1007/s11033-019-05178-8. Epub 2019 Nov 12.
• [6] 3'UTR variants of TNS3, PHLDB1, NTN4, and GNG2 genes are associated with IgA nephropathy risk in Chinese Han population.Int Immunopharmacol. 2019 Jun;71:295-300. doi: 10.1016/j.intimp.2019.03.041. Epub 2019 Mar 28.
• [7] A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet. 2010 Jul;42(7):599-603. doi: 10.1038/ng.601. Epub 2010 May 30.
• [8] Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.Nat Genet. 2013 Jun;45(6):670-5. doi: 10.1038/ng.2616. Epub 2013 Apr 21.
• [9] Three SNPs in chromosome 11q23.3 are independently associated with systemic lupus erythematosus in Asians.Hum Mol Genet. 2014 Jan 15;23(2):524-33. doi: 10.1093/hmg/ddt424. Epub 2013 Sep 2.
• [10] Genome-wide association study identifies five susceptibility loci for glioma.Nat Genet. 2009 Aug;41(8):899-904. doi: 10.1038/ng.407. Epub 2009 Jul 5.
• [11] 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.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [14] 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.
• [15] Quantitative proteomic analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS. 2009 Apr;13(2):93-103. doi: 10.1089/omi.2008.0075.
• [16] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] 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.
• [20] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [21] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.