Details of Drug Off-Target (DOT)

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

• DOT Name: Pleckstrin homology domain-containing family A member 4 (PLEKHA4)
• Synonyms: PH domain-containing family A member 4; Phosphoinositol 3-phosphate-binding protein 1; PEPP-1
• Gene Name: PLEKHA4
• Related Disease: Pneumocystis pneumonia
• UniProt ID: PKHA4_HUMAN
• PDB ID: 1UPQ; 1UPR
• Pfam ID: PF00169
• Sequence:
  MEGSRPRSSLSLASSASTISSLSSLSPKKPTRAVNKIHAFGKRGNALRRDPNLPVHIRGW
  LHKQDSSGLRLWKRRWFVLSGHCLFYYKDSREESVLGSVLLPSYNIRPDGPGAPRGRRFT
  FTAEHPGMRTYVLAADTLEDLRGWLRALGRASRAEGDDYGQPRSPARPQPGEGPGGPGGP
  PEVSRGEEGRISESPEVTRLSRGRGRPRLLTPSPTTDLHSGLQMRRARSPDLFTPLSRPP
  SPLSLPRPRSAPARRPPAPSGDTAPPARPHTPLSRIDVRPPLDWGPQRQTLSRPPTPRRG
  PPSEAGGGKPPRSPQHWSQEPRTQAHSGSPTYLQLPPRPPGTRASMVLLPGPPLESTFHQ
  SLETDTLLTKLCGQDRLLRRLQEEIDQKQEEKEQLEAALELTRQQLGQATREAGAPGRAW
  GRQRLLQDRLVSVRATLCHLTQERERVWDTYSGLEQELGTLRETLEYLLHLGSPQDRVSA
  QQQLWMVEDTLAGLGGPQKPPPHTEPDSPSPVLQGEESSERESLPESLELSSPRSPETDW
  GRPPGGDKDLASPHLGLGSPRVSRASSPEGRHLPSPQLGTKAPVARPRMSAQEQLERMRR
  NQECGRPFPRPTSPRLLTLGRTLSPARRQPDVEQRPVVGHSGAQKWLRSSGSWSSPRNTT
  PYLPTSEGHRERVLSLSQALATEASQWHRMMTGGNLDSQGDPLPGVPLPPSDPTRQETPP
  PRSPPVANSGSTGFSRRGSGRGGGPTPWGPAWDAGIAPPVLPQDEGAWPLRVTLLQSSF
• Function: Binds specifically to phosphatidylinositol 3-phosphate (PtdIns3P), but not to other phosphoinositides.
• Tissue Specificity: Highly expressed in melanoma. Detected at low levels in heart, skeletal muscle, kidney, liver and small intestine.
• Reactome Pathway: Synthesis of PIPs at the plasma membrane (R-HSA-1660499)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pneumocystis pneumonia	DISFSOM3	Limited	Biomarker	[1]

7 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 Pleckstrin homology domain-containing family A member 4 (PLEKHA4).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pleckstrin homology domain-containing family A member 4 (PLEKHA4).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Pleckstrin homology domain-containing family A member 4 (PLEKHA4).	[4]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Pleckstrin homology domain-containing family A member 4 (PLEKHA4).	[5]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Pleckstrin homology domain-containing family A member 4 (PLEKHA4).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Pleckstrin homology domain-containing family A member 4 (PLEKHA4).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Pleckstrin homology domain-containing family A member 4 (PLEKHA4).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Pleckstrin homology domain-containing family A member 4 (PLEKHA4).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Pleckstrin homology domain-containing family A member 4 (PLEKHA4).	[10]

References

• [1] PLEKHA4/kramer Attenuates Dishevelled Ubiquitination to Modulate Wnt and Planar Cell Polarity Signaling.Cell Rep. 2019 May 14;27(7):2157-2170.e8. doi: 10.1016/j.celrep.2019.04.060.
• [2] 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.
• [3] 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.
• [4] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [5] 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.
• [6] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [7] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [8] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [9] 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.
• [10] 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.