Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY2AP6T)

• DOT Name: Pleckstrin homology domain-containing family A member 2 (PLEKHA2)
• Synonyms: PH domain-containing family A member 2; Tandem PH domain-containing protein 2; TAPP-2
• Gene Name: PLEKHA2
• Related Disease:
  Esophageal squamous cell carcinoma
  Adult lymphoma
  Lymphoma
  Pediatric lymphoma
• UniProt ID: PKHA2_HUMAN
• Pfam ID: PF00169
• Sequence:
  MPYVDRQNRICGFLDIEEHENSGKFLRRYFILDTQANCLLWYMDNPQNLAMGAGAVGALQ
  LTYISKVSIATPKQKPKTPFCFVINALSQRYFLQANDQKDMKDWVEALNQASKITVPKGG
  GLPMTTEVLKSLAAPPALEKKPQVAYKTEIIGGVVVHTPISQNGGDGQEGSEPGSHTILR
  RSQSYIPTSGCRASTGPPLIKSGYCVKQGNVRKSWKRRFFALDDFTICYFKCEQDREPLR
  TIFLKDVLKTHECLVKSGDLLMRDNLFEIITSSRTFYVQADSPEDMHSWIKEIGAAVQAL
  KCHPRETSFSRSISLTRPGSSSLSSGPNSILCRGRPPLEEKKALCKAPSVASSWQPWTPV
  PQAGEKLLPPGDTSEDSLFTPRPGEGSAPGVLPSSRIRHRSEPQHPKEKPFMFNLDDENI
  RTSDV
• Function: Binds specifically to phosphatidylinositol 3,4-diphosphate (PtdIns3,4P2), but not to other phosphoinositides. May recruit other proteins to the plasma membrane.
• Tissue Specificity: Highly expressed in heart, kidney, spleen and peripheral blood leukocytes. Detected at lower levels in brain, skeletal muscle, colon, thymus, liver, small intestine, placenta and lung.
• Reactome Pathway: Synthesis of PIPs at the plasma membrane (R-HSA-1660499)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[1]
Adult lymphoma	DISK8IZR	Limited	Biomarker	[2]
Lymphoma	DISN6V4S	Limited	Biomarker	[2]
Pediatric lymphoma	DIS51BK2	Limited	Biomarker	[2]

24 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 Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[13]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[14]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[15]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[18]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[22]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[26]

3 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 decreases the methylation of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[19]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Pleckstrin homology domain-containing family A member 2 (PLEKHA2).	[23]

References

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• [2] TAPP1 and TAPP2 are targets of phosphatidylinositol 3-kinase signaling in B cells: sustained plasma membrane recruitment triggered by the B-cell antigen receptor.Mol Cell Biol. 2002 Aug;22(15):5479-91. doi: 10.1128/MCB.22.15.5479-5491.2002.
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• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] 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.
• [15] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [16] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
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• [19] 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.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [21] 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.
• [22] 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.
• [23] 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.
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