Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3TK3NN)

• DOT Name: Pleckstrin homology domain-containing family H member 2 (PLEKHH2)
• Gene Name: PLEKHH2
• Related Disease:
  Diabetic kidney disease
  Focal segmental glomerulosclerosis
  High blood pressure
  Type-1/2 diabetes
• UniProt ID: PKHH2_HUMAN
• Pfam ID: PF00373 ; PF00784 ; PF00169
• Sequence:
  MAELSEPEGPVDWKERCVALESQLMKFRVQASKIRELLAEKMQQLERQVIDAERQAEKAF
  QQVQVMEDKLKAANIQTSESETRLYNKCQDLESLIQEKDDVIQNLELQLEEQKQIRIQEA
  KIIEEKAAKIKEWVTVKLNELELENQNLRLINQNQTEEIRTMQSKLQEVQGKKSSTVSTL
  KLSEGQRLSSLTFGCFLSRARSPPQVVKSEEMSKISSKEPEFTEGKDMEEMEIPEKSVDN
  QVLENNRGQRTLHQTPCGSEQNRKTRTSFATDGGISQNSGAPVSDWSSDEEDGSKGRSKS
  RCTSTLSSHTSEEGVQCSRMGSEMYLTASDDSSSIFEEETFGIKRPEHKKLYSWQQEAQW
  KALNSPLGKGNSELSKKEQDSSSDELNKKFQSQRLDYSSSSSEANTPSPILTPALMPKHP
  NSLSGKGTQLVPSSHLPPPKLRIPNVFSISVALAKRHLSQPQLSSDRMFGTNRNAISMIR
  PLRPQETDLDLVDGDSTEVLENMDTSCDDGLFSYDSLDSPNSDDQEHCDSAKKVAYSKPP
  TPPLHRFPSWESRIYAVAKSGIRMSEAFNMESVNKNSAATLSYTTSGLYTSLIYKNMTTP
  VYTTLKGKATQISSSPFLDDSSGSEEEDSSRSSSRTSESDSRSRSGPGSPRAMKRGVSLS
  SVASESDYAIPPDAYSTDTEYSQPEQKLPKTCSSSSDNGKNEPLEKSGYLLKMSGKVKSW
  KRRWFVLKGGELLYYKSPSDVIRKPQGHIELSASCSILRGDNKQTVQLTTEKHTYYLTAD
  SPNILEEWIKVLQNVLRVQAANPLSLQPEGKPTMKGLLTKVKHGYSKRVWCTLIGKTLYY
  FRSQEDKFPLGQIKLWEAKVEEVDRSCDSDEDYEASGRSLLSTHYTIVIHPKDQGPTYLL
  IGSKHEKDTWLYHLTVAAGSNNVNVGSEFEQLVCKLLNIDGEPSSQIWRHPTLCHSKEGI
  ISPLTTLPSEALQTEAIKLFKTCQLFINAAVDSPAIDYHISLAQSALQICLTHPELQNEI
  CCQLIKQTRRRQPQNQPGPLQGWQLLALCVGLFLPHHPFLWLLRLHLKRNADSRTEFGKY
  AIYCQRCVERTQQNGDREARPSRMEILSTLLRNPYHHSLPFSIPVHFMNGIYQVVGFDAS
  TTVEEFLNTLNQDTGMRKPAQSGFALFTDDPSGRDLEHCLQGNIKICDIISKWEQASKEQ
  QPGKCEGTRTVRLTYKNRLYFSVQARGETDREKLLLMYQTNDQIINGLFPLNKDLALEMA
  ALLSQVEIGDFERPFSTPAGHVTNQCKVNQTLKQVIEKFYPKRYRDGCSEEQLRQLCQRL
  STRWMALRGHSAADCVRIYLTVARKWPFFGAKLFLAKPITPSSLGSTFLWLAVHEDGLSL
  LEYNSMRLIVSYVYKSLMTFGGYQDDFMVVINNTHSKDKPTEKLLFAMAKPKILEITLLI
  ASYINNFHQQKAAFHHLSAPALLSAQTRGPQARMMGSQPLLSSSRPTKGPTLL
• Function: In the kidney glomerulus may play a role in linking podocyte foot processes to the glomerular basement membrane. May be involved in stabilization of F-actin by attenuating its depolymerization. Can recruit TGFB1I1 from focal adhesions to podocyte lamellipodia.
• Tissue Specificity: Kidney. Reduced expression in patients with focal segmental glomerulosclerosis.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetic kidney disease	DISJMWEY	Strong	Altered Expression	[1]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Altered Expression	[2]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[3]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[3]

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 Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[13]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[11]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[18]

1 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 affects the methylation of Pleckstrin homology domain-containing family H member 2 (PLEKHH2).	[16]

References

• [1] Sequence variants in the PLEKHH2 region are associated with diabetic nephropathy in the GoKinD study population.Hum Genet. 2008 Oct;124(3):255-62. doi: 10.1007/s00439-008-0548-y. Epub 2008 Aug 28.
• [2] Plekhh2, a novel podocyte protein downregulated in human focal segmental glomerulosclerosis, is involved in matrix adhesion and actin dynamics.Kidney Int. 2012 Nov;82(10):1071-83. doi: 10.1038/ki.2012.252. Epub 2012 Jul 25.
• [3] Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes.Pharmacogenomics J. 2018 Jan;18(1):106-112. doi: 10.1038/tpj.2016.67. Epub 2016 Sep 27.
• [4] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [11] 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.
• [12] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [13] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [14] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [15] Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol. 2008 Sep;39(3):312-23. doi: 10.1165/rcmb.2008-0012OC. Epub 2008 Apr 17.
• [16] 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.
• [17] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [18] 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.