Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXFUDO2)

• DOT Name: Pleckstrin homology-like domain family A member 3 (PHLDA3)
• Synonyms: TDAG51/Ipl homolog 1
• Gene Name: PHLDA3
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Congestive heart failure
  Esophageal squamous cell carcinoma
  Lung cancer
  Neoplasm
  Neuroendocrine neoplasm
  Squamous cell carcinoma
• UniProt ID: PHLA3_HUMAN
• Pfam ID: PF00169
• Sequence:
  MTAAATATVLKEGVLEKRSGGLLQLWKRKRCVLTERGLQLFEAKGTGGRPKELSFARIKA
  VECVESTGRHIYFTLVTEGGGEIDFRCPLEDPGWNAQITLGLVKFKNQQAIQTVRARQSL
  GTGTLVS
• Function: p53/TP53-regulated repressor of Akt/AKT1 signaling. Represses AKT1 by preventing AKT1-binding to membrane lipids, thereby inhibiting AKT1 translocation to the cellular membrane and activation. Contributes to p53/TP53-dependent apoptosis by repressing AKT1 activity. Its direct transcription regulation by p53/TP53 may explain how p53/TP53 can negatively regulate AKT1. May act as a tumor suppressor.
• Tissue Specificity: Widely expressed with lowest expression in liver and spleen.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Neuroendocrine neoplasm	DISNPLOO	Strong	Genetic Variation	[6]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[1]

23 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-like domain family A member 3 (PHLDA3).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[15]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[17]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[18]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[19]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[17]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[17]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[20]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea increases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[20]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[17]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[25]

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 decreases the methylation of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Pleckstrin homology-like domain family A member 3 (PHLDA3).	[24]

References

• [1] Low PHLDA3 expression in oesophageal squamous cell carcinomas is associated with poor prognosis.Anticancer Res. 2015 Feb;35(2):949-54.
• [2] IPH-926 lobular breast cancer cells harbor a p53 mutant with temperature-sensitive functional activity and allow for profiling of p53-responsive genes.Lab Invest. 2012 Nov;92(11):1635-47. doi: 10.1038/labinvest.2012.126. Epub 2012 Sep 3.
• [3] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [4] Novel Role for Pleckstrin Homology-Like Domain Family A, Member 3 in the Regulation of Pathological Cardiac Hypertrophy.J Am Heart Assoc. 2019 Aug 20;8(16):e011830. doi: 10.1161/JAHA.118.011830. Epub 2019 Aug 20.
• [5] PH domain-only protein PHLDA3 is a p53-regulated repressor of Akt.Cell. 2009 Feb 6;136(3):535-50. doi: 10.1016/j.cell.2008.12.002.
• [6] A vicious partnership between AKT and PHLDA3 to facilitate neuroendocrine tumors.Cancer Sci. 2017 Jun;108(6):1101-1108. doi: 10.1111/cas.13235. Epub 2017 May 22.
• [7] 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.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
• [13] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [14] 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.
• [15] 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.
• [16] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [17] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [18] Transcriptional profiling of MCF7 breast cancer cells in response to 5-Fluorouracil: relationship with cell cycle changes and apoptosis, and identification of novel targets of p53. Int J Cancer. 2006 Sep 1;119(5):1164-75.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] 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.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [24] 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.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.