Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWE5G4T)

• DOT Name: Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1)
• Synonyms: PI3K-interacting protein 1; Kringle domain-containing protein HGFL
• Gene Name: PIK3IP1
• Related Disease:
  Acute liver failure
  Breast cancer
  Breast carcinoma
  Carcinoid tumor
  Mantle cell lymphoma
  Narcolepsy
  Neoplasm
  Psoriasis
  Small-cell lung cancer
  Advanced cancer
• UniProt ID: P3IP1_HUMAN
• Pfam ID: PF00051
• Sequence:
  MLLAWVQAFLVSNMLLAEAYGSGGCFWDNGHLYREDQTSPAPGLRCLNWLDAQSGLASAP
  VSGAGNHSYCRNPDEDPRGPWCYVSGEAGVPEKRPCEDLRCPETTSQALPAFTTEIQEAS
  EGPGADEVQVFAPANALPARSEAAAVQPVIGISQRVRMNSKEKKDLGTLGYVLGITMMVI
  IIAIGAGIILGYSYKRGKDLKEQHDQKVCEREMQRITLPLSAFTNPTCEIVDEKTVVVHT
  SQTPVDPQEGTTPLMGQAGTPGA
• Function: Negative regulator of hepatic phosphatidylinositol 3-kinase (PI3K) activity.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute liver failure	DIS5EZKX	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Carcinoid tumor	DISMNRDC	Strong	Altered Expression	[3]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[4]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Psoriasis	DIS59VMN	Strong	Biomarker	[7]
Small-cell lung cancer	DISK3LZD	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Disputed	Biomarker	[8]

22 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 Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[15]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[15]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[16]
Marinol	DM70IK5	Approved	Marinol increases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[17]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[18]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[19]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[20]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[21]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[21]
Idelalisib	DM602WT	Approved	Idelalisib increases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[4]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[23]
GDC0941	DM1YAK6	Phase 2	GDC0941 increases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[24]
GDC-0980/RG7422	DMF3MV1	Phase 2	GDC-0980/RG7422 increases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[27]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1).	[14]

References

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• [2] HGFL-mediated RON signaling supports breast cancer stem cell phenotypes via activation of non-canonical -catenin signaling.Oncotarget. 2017 Jul 22;8(35):58918-58933. doi: 10.18632/oncotarget.19441. eCollection 2017 Aug 29.
• [3] Differential screening of a human chromosome 3 library identifies hepatocyte growth factor-like/macrophage-stimulating protein and its receptor in injured lung. Possible implications for neuroendocrine cell survival.J Clin Invest. 1997 Jun 15;99(12):2979-91. doi: 10.1172/JCI119493.
• [4] Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3K inhibition through PIK3IP1. Cell Cycle. 2013 Jun 15;12(12):1892-900. doi: 10.4161/cc.24928. Epub 2013 May 15.
• [5] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [6] Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity.Clin Cancer Res. 2019 Oct 15;25(20):6180-6194. doi: 10.1158/1078-0432.CCR-18-4134. Epub 2019 Jul 26.
• [7] Fumaric acid esters for psoriasis: a systematic review.Ir J Med Sci. 2017 Feb;186(1):161-177. doi: 10.1007/s11845-016-1470-2. Epub 2016 Jun 7.
• [8] Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality.Nat Commun. 2017 Dec 19;8(1):2200. doi: 10.1038/s41467-017-02287-5.
• [9] 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.
• [10] 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.
• [11] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [18] 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.
• [19] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [20] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [21] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [22] Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3K inhibition through PIK3IP1. Cell Cycle. 2013 Jun 15;12(12):1892-900. doi: 10.4161/cc.24928. Epub 2013 May 15.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models. Clin Cancer Res. 2012 Dec 15;18(24):6771-83. doi: 10.1158/1078-0432.CCR-12-2347. Epub 2012 Nov 7.
• [25] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [26] 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.
• [27] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [28] Effects of nickel treatment on H3K4 trimethylation and gene expression. PLoS One. 2011 Mar 24;6(3):e17728. doi: 10.1371/journal.pone.0017728.