Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTN49JK)

• DOT Name: WD repeat domain phosphoinositide-interacting protein 4
• Synonyms: WIPI-4; WD repeat-containing protein 45
• Gene Name: WDR45
• Related Disease:
  Neurodegeneration with brain iron accumulation 5
  X-linked complex neurodevelopmental disorder
  West syndrome
• UniProt ID: WIPI4_HUMAN
• Pfam ID: PF21032
• Sequence:
  MTQQPLRGVTSLRFNQDQSCFCCAMETGVRIYNVEPLMEKGHLDHEQVGSMGLVEMLHRS
  NLLALVGGGSSPKFSEISVLIWDDAREGKDSKEKLVLEFTFTKPVLSVRMRHDKIVIVLK
  NRIYVYSFPDNPRKLFEFDTRDNPKGLCDLCPSLEKQLLVFPGHKCGSLQLVDLASTKPG
  TSSAPFTINAHQSDIACVSLNQPGTVVASASQKGTLIRLFDTQSKEKLVELRRGTDPATL
  YCINFSHDSSFLCASSDKGTVHIFALKDTRLNRRSALARVGKVGPMIGQYVDSQWSLASF
  TVPAESACICAFGRNTSKNVNSVIAICVDGTFHKYVFTPDGNCNREAFDVYLDICDDDDF
• Function: Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation. Binds phosphatidylinositol 3-phosphate (PtdIns3P). Activated by the STK11/AMPK signaling pathway upon starvation, WDR45 is involved in autophagosome assembly downstream of WIPI2, regulating the size of forming autophagosomes. Together with WIPI1, promotes ATG2 (ATG2A or ATG2B)-mediated lipid transfer by enhancing ATG2-association with phosphatidylinositol 3-monophosphate (PI3P)-containing membranes. Probably recruited to membranes through its PtdIns3P activity.
• Tissue Specificity: Ubiquitously expressed, with high expression in skeletal muscle and heart. Weakly expressed in liver and placenta. Expression is down-regulated in pancreatic and in kidney tumors.
• KEGG Pathway: Autophagy - animal (hsa04140)
• Reactome Pathway: Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodegeneration with brain iron accumulation 5	DISW9SFJ	Definitive	X-linked	[1]
X-linked complex neurodevelopmental disorder	DISI3QE9	Definitive	X-linked	[2]
West syndrome	DISLIAU9	Supportive	Autosomal dominant	[3]

13 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of WD repeat domain phosphoinositide-interacting protein 4.	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of WD repeat domain phosphoinositide-interacting protein 4.	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of WD repeat domain phosphoinositide-interacting protein 4.	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of WD repeat domain phosphoinositide-interacting protein 4.	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of WD repeat domain phosphoinositide-interacting protein 4.	[8]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of WD repeat domain phosphoinositide-interacting protein 4.	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of WD repeat domain phosphoinositide-interacting protein 4.	[10]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of WD repeat domain phosphoinositide-interacting protein 4.	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of WD repeat domain phosphoinositide-interacting protein 4.	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of WD repeat domain phosphoinositide-interacting protein 4.	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of WD repeat domain phosphoinositide-interacting protein 4.	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of WD repeat domain phosphoinositide-interacting protein 4.	[17]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of WD repeat domain phosphoinositide-interacting protein 4.	[18]

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 WD repeat domain phosphoinositide-interacting protein 4.	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of WD repeat domain phosphoinositide-interacting protein 4.	[14]

References

• [1] Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am J Hum Genet. 2012 Dec 7;91(6):1144-9. doi: 10.1016/j.ajhg.2012.10.019. Epub 2012 Nov 21.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] WDR45 mutations in three male patients with West syndrome. J Hum Genet. 2016 Jul;61(7):653-61. doi: 10.1038/jhg.2016.27. Epub 2016 Mar 31.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [12] 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.
• [13] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [14] 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.
• [15] 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.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] 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.
• [18] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.