Details of Drug Off-Target (DOT)

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

• DOT Name: Protein diaphanous homolog 2 (DIAPH2)
• Synonyms: Diaphanous-related formin-2; DRF2
• Gene Name: DIAPH2
• Related Disease:
  Hypoparathyroidism
  Type-1 diabetes
  Age-related macular degeneration
  Astrocytoma
  Autoimmune disease
  Brain neoplasm
  Depression
  Female hypogonadism
  Hepatitis C virus infection
  Mental disorder
  Neoplasm
  Non-insulin dependent diabetes
  Schizophrenia
  Laryngeal squamous cell carcinoma
  Stroke
  Graves disease
  Advanced cancer
  Neurofibromatosis type 1
  Premature ovarian failure 2A
• UniProt ID: DIAP2_HUMAN
• Pfam ID: PF06367 ; PF06371 ; PF02181
• Sequence:
  MEQPGAAASGAGGGSEEPGGGRSNKRSAGNRAANEEETKNKPKLNIQIKTLADDVRDRIT
  SFRKSTVKKEKPLIQHPIDSQVAMSEFPAAQPLYDERSLNLSEKEVLDLFEKMMEDMNLN
  EEKKAPLRNKDFTTKREMVVQYISATAKSGGLKNSKHECTLSSQEYVHELRSGISDEKLL
  NCLESLRVSLTSNPVSWVNNFGHEGLGLLLDELEKLLDKKQQENIDKKNQYKLIQCLKAF
  MNNKFGLQRILGDERSLLLLARAIDPKQPNMMTEIVKILSAICIVGEENILDKLLGAITT
  AAERNNRERFSPIVEGLENQEALQLQVACMQFINALVTSPYELDFRIHLRNEFLRSGLKT
  MLPDLKEKENDELDIQLKVFDENKEDDLTELSHRLNDIRAEMDDMNEVYHLLYNMLKDTA
  AENYFLSILQHFLLIRNDYYIRPQYYKIIEECVSQIVLHCSGMDPDFKYRQRLDIDLTHL
  IDSCVNKAKVEESEQKAAEFSKKFDEEFTARQEAQAELQKRDEKIKELEAEIQQLRTQAQ
  VLSSSSGIPGPPAAPPLPGVGPPPPPPAPPLPGGAPLPPPPPPLPGMMGIPPPPPPPLLF
  GGPPPPPPLGGVPPPPGISLNLPYGMKQKKMYKPEVSMKRINWSKIEPTELSENCFWLRV
  KEDKFENPDLFAKLALNFATQIKVQKNAEALEEKKTGPTKKKVKELRILDPKTAQNLSIF
  LGSYRMPYEDIRNVILEVNEDMLSEALIQNLVKHLPEQKILNELAELKNEYDDLCEPEQF
  GVVMSSVKMLQPRLSSILFKLTFEEHINNIKPSIIAVTLACEELKKSESFNRLLELVLLV
  GNYMNSGSRNAQSLGFKINFLCKIRDTKSADQKTTLLHFIADICEEKYRDILKFPEELEH
  VESASKVSAQILKSNLASMEQQIVHLERDIKKFPQAENQHDKFVEKMTSFTKTAREQYEK
  LSTMHNNMMKLYENLGEYFIFDSKTVSIEEFFGDLNNFRTLFLEAVRENNKRREMEEKTR
  RAKLAKEKAEQEKLERQKKKKQLIDINKEGDETGVMDNLLEALQSGAAFRDRRKRIPRNP
  DNRRVPLERSRSRHNGAISSK
• Function: Could be involved in oogenesis. Involved in the regulation of endosome dynamics. Implicated in a novel signal transduction pathway, in which isoform 3 and CSK are sequentially activated by RHOD to regulate the motility of early endosomes through interactions with the actin cytoskeleton.
• Tissue Specificity: Expressed in testis, ovary, small intestine, prostate, lung, liver, kidney and leukocytes.
• KEGG Pathway:
  Regulation of actin cytoskeleton (hsa04810)
  Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway:
  RHOF GTPase cycle (R-HSA-9035034)
  RHO GTPases Activate Formins (R-HSA-5663220)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypoparathyroidism	DISICS0V	Definitive	Biomarker	[1]
Type-1 diabetes	DIS7HLUB	Definitive	Genetic Variation	[1]
Age-related macular degeneration	DIS0XS2C	Strong	Biomarker	[2]
Astrocytoma	DISL3V18	Strong	Genetic Variation	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[5]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Female hypogonadism	DISWASB4	Strong	Biomarker	[7]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[8]
Mental disorder	DIS3J5R8	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[11]
Schizophrenia	DISSRV2N	Strong	Biomarker	[9]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Genetic Variation	[10]
Stroke	DISX6UHX	moderate	Biomarker	[12]
Graves disease	DISU4KOQ	Disputed	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[13]
Neurofibromatosis type 1	DIS53JH9	Limited	Biomarker	[13]
Premature ovarian failure 2A	DISPCURP	Limited	Unknown	[14]

17 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 Protein diaphanous homolog 2 (DIAPH2).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein diaphanous homolog 2 (DIAPH2).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein diaphanous homolog 2 (DIAPH2).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein diaphanous homolog 2 (DIAPH2).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein diaphanous homolog 2 (DIAPH2).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein diaphanous homolog 2 (DIAPH2).	[20]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Protein diaphanous homolog 2 (DIAPH2).	[21]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein diaphanous homolog 2 (DIAPH2).	[22]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Protein diaphanous homolog 2 (DIAPH2).	[23]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Protein diaphanous homolog 2 (DIAPH2).	[24]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Protein diaphanous homolog 2 (DIAPH2).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein diaphanous homolog 2 (DIAPH2).	[24]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Protein diaphanous homolog 2 (DIAPH2).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein diaphanous homolog 2 (DIAPH2).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein diaphanous homolog 2 (DIAPH2).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein diaphanous homolog 2 (DIAPH2).	[29]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Protein diaphanous homolog 2 (DIAPH2).	[30]

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 increases the methylation of Protein diaphanous homolog 2 (DIAPH2).	[26]

References

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• [10] DIAPH2 alterations increase cellular motility and may contribute to the metastatic potential of laryngeal squamous cell carcinoma.Carcinogenesis. 2019 Oct 16;40(10):1251-1259. doi: 10.1093/carcin/bgz035.
• [11] Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials.Am J Physiol Gastrointest Liver Physiol. 2019 Mar 1;316(3):G372-G386. doi: 10.1152/ajpgi.00051.2018. Epub 2018 Nov 29.
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• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
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• [17] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [18] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [19] 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.
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• [21] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [22] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
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• [25] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [26] 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.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] 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.
• [29] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [30] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.