Details of Drug Off-Target (DOT)

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

• DOT Name: Protein diaphanous homolog 1 (DIAPH1)
• Synonyms: Diaphanous-related formin-1; DRF1
• Gene Name: DIAPH1
• Related Disease:
  DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome
  Wolfram syndrome
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease
  Autosomal dominant nonsyndromic hearing loss 1
  Autosomal dominant nonsyndromic hearing loss 13
  Autosomal dominant nonsyndromic hearing loss 9
  Autosomal recessive nonsyndromic hearing loss 2
  Deafness
  Glioblastoma multiforme
  Glioma
  Intellectual disability
  Isolated congenital microcephaly
  Melanoma
  Myelodysplastic syndrome
  Neoplasm
  Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome
  Sensorineural hearing loss disorder
  Bronchiectasis
  Coronary atherosclerosis
  Gastrointestinal stromal tumour
  Head-neck squamous cell carcinoma
  Laryngeal squamous cell carcinoma
  Myocardial ischemia
  Neurodevelopmental disorder
  Colon cancer
  Colon carcinoma
  Metastatic malignant neoplasm
  Nephropathy
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Type-1/2 diabetes
• UniProt ID: DIAP1_HUMAN
• PDB ID: 8FG1
• Pfam ID: PF06346 ; PF06367 ; PF06371 ; PF02181
• Sequence:
  MEPPGGSLGPGRGTRDKKKGRSPDELPSAGGDGGKSKKFTLKRLMADELERFTSMRIKKE
  KEKPNSAHRNSSASYGDDPTAQSLQDVSDEQVLVLFEQMLLDMNLNEEKQQPLREKDIII
  KREMVSQYLYTSKAGMSQKESSKSAMMYIQELRSGLRDMPLLSCLESLRVSLNNNPVSWV
  QTFGAEGLASLLDILKRLHDEKEETAGSYDSRNKHEIIRCLKAFMNNKFGIKTMLETEEG
  ILLLVRAMDPAVPNMMIDAAKLLSALCILPQPEDMNERVLEAMTERAEMDEVERFQPLLD
  GLKSGTTIALKVGCLQLINALITPAEELDFRVHIRSELMRLGLHQVLQDLREIENEDMRV
  QLNVFDEQGEEDSYDLKGRLDDIRMEMDDFNEVFQILLNTVKDSKAEPHFLSILQHLLLV
  RNDYEARPQYYKLIEECISQIVLHKNGADPDFKCRHLQIEIEGLIDQMIDKTKVEKSEAK
  AAELEKKLDSELTARHELQVEMKKMESDFEQKLQDLQGEKDALHSEKQQIATEKQDLEAE
  VSQLTGEVAKLTKELEDAKKEMASLSAAAITVPPSVPSRAPVPPAPPLPGDSGTIIPPPP
  APGDSTTPPPPPPPPPPPPPLPGGVCISSPPSLPGGTAISPPPPLSGDATIPPPPPLPEG
  VGIPSPSSLPGGTAIPPPPPLPGSARIPPPPPPLPGSAGIPPPPPPLPGEAGMPPPPPPL
  PGGPGIPPPPPFPGGPGIPPPPPGMGMPPPPPFGFGVPAAPVLPFGLTPKKLYKPEVQLR
  RPNWSKLVAEDLSQDCFWTKVKEDRFENNELFAKLTLTFSAQTKTSKAKKDQEGGEEKKS
  VQKKKVKELKVLDSKTAQNLSIFLGSFRMPYQEIKNVILEVNEAVLTESMIQNLIKQMPE
  PEQLKMLSELKDEYDDLAESEQFGVVMGTVPRLRPRLNAILFKLQFSEQVENIKPEIVSV
  TAACEELRKSESFSNLLEITLLVGNYMNAGSRNAGAFGFNISFLCKLRDTKSTDQKMTLL
  HFLAELCENDYPDVLKFPDELAHVEKASRVSAENLQKNLDQMKKQISDVERDVQNFPAAT
  DEKDKFVEKMTSFVKDAQEQYNKLRMMHSNMETLYKELGEYFLFDPKKLSVEEFFMDLHN
  FRNMFLQAVKENQKRRETEEKMRRAKLAKEKAEKERLEKQQKREQLIDMNAEGDETGVMD
  SLLEALQSGAAFRRKRGPRQANRKAGCAVTSLLASELTKDDAMAAVPAKVSKNSETFPTI
  LEEAKELVGRAS
• Function: Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers. Binds to the barbed end of the actin filament and slows down actin polymerization and depolymerization. Required for cytokinesis, and transcriptional activation of the serum response factor. DFR proteins couple Rho and Src tyrosine kinase during signaling and the regulation of actin dynamics. Functions as a scaffold protein for MAPRE1 and APC to stabilize microtubules and promote cell migration. Has neurite outgrowth promoting activity. Acts in a Rho-dependent manner to recruit PFY1 to the membrane. In hear cells, it may play a role in the regulation of actin polymerization in hair cells. The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization. Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape. Plays a role in brain development. Also acts as an actin nucleation and elongation factor in the nucleus by promoting nuclear actin polymerization inside the nucleus to drive serum-dependent SRF-MRTFA activity.
• Tissue Specificity: Expressed in brain, heart, placenta, lung, kidney, pancreas, liver, skeletal muscle and cochlea. Expressed in platelets .
• KEGG Pathway:
  Focal adhesion (hsa04510)
  Regulation of actin cytoskeleton (hsa04810)
  Cytoskeleton in muscle cells (hsa04820)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Shigellosis (hsa05131)
• Reactome Pathway:
  ERBB2 Regulates Cell Motility (R-HSA-6785631)
  Neutrophil degranulation (R-HSA-6798695)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  RHOD GTPase cycle (R-HSA-9013405)
  RHOF GTPase cycle (R-HSA-9035034)
  RHO GTPases Activate Formins (R-HSA-5663220)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome	DISNNPK1	Definitive	Autosomal dominant	[1]
Wolfram syndrome	DISN16XW	Definitive	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Autosomal dominant nonsyndromic hearing loss 1	DISDZ6CC	Strong	Autosomal dominant	[6]
Autosomal dominant nonsyndromic hearing loss 13	DISFLETQ	Strong	Genetic Variation	[7]
Autosomal dominant nonsyndromic hearing loss 9	DISD5HDW	Strong	Genetic Variation	[7]
Autosomal recessive nonsyndromic hearing loss 2	DIS1P51S	Strong	Genetic Variation	[7]
Deafness	DISKCLH4	Strong	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[9]
Intellectual disability	DISMBNXP	Strong	Biomarker	[8]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[10]
Melanoma	DIS1RRCY	Strong	Altered Expression	[11]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome	DISB78LB	Strong	Autosomal recessive	[14]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[15]
Bronchiectasis	DIS5MYEE	moderate	Genetic Variation	[8]
Coronary atherosclerosis	DISKNDYU	moderate	Biomarker	[16]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[17]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[18]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Altered Expression	[18]
Myocardial ischemia	DISFTVXF	moderate	Biomarker	[16]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[8]
Colon cancer	DISVC52G	Limited	Biomarker	[19]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[19]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[19]
Nephropathy	DISXWP4P	Limited	Biomarker	[20]
Thyroid cancer	DIS3VLDH	Limited	Biomarker	[21]
Thyroid gland carcinoma	DISMNGZ0	Limited	Biomarker	[21]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[21]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[20]

12 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 1 (DIAPH1).	[22]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein diaphanous homolog 1 (DIAPH1).	[23]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein diaphanous homolog 1 (DIAPH1).	[24]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein diaphanous homolog 1 (DIAPH1).	[25]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein diaphanous homolog 1 (DIAPH1).	[26]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein diaphanous homolog 1 (DIAPH1).	[27]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein diaphanous homolog 1 (DIAPH1).	[28]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Protein diaphanous homolog 1 (DIAPH1).	[29]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Protein diaphanous homolog 1 (DIAPH1).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein diaphanous homolog 1 (DIAPH1).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein diaphanous homolog 1 (DIAPH1).	[34]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Protein diaphanous homolog 1 (DIAPH1).	[35]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Protein diaphanous homolog 1 (DIAPH1).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein diaphanous homolog 1 (DIAPH1).	[33]

References

• [1] 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.
• [2] DFNA54, a third locus for low-frequency hearing loss.J Mol Med (Berl). 2004 Nov;82(11):775-80. doi: 10.1007/s00109-004-0597-1. Epub 2004 Oct 13.
• [3] Mammalian diaphanous-related formin 1 is required for motility and invadopodia formation in human U87 glioblastoma cells.Int J Mol Med. 2014 Feb;33(2):383-91. doi: 10.3892/ijmm.2013.1577. Epub 2013 Dec 5.
• [4] Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion.Genes Dev. 2007 Jun 15;21(12):1478-83. doi: 10.1101/gad.424807.
• [5] Diaphanous 1 (DIAPH1) is Highly Expressed in the Aged Human Medial Temporal Cortex and Upregulated in Myeloid Cells During Alzheimer's Disease.J Alzheimers Dis. 2018;64(3):995-1007. doi: 10.3233/JAD-180088.
• [6] Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans. Eur J Hum Genet. 2015 Feb;23(2):165-72. doi: 10.1038/ejhg.2014.82. Epub 2014 Apr 30.
• [7] Hereditary deafness and phenotyping in humans.Br Med Bull. 2002;63:73-94. doi: 10.1093/bmb/63.1.73.
• [8] Novel loss-of-function variants in DIAPH1 associated with syndromic microcephaly, blindness, and early onset seizures.Am J Med Genet A. 2016 Feb;170A(2):435-440. doi: 10.1002/ajmg.a.37422. Epub 2015 Oct 13.
• [9] Knockdown of Diaph1 expression inhibits migration and decreases the expression of MMP2 and MMP9 in human glioma cells.Biomed Pharmacother. 2017 Dec;96:596-602. doi: 10.1016/j.biopha.2017.10.031. Epub 2017 Oct 13.
• [10] Extension of the clinical and molecular phenotype of DIAPH1-associated autosomal dominant hearing loss (DFNA1).Clin Genet. 2017 Jun;91(6):892-901. doi: 10.1111/cge.12915. Epub 2016 Dec 16.
• [11] Mitf regulation of Dia1 controls melanoma proliferation and invasiveness.Genes Dev. 2006 Dec 15;20(24):3426-39. doi: 10.1101/gad.406406.
• [12] 5q- myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics.Oncogene. 2009 Oct 1;28(39):3429-41. doi: 10.1038/onc.2009.207. Epub 2009 Jul 13.
• [13] Clinical relevance of cytoskeleton associated proteins for ovarian cancer.J Cancer Res Clin Oncol. 2018 Nov;144(11):2195-2205. doi: 10.1007/s00432-018-2710-9. Epub 2018 Aug 9.
• [14] Can fighting worms lower the birth rate?. People. 1976;3(4):22-4.
• [15] A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss. Blood. 2016 Jun 9;127(23):2903-14. doi: 10.1182/blood-2015-10-675629. Epub 2016 Feb 24.
• [16] The Formin, DIAPH1, is a Key Modulator of Myocardial Ischemia/Reperfusion Injury.EBioMedicine. 2017 Dec;26:165-174. doi: 10.1016/j.ebiom.2017.11.012. Epub 2017 Nov 21.
• [17] Novel clinically relevant genes in gastrointestinal stromal tumors identified by exome sequencing.Clin Cancer Res. 2013 Oct 1;19(19):5329-39. doi: 10.1158/1078-0432.CCR-12-3863. Epub 2013 Aug 13.
• [18] DIAPH1 Is Upregulated and Inhibits Cell Apoptosis through ATR/p53/Caspase-3 Signaling Pathway in Laryngeal Squamous Cell Carcinoma.Dis Markers. 2019 Jan 14;2019:6716472. doi: 10.1155/2019/6716472. eCollection 2019.
• [19] Drosophila homologue of Diaphanous 1 (DIAPH1) controls the metastatic potential of colon cancer cells by regulating microtubule-dependent adhesion.Oncotarget. 2015 Jul 30;6(21):18577-89. doi: 10.18632/oncotarget.4094.
• [20] Deletion of the formin Diaph1 protects from structural and functional abnormalities in the murine diabetic kidney.Am J Physiol Renal Physiol. 2018 Dec 1;315(6):F1601-F1612. doi: 10.1152/ajprenal.00075.2018. Epub 2018 Aug 22.
• [21] RAGE Mediates the Pro-Migratory Response of Extracellular S100A4 in Human Thyroid Cancer Cells.Thyroid. 2015 May;25(5):514-27. doi: 10.1089/thy.2014.0257. Epub 2015 Apr 3.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] 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.
• [24] 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.
• [25] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [26] 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.
• [27] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [28] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [29] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [30] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [31] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [32] 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.
• [33] 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.
• [34] 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.
• [35] 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.