Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT2OQOV)

• DOT Name: Drebrin-like protein (DBNL)
• Synonyms: Cervical SH3P7; Cervical mucin-associated protein; Drebrin-F; HPK1-interacting protein of 55 kDa; HIP-55; SH3 domain-containing protein 7
• Gene Name: DBNL
• Related Disease:
  Asthma
  Bipolar disorder
  Cerebral cavernous malformation
  Chronic inflammatory demyelinating polyneuropathy
  Glycogen storage disease due to phosphoglycerate mutase deficiency
  Lissencephaly spectrum disorders
  Non-insulin dependent diabetes
  Peripheral neuropathy
  Rhinitis
  Spinal muscular atrophy, type II
  Subcortical band heterotopia
  Ulcerative colitis
  Amyotrophic lateral sclerosis
  Type-1/2 diabetes
  Advanced cancer
  Colorectal carcinoma
  Parkinson disease
• UniProt ID: DBNL_HUMAN
• PDB ID: 1X67
• Pfam ID: PF00241 ; PF14604
• Sequence:
  MAANLSRNGPALQEAYVRVVTEKSPTDWALFTYEGNSNDIRVAGTGEGGLEEMVEELNSG
  KVMYAFCRVKDPNSGLPKFVLINWTGEGVNDVRKGACASHVSTMASFLKGAHVTINARAE
  EDVEPECIMEKVAKASGANYSFHKESGRFQDVGPQAPVGSVYQKTNAVSEIKRVGKDSFW
  AKAEKEEENRRLEEKRRAEEAQRQLEQERRERELREAARREQRYQEQGGEASPQRTWEQQ
  QEVVSRNRNEQESAVHPREIFKQKERAMSTTSISSPQPGKLRSPFLQKQLTQPETHFGRE
  PAAAISRPRADLPAEEPAPSTPPCLVQAEEEAVYEEPPEQETFYEQPPLVQQQGAGSEHI
  DHHIQGQGLSGQGLCARALYDYQAADDTEISFDPENLITGIEVIDEGWWRGYGPDGHFGM
  FPANYVELIE
• Function: Adapter protein that binds F-actin and DNM1, and thereby plays a role in receptor-mediated endocytosis. Plays a role in the reorganization of the actin cytoskeleton, formation of cell projections, such as neurites, in neuron morphogenesis and synapse formation via its interaction with WASL and COBL. Does not bind G-actin and promote actin polymerization by itself. Required for the formation of organized podosome rosettes. May act as a common effector of antigen receptor-signaling pathways in leukocytes. Acts as a key component of the immunological synapse that regulates T-cell activation by bridging TCRs and the actin cytoskeleton to gene activation and endocytic processes.
• Reactome Pathway:
  Neurexins and neuroligins (R-HSA-6794361)
  Neutrophil degranulation (R-HSA-6798695)
  Caspase-mediated cleavage of cytoskeletal proteins (R-HSA-264870)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Strong	Genetic Variation	[1]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[2]
Cerebral cavernous malformation	DISLKNYA	Strong	Biomarker	[3]
Chronic inflammatory demyelinating polyneuropathy	DISNGBLD	Strong	Genetic Variation	[4]
Glycogen storage disease due to phosphoglycerate mutase deficiency	DISC5WDN	Strong	CausalMutation	[5]
Lissencephaly spectrum disorders	DISBCZL7	Strong	Biomarker	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[7]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[7]
Rhinitis	DISKLMN7	Strong	Genetic Variation	[1]
Spinal muscular atrophy, type II	DIS3GNQ4	Strong	Biomarker	[8]
Subcortical band heterotopia	DISHN7JS	Strong	Biomarker	[6]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[9]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Biomarker	[10]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[11]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[12]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[13]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[14]

6 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 Drebrin-like protein (DBNL).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Drebrin-like protein (DBNL).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Drebrin-like protein (DBNL).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Drebrin-like protein (DBNL).	[19]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Drebrin-like protein (DBNL).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Drebrin-like protein (DBNL).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the cleavage of Drebrin-like protein (DBNL).	[18]

4 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 affects the methylation of Drebrin-like protein (DBNL).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Drebrin-like protein (DBNL).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Drebrin-like protein (DBNL).	[21]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Drebrin-like protein (DBNL).	[24]

References

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• [3] Cobl-like promotes actin filament formation and dendritic branching using only a single WH2 domain.J Cell Biol. 2018 Jan 2;217(1):211-230. doi: 10.1083/jcb.201704071. Epub 2017 Dec 12.
• [4] Blink R1 latency utility in diagnosis and treatment assessment of polyradiculoneuropathy-organomegaly-endocrinopathy-monoclonal protein-skin changes and chronic inflammatory demyelinating polyradiculoneuropathy.Muscle Nerve. 2018 Jan;57(1):E8-E13. doi: 10.1002/mus.25731. Epub 2017 Jul 7.
• [5] Phosphoglycerate mutase deficiency (glycogen storage disease X) caused by a novel variant in PGAM-M.Neuromuscul Disord. 2016 Oct;26(10):688-690. doi: 10.1016/j.nmd.2016.08.002. Epub 2016 Aug 11.
• [6] Drebrin-like (Dbnl) Controls Neuronal Migration via Regulating N-Cadherin Expression in the Developing Cerebral Cortex.J Neurosci. 2019 Jan 23;39(4):678-691. doi: 10.1523/JNEUROSCI.1634-18.2018. Epub 2018 Nov 30.
• [7] The role of dietary non-heme iron load and peripheral nerve inflammation in the development of peripheral neuropathy (PN) in obese non-diabetic leptin-deficient ob/ob mice.Neurol Res. 2019 Apr;41(4):341-353. doi: 10.1080/01616412.2018.1564191. Epub 2019 Jan 13.
• [8] Peripheral nerve abnormalities in pediatric patients with spinal muscular atrophy.Brain Dev. 2013 Feb;35(2):165-71. doi: 10.1016/j.braindev.2012.03.009. Epub 2012 Apr 17.
• [9] Severity of ulcerative colitis is associated with a polymorphism at diamine oxidase gene but not at histamine N-methyltransferase gene.World J Gastroenterol. 2006 Jan 28;12(4):615-20. doi: 10.3748/wjg.v12.i4.615.
• [10] The split hand in amyotrophic lateral sclerosis: a possible role for the neuromuscular junction.Amyotroph Lateral Scler Frontotemporal Degener. 2019 Aug;20(5-6):368-375. doi: 10.1080/21678421.2019.1606245. Epub 2019 May 6.
• [11] Influence of comorbidities on the phenotype of patients affected by Charcot-Marie-Tooth neuropathy type 1A.Neuromuscul Disord. 2013 Nov;23(11):902-6. doi: 10.1016/j.nmd.2013.07.002. Epub 2013 Jul 23.
• [12] Identifying prognostic signature in ovarian cancer using DirGenerank.Oncotarget. 2017 Jul 11;8(28):46398-46413. doi: 10.18632/oncotarget.18189.
• [13] Analysis of the K-ras/B-raf/Erk signal cascade, p53 and CMAP as markers for tumor progression in colorectal cancer patients.Oncol Rep. 2008 Jul;20(1):3-11.
• [14] Nonsynonymous polymorphisms of histamine-metabolising enzymes in patients with Parkinson's disease.Neuromolecular Med. 2008;10(1):10-6. doi: 10.1007/s12017-007-8017-7. Epub 2007 Nov 6.
• [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] 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.
• [17] 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.
• [18] PRAM-1 potentiates arsenic trioxide-induced JNK activation. J Biol Chem. 2005 Mar 11;280(10):9043-8. doi: 10.1074/jbc.M413564200. Epub 2005 Jan 6.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] 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.
• [22] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [23] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [24] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.