Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTTKV7V)

• DOT Name: Protein Hook homolog 1 (HOOK1)
• Synonyms: h-hook1; hHK1
• Gene Name: HOOK1
• Related Disease:
  Cognitive impairment
  Advanced cancer
  Alzheimer disease
  Atypical Rett syndrome
  CLN2 Batten disease
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Male infertility
  Neoplasm
  Non-small-cell lung cancer
  Schizophrenia
  Thyroid gland carcinoma
  Osteoarthritis
  Rett syndrome
  Rheumatoid arthritis
• UniProt ID: HOOK1_HUMAN
• Pfam ID: PF05622 ; PF19047
• Sequence:
  MEETQPPPQPKLPLCDSLMIWLQTFNTASPCQDVKQLTSGVAMAQVLHQIDAAWFNESWL
  SRIKEDVGDNWRIKASNVKKVLQGIMSYYHEFLGQQISEALIPDLNQITECSDPVELGRL
  LQLILGCAINCEKKQEHIQNIMTLEESVQHVVMTAIQELMSKEILSSPPNDAVGELEQQL
  KRALEELQEALAEKEELRQRCEELDMQVTTLQDEKNSLVSENEMMNEKLDQLDGSFDDPN
  TVVAKKYFHAQLQLEQLQEENFRLEAAKDDYRVHCEELEKQLIEFQHRNDELTSLAEETR
  ALKDEIDVLRATSDKANKLESTVEIYRQKLQDLNDLRKQVKTLQETNMMYMHNTVSLEEE
  LKKANAARTQLETYKRQVQDLHVKLSSESKRADTLAFEMKRLEEKHEALLKEKERLIEQR
  DTLKETNEELRCSQVQQDHLNQTDASATKSYENLAAEIMPVEYREVFIRLQHENKMLRLQ
  QEGSENERIEELQEQLEQKHRKMNELETEQRLSKERIRELQQQIEDLQKSLQEQGSKSEG
  ESSSKLKQKLEAHMEKLTEVHEELQKKQELIEDLQPDINQNVQKINELEAALQKKDEDMK
  AMEERYKMYLEKARNVIKTLDPKLNPASAEIMLLRKQLAEKERRIEILESECKVAKFRDY
  EEKLIVSAWYNKSLAFQKLGMESRLVSGGGACSDTGACTPARSFLAQQRHITNTRRNLSV
  KVPATTSD
• Function: Component of the FTS/Hook/FHIP complex (FHF complex). The FHF complex may function to promote vesicle trafficking and/or fusion via the homotypic vesicular protein sorting complex (the HOPS complex). FHF complex promotes the distribution of AP-4 complex to the perinuclear area of the cell. Required for spermatid differentiation. Probably involved in the positioning of the microtubules of the manchette and the flagellum in relation to the membrane skeleton.

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cognitive impairment	DISH2ERD	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Atypical Rett syndrome	DISWF699	Strong	Genetic Variation	[4]
CLN2 Batten disease	DISZC5YB	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Lung cancer	DISCM4YA	Strong	Altered Expression	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[6]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[4]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[8]
Osteoarthritis	DIS05URM	Limited	Altered Expression	[9]
Rett syndrome	DISGG5UV	Limited	Biomarker	[10]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Protein Hook homolog 1 (HOOK1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein Hook homolog 1 (HOOK1).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein Hook homolog 1 (HOOK1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein Hook homolog 1 (HOOK1).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein Hook homolog 1 (HOOK1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein Hook homolog 1 (HOOK1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein Hook homolog 1 (HOOK1).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein Hook homolog 1 (HOOK1).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein Hook homolog 1 (HOOK1).	[17]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Protein Hook homolog 1 (HOOK1).	[18]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Protein Hook homolog 1 (HOOK1).	[19]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Protein Hook homolog 1 (HOOK1).	[20]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Protein Hook homolog 1 (HOOK1).	[21]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Protein Hook homolog 1 (HOOK1).	[22]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Protein Hook homolog 1 (HOOK1).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein Hook homolog 1 (HOOK1).	[24]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Protein Hook homolog 1 (HOOK1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein Hook homolog 1 (HOOK1).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein Hook homolog 1 (HOOK1).	[21]

References

• [1] Disruption of AT-hook 1 domain in MeCP2 protein caused behavioral abnormality in mice.Biochim Biophys Acta Mol Basis Dis. 2018 Feb;1864(2):347-358. doi: 10.1016/j.bbadis.2017.10.022. Epub 2017 Oct 24.
• [2] Hook1 inhibits malignancy and epithelial-mesenchymal transition in hepatocellular carcinoma.Tumour Biol. 2017 Jul;39(7):1010428317711098. doi: 10.1177/1010428317711098.
• [3] Hook proteins: association with Alzheimer pathology and regulatory role of hook3 in amyloid beta generation.PLoS One. 2015 Mar 23;10(3):e0119423. doi: 10.1371/journal.pone.0119423. eCollection 2015.
• [4] MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro.Hum Mutat. 2018 May;39(5):717-728. doi: 10.1002/humu.23409. Epub 2018 Mar 8.
• [5] Btn2, a Hook1 ortholog and potential Batten disease-related protein, mediates late endosome-Golgi protein sorting in yeast.Mol Cell Biol. 2007 Jan;27(2):605-21. doi: 10.1128/MCB.00699-06. Epub 2006 Nov 13.
• [6] The prognostic significance of SHP2 and its binding protein Hook1 in non-small cell lung cancer.Onco Targets Ther. 2019 Jul 22;12:5897-5906. doi: 10.2147/OTT.S210223. eCollection 2019.
• [7] Ccdc181 is a microtubule-binding protein that interacts with Hook1 in haploid male germ cells and localizes to the sperm tail and motile cilia.Eur J Cell Biol. 2017 May;96(3):276-288. doi: 10.1016/j.ejcb.2017.02.003. Epub 2017 Feb 20.
• [8] Clinicopathological and prognostic significance of SHP2 and Hook1 expression in patients with thyroid carcinoma.Hum Pathol. 2018 Nov;81:105-112. doi: 10.1016/j.humpath.2018.06.016. Epub 2018 Jun 25.
• [9] Inhibition of hexokinases holds potential as treatment strategy for rheumatoid arthritis.Arthritis Res Ther. 2019 Apr 3;21(1):87. doi: 10.1186/s13075-019-1865-3.
• [10] Clinical, Molecular, and Computational Analysis in Patients With a Novel Double Mutation and a New Synonymous Variant in MeCP2: Report of the First Missense Mutation Within the AT-hook1 Cluster in Rett Syndrome.J Child Neurol. 2017 Jul;32(8):694-703. doi: 10.1177/0883073817701622. Epub 2017 Apr 11.
• [11] 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.
• [12] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [13] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [14] 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.
• [15] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [16] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [17] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [18] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [19] 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.
• [20] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009 Aug 21;138(4):645-659. doi: 10.1016/j.cell.2009.06.034. Epub 2009 Aug 13.
• [23] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [24] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [25] 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.
• [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] 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.