Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ6D9X1)

• DOT Name: Homer protein homolog 3 (HOMER3)
• Synonyms: Homer-3
• Gene Name: HOMER3
• Related Disease:
  Acute myelogenous leukaemia
  Cerebellar ataxia
  Cerebellar disorder
• UniProt ID: HOME3_HUMAN
• PDB ID: 2P8V; 3CVF
• Pfam ID: PF00568
• Sequence:
  MSTAREQPIFSTRAHVFQIDPATKRNWIPAGKHALTVSYFYDATRNVYRIISIGGAKAII
  NSTVTPNMTFTKTSQKFGQWADSRANTVYGLGFASEQHLTQFAEKFQEVKEAARLAREKS
  QDGGELTSPALGLASHQVPPSPLVSANGPGEEKLFRSQSADAPGPTERERLKKMLSEGSV
  GEVQWEAEFFALQDSNNKLAGALREANAAAAQWRQQLEAQRAEAERLRQRVAELEAQAAS
  EVTPTGEKEGLGQGQSLEQLEALVQTKDQEIQTLKSQTGGPREALEAAEREETQQKVQDL
  ETRNAELEHQLRAMERSLEEARAERERARAEVGRAAQLLDVSLFELSELREGLARLAEAA
  P
• Function: Postsynaptic density scaffolding protein. Binds and cross-links cytoplasmic regions of GRM1, GRM5, ITPR1, DNM3, RYR1, RYR2, SHANK1 and SHANK3. By physically linking GRM1 and GRM5 with ER-associated ITPR1 receptors, it aids the coupling of surface receptors to intracellular calcium release. Isoforms can be differently regulated and may play an important role in maintaining the plasticity at glutamatergic synapses. Negatively regulates T cell activation by inhibiting the calcineurin-NFAT pathway. Acts by competing with calcineurin/PPP3CA for NFAT protein binding, hence preventing NFAT activation by PPP3CA.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  Glutamatergic sy.pse (hsa04724)
• Reactome Pathway: Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[2]
Cerebellar disorder	DIS2O7WM	Strong	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Homer protein homolog 3 (HOMER3).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Homer protein homolog 3 (HOMER3).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Homer protein homolog 3 (HOMER3).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Homer protein homolog 3 (HOMER3).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Homer protein homolog 3 (HOMER3).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Homer protein homolog 3 (HOMER3).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Homer protein homolog 3 (HOMER3).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Homer protein homolog 3 (HOMER3).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Homer protein homolog 3 (HOMER3).	[10]
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the expression of Homer protein homolog 3 (HOMER3).	[11]
Lithium	DMZ3OU6	Phase 2	Lithium decreases the expression of Homer protein homolog 3 (HOMER3).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homer protein homolog 3 (HOMER3).	[14]

References

• [1] Growth and differentiation effects of Homer3 on a leukemia cell line.Asian Pac J Cancer Prev. 2013;14(4):2525-8. doi: 10.7314/apjcp.2013.14.4.2525.
• [2] Anti-Homer-3 antibody associated cerebellar ataxia: A rare case report and literature review.J Neuroimmunol. 2019 May 15;330:155-158. doi: 10.1016/j.jneuroim.2019.01.002. Epub 2019 Mar 13.
• [3] CNS syndromes associated with antibodies against metabotropic receptors.Curr Opin Neurol. 2017 Jun;30(3):354-360. doi: 10.1097/WCO.0000000000000448.
• [4] 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.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] 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.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] 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.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [12] Effect of mood stabilizers on gene expression in lymphoblastoid cells. J Neural Transm (Vienna). 2010 Feb;117(2):155-64.
• [13] 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.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [15] 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.