Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLO2374)

• DOT Name: BLOC-2 complex member HPS5 (HPS5)
• Synonyms: Alpha-integrin-binding protein 63; Hermansky-Pudlak syndrome 5 protein; Ruby-eye protein 2 homolog; Ru2
• Gene Name: HPS5
• Related Disease:
  Hermansky-Pudlak syndrome 5
  Advanced cancer
  Albinism
  Amyloidosis
  Breast cancer
  Breast carcinoma
  Coagulation defect
  Colon cancer
  Colon carcinoma
  Hantavirus infection
  Hepatocellular carcinoma
  Hermansky-Pudlak syndrome
  Hypopigmentation of the skin
  Inflammatory bowel disease
  Lung neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Platelet storage pool deficiency
  Prostate cancer
  Prostate carcinoma
  Hermansky-Pudlak syndrome without pulmonary fibrosis
  Triple negative breast cancer
• UniProt ID: HPS5_HUMAN
• Sequence:
  MAFVPVIPESYSHVLAEFESLDPLLSALRLDSSRLKCTSIAVSRKWLALGSSGGGLHLIQ
  KEGWKHRLFLSHREGAISQVACCLHDDDYVAVATSQGLVVVWELNQERRGKPEQMYVSSE
  HKGRRVTALCWDTAILRVFVGDHAGKVSAIKLNTSKQAKAAAAFVMFPVQTITTVDSCVV
  QLDYLDGRLLISSLTRSFLCDTEREKFWKIGNKERDGEYGACFFPGRCSGGQQPLIYCAR
  PGSRMWEVNFDGEVISTHQFKKLLSLPPLPVITLRSEPQYDHTAGSSQSLSFPKLLHLSE
  HCVLTWTERGIYIFIPQNVQVLLWSEVKDIQDVAVCRNELFCLHLNGKVSHLSLISVERC
  VERLLRRGLWNLAARTCCLFQNSVIASRARKTLTADKLEHLKSQLDHGTYNDLISQLEEL
  ILKFEPLDSACSSRRSSISSHESFSILDSGIYRIISSRRGSQSDEDSCSLHSQTLSEDER
  FKEFTSQQEEDLPDQCCGSHGNEDNVSHAPVMFETDKNETFLPFGIPLPFRSPSPLVSLQ
  AVKESVSSFVRKTTEKIGTLHTSPDLKVRPELRGDEQSCEEDVSSDTCPKEEDTEEEKEV
  TSPPPEEDRFQELKVATAEAMTKLQDPLVLFESESLRMVLQEWLSHLEKTFAMKDFSGVS
  DTDNSSMKLNQDVLLVNESKKGILDEDNEKEKRDSLGNEESVDKTACECVRSPRESLDDL
  FQICSPCAIASGLRNDLAELTTLCLELNVLNSKIKSTSGHVDHTLQQYSPEILACQFLKK
  YFFLLNLKRAKESIKLSYSNSPSVWDTFIEGLKEMASSNPVYMEMEKGDLPTRLKLLDDE
  VPFDSPLLVVYATRLYEKFGESALRSLIKFFPSILPSDIIQLCHHHPAEFLAYLDSLVKS
  RPEDQRSSFLESLLQPESLRLDWLLLAVSLDAPPSTSTMDDEGYPRPHSHLLSWGYSQLI
  LHLIKLPADFITKEKMTDICRSCGFWPGYLILCLELERRREAFTNIVYLNDMSLMEGDNG
  WIPETVEEWKLLLHLIQSKSTRPAPQESLNGSLSDGPSPINVENVALLLAKAMGPDRAWS
  LLQECGLALELSEKFTRTCDILRIAEKRQRALIQSMLEKCDRFLWSQQA
• Function: May regulate the synthesis and function of lysosomes and of highly specialized organelles, such as melanosomes and platelet dense granules. Regulates intracellular vesicular trafficking in fibroblasts. May be involved in the regulation of general functions of integrins.
• Tissue Specificity: Widely expressed. Isoform 1:Highly expressed in lungs and testis. Isoform 2:Highly expressed in placenta, kidney, testis ovary, lung and thymus.

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hermansky-Pudlak syndrome 5	DIS37WS6	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Albinism	DIS5D82I	Strong	Genetic Variation	[3]
Amyloidosis	DISHTAI2	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Coagulation defect	DIS9X3H6	Strong	Genetic Variation	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Hantavirus infection	DISZFTMH	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Hermansky-Pudlak syndrome	DISCY0HQ	Strong	Genetic Variation	[9]
Hypopigmentation of the skin	DIS39YKC	Strong	Genetic Variation	[6]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[10]
Lung neoplasm	DISVARNB	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[13]
Platelet storage pool deficiency	DISHODOH	Strong	Biomarker	[14]
Prostate cancer	DISF190Y	Strong	Biomarker	[15]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[15]
Hermansky-Pudlak syndrome without pulmonary fibrosis	DIS0UYNY	Supportive	Autosomal recessive	[16]
Triple negative breast cancer	DISAMG6N	Limited	Genetic Variation	[5]

5 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 BLOC-2 complex member HPS5 (HPS5).	[17]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of BLOC-2 complex member HPS5 (HPS5).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of BLOC-2 complex member HPS5 (HPS5).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of BLOC-2 complex member HPS5 (HPS5).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of BLOC-2 complex member HPS5 (HPS5).	[24]

7 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 BLOC-2 complex member HPS5 (HPS5).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of BLOC-2 complex member HPS5 (HPS5).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of BLOC-2 complex member HPS5 (HPS5).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of BLOC-2 complex member HPS5 (HPS5).	[21]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of BLOC-2 complex member HPS5 (HPS5).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of BLOC-2 complex member HPS5 (HPS5).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of BLOC-2 complex member HPS5 (HPS5).	[26]

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] Photochemical property of two Ru(II) compounds based on 5-(2-pyrazinyl)tetrazole for cancer phototherapy by changing auxiliary ligand.J Inorg Biochem. 2019 Apr;193:124-129. doi: 10.1016/j.jinorgbio.2019.01.015. Epub 2019 Jan 28.
• [3] Clinico-molecular analysis of eleven patients with Hermansky-Pudlak type 5 syndrome, a mild form of HPS.Pigment Cell Melanoma Res. 2017 Jan;30(6):563-570. doi: 10.1111/pcmr.12608. Epub 2017 Oct 20.
• [4] Acetylcholinesterase and A Aggregation Inhibition by Heterometallic Ruthenium(II)-Platinum(II) Polypyridyl Complexes.Inorg Chem. 2018 Jul 2;57(13):7524-7535. doi: 10.1021/acs.inorgchem.8b00091. Epub 2018 Jun 12.
• [5] Half-sandwich Ru((6)-p-cymene) complexes featuring pyrazole appended ligands: Synthesis, DNA binding and in vitro cytotoxicity.J Inorg Biochem. 2019 May;194:74-84. doi: 10.1016/j.jinorgbio.2019.02.012. Epub 2019 Feb 23.
• [6] Hermansky-Pudlak syndrome subtype 5 (HPS-5) novel mutation in a 65 year-old with oculocutaneous hypopigmentation and mild bleeding diathesis: The importance of recognizing a subtle phenotype.Platelets. 2018 Jan;29(1):91-94. doi: 10.1080/09537104.2017.1361019. Epub 2017 Nov 1.
• [7] Ru(II)-thymine complex causes DNA damage and apoptotic cell death in human colon carcinoma HCT116 cells mediated by JNK/p38/ERK1/2 via a p53-independent signaling.Sci Rep. 2019 Jul 31;9(1):11094. doi: 10.1038/s41598-019-47539-0.
• [8] Ruthenium Complexes Induce HepG2 Human Hepatocellular Carcinoma Cell Apoptosis and Inhibit Cell Migration and Invasion through Regulation of the Nrf2 Pathway.Int J Mol Sci. 2016 May 19;17(5):775. doi: 10.3390/ijms17050775.
• [9] Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.Blood. 2019 Dec 5;134(23):2082-2091. doi: 10.1182/blood.2018891192.
• [10] Simple chronic colitis model using hypopigmented mice with a Hermansky-Pudlak syndrome 5 gene mutation.Pigment Cell Melanoma Res. 2016 Sep;29(5):578-82. doi: 10.1111/pcmr.12504. Epub 2016 Aug 8.
• [11] Hydrolysis reaction promotes changes in coordination mode of Ru(II)/acylthiourea organometallic complexes with cytotoxicity against human lung tumor cell lines.J Inorg Biochem. 2018 Sep;186:147-156. doi: 10.1016/j.jinorgbio.2018.06.007. Epub 2018 Jun 18.
• [12] Synthesis, Characterization, and Inducing Tumor Cell Apoptosis of Two Ru(II) Complexes Containing Guanidinium as Ligands.Anticancer Agents Med Chem. 2018;18(1):110-120. doi: 10.2174/1871520617666170419122056.
• [13] Anticancer activity and mechanism of bis-pyrimidine based dimetallic Ru(II)((6)-p-cymene) complex in human non-small cell lung cancer via p53-dependent pathway.J Inorg Biochem. 2019 May;194:52-64. doi: 10.1016/j.jinorgbio.2019.01.019. Epub 2019 Feb 23.
• [14] Analysis of atherosclerosis susceptibility in mice with genetic defects in platelet function.Arteriosclerosis. 1990 Jul-Aug;10(4):648-52. doi: 10.1161/01.atv.10.4.648.
• [15] Antitumour and Toxicity Evaluation of a Ru(II)-Cyclopentadienyl Complex in a Prostate Cancer Model by Imaging Tools.Anticancer Agents Med Chem. 2019;19(10):1262-1275. doi: 10.2174/1871520619666190318152726.
• [16] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [23] 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.
• [24] 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.
• [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] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.