Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAKROK7)

• DOT Name: BLOC-2 complex member HPS3 (HPS3)
• Synonyms: Hermansky-Pudlak syndrome 3 protein
• Gene Name: HPS3
• Related Disease:
  Hermansky-Pudlak syndrome 3
  Albinism
  Hantavirus infection
  Hermansky-Pudlak syndrome
  Hypopigmentation of the skin
  Platelet storage pool deficiency
  Hermansky-Pudlak syndrome without pulmonary fibrosis
• UniProt ID: HPS3_HUMAN
• Pfam ID: PF14763 ; PF14761
• Sequence:
  MVQLYNLHPFGSQQVVPCKLEPDRFCGGGRDALFVAAGCKVEAFAVAGQELCQPRCAFST
  LGRVLRLAYSEAGDYLVAIEEKNKATFLRAYVNWRNKRTENSRVCIRMIGHNVEGPFSKA
  FRDQMYIIEMPLSEAPLCISCCPVKGDLLVGCTNKLVLFSLKYQIINEEFSLLDFERSLI
  IHIDNITPVEVSFCVGYVAVMSDLEVLIVKLESGPKNGERVHHHPHKTNNRIRRTEEGIS
  NEISQLESDDFVICQKPLELLGEKSEQSGLSVTLESTGLADEKRKYSHFQHLLYRRFAPD
  ISSYVLSDDIKLHSLQLLPIYQTGSLTSDGKNLSQEKELLSLFCFFSLPHVGYLYMVVKS
  VELMSVYQYPEKSQQAVLTPQFLHVITSNNLQCFTVRCSAAAAREEDPYMDTTLKACPPV
  SMDVCALRIQLFIGLKAICHFKNHIILLTKAEPEAIPERRQSPKRLLSRKDTSVKIKIPP
  VAEAGWNLYIVNTISPVQLYKEMVDYSNTYKTVKTQSCIHLLSEAHLLVRAALMDASQLE
  PGEKAELLEAFKESCGHLGDCYSRLDSQHSHLTLPYYKMSGLSMAEVLARTDWTVEDGLQ
  KYERGLIFYINHSLYENLDEELNEELAAKVVQMFYVAEPKQVPHILCSPSMKNINPLTAM
  SYLRKLDTSGFSSILVTLTKAAVALKMGDLDMHRNEMKSHSEMKLVCGFILEPRLLIQQR
  KGQIVPTELALHLKETQPGLLVASVLGLQKNNKIGIEEADSFFKVLCAKDEDTIPQLLVD
  FWEAQLVACLPDVVLQELFFKLTSQYIWRLSKRQPPDTTPLRTSEDLINACSHYGLIYPW
  VHVVISSDSLADKNYTEDLSKLQSLICGPSFDIASIIPFLEPLSEDTIAGLSVHVLCRTR
  LKEYEQCIDILLERCPEAVIPYANHELKEENRTLWWKKLLPELCQRIKCGGEKYQLYLSS
  LKETLSIVAVELELKDFMNVLPEDGTATFFLPYLLYCSRKKPLT
• Function: Involved in early stages of melanosome biogenesis and maturation.
• Tissue Specificity: Widely expressed. Higher levels of expression are observed in kidney, liver and placenta.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hermansky-Pudlak syndrome 3	DIS7GFO2	Definitive	Autosomal recessive	[1]
Albinism	DIS5D82I	Strong	Genetic Variation	[2]
Hantavirus infection	DISZFTMH	Strong	Genetic Variation	[3]
Hermansky-Pudlak syndrome	DISCY0HQ	Strong	Genetic Variation	[3]
Hypopigmentation of the skin	DIS39YKC	Strong	Biomarker	[4]
Platelet storage pool deficiency	DISHODOH	Strong	Biomarker	[5]
Hermansky-Pudlak syndrome without pulmonary fibrosis	DIS0UYNY	Supportive	Autosomal recessive	[6]

1 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 HPS3 (HPS3).	[7]

10 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 BLOC-2 complex member HPS3 (HPS3).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of BLOC-2 complex member HPS3 (HPS3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BLOC-2 complex member HPS3 (HPS3).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of BLOC-2 complex member HPS3 (HPS3).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of BLOC-2 complex member HPS3 (HPS3).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of BLOC-2 complex member HPS3 (HPS3).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of BLOC-2 complex member HPS3 (HPS3).	[14]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of BLOC-2 complex member HPS3 (HPS3).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of BLOC-2 complex member HPS3 (HPS3).	[16]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of BLOC-2 complex member HPS3 (HPS3).	[17]

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] Ocular Findings in Patients with the Hermansky-Pudlak Syndrome (Types 1 and 3).Ophthalmic Genet. 2016;37(1):89-94. doi: 10.3109/13816810.2014.907920. Epub 2014 Apr 28.
• [3] Hermansky-Pudlak syndrome and oculocutaneous albinism in Chinese children with pigmentation defects and easy bruising.Orphanet J Rare Dis. 2019 Feb 21;14(1):52. doi: 10.1186/s13023-019-1023-7.
• [4] Melanocyte-specific proteins are aberrantly trafficked in melanocytes of Hermansky-Pudlak syndrome-type 3.Am J Pathol. 2005 Jan;166(1):231-40. doi: 10.1016/S0002-9440(10)62247-X.
• [5] Melanosome morphologies in murine models of hermansky-pudlak syndrome reflect blocks in organelle development.J Invest Dermatol. 2002 Nov;119(5):1156-64. doi: 10.1046/j.1523-1747.2002.19535.x.
• [6] 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.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [14] 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.
• [15] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [16] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [17] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.