Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKS5I7T)

• DOT Name: BLOC-3 complex member HPS1 (HPS1)
• Synonyms: Hermansky-Pudlak syndrome 1 protein
• Gene Name: HPS1
• Related Disease:
  Chediak-Higashi syndrome
  Hermansky-Pudlak syndrome 1
  Albinism
  Alzheimer disease
  Benign prostatic hyperplasia
  Breast cancer
  Breast carcinoma
  Coagulation defect
  Colitis
  Colorectal carcinoma
  Griscelli syndrome
  Hantavirus infection
  Hermansky-Pudlak syndrome
  Hermansky-Pudlak syndrome 4
  Hypopigmentation of the skin
  Inflammatory bowel disease
  Limb-girdle muscular dystrophy
  Nephropathy
  Ocular albinism
  Platelet storage pool deficiency
  Polyp
  Pulmonary disease
  Schizophrenia
  Usher syndrome type 1B
  Acute myelogenous leukaemia
  Bartter disease type 3
  Bartter syndrome
  Hemophagocytic syndrome
  Nephrocalcinosis
  Hermansky-Pudlak syndrome with pulmonary fibrosis
  Hermansky-Pudlak syndrome 3
• UniProt ID: HPS1_HUMAN
• Pfam ID: PF19036 ; PF19037 ; PF19038
• Sequence:
  MKCVLVATEGAEVLFYWTDQEFEESLRLKFGQSENEEEELPALEDQLSTLLAPVIISSMT
  MLEKLSDTYTCFSTENGNFLYVLHLFGECLFIAINGDHTESEGDLRRKLYVLKYLFEVHF
  GLVTVDGHLIRKELRPPDLAQRVQLWEHFQSLLWTYSRLREQEQCFAVEALERLIHPQLC
  ELCIEALERHVIQAVNTSPERGGEEALHAFLLVHSKLLAFYSSHSASSLRPADLLALILL
  VQDLYPSESTAEDDIQPSPRRARSSQNIPVQQAWSPHSTGPTGGSSAETETDSFSLPEEY
  FTPAPSPGDQSSGSTIWLEGGTPPMDALQIAEDTLQTLVPHCPVPSGPRRIFLDANVKES
  YCPLVPHTMYCLPLWQGINLVLLTRSPSAPLALVLSQLMDGFSMLEKKLKEGPEPGASLR
  SQPLVGDLRQRMDKFVKNRGAQEIQSTWLEFKAKAFSKSEPGSSWELLQACGKLKRQLCA
  IYRLNFLTTAPSRGGPHLPQHLQDQVQRLMREKLTDWKDFLLVKSRRNITMVSYLEDFPG
  LVHFIYVDRTTGQMVAPSLNCSQKTSSELGKGPLAAFVKTKVWSLIQLARRYLQKGYTTL
  LFQEGDFYCSYFLWFENDMGYKLQMIEVPVLSDDSVPIGMLGGDYYRKLLRYYSKNRPTE
  AVRCYELLALHLSVIPTDLLVQQAGQLARRLWEASRIPLL
• Function: Component of the BLOC-3 complex, a complex that acts as a guanine exchange factor (GEF) for RAB32 and RAB38, promotes the exchange of GDP to GTP, converting them from an inactive GDP-bound form into an active GTP-bound form. The BLOC-3 complex plays an important role in the control of melanin production and melanosome biogenesis and promotes the membrane localization of RAB32 and RAB38.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway: RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chediak-Higashi syndrome	DISPJLLO	Definitive	Genetic Variation	[1]
Hermansky-Pudlak syndrome 1	DIS966LQ	Definitive	Autosomal recessive	[2]
Albinism	DIS5D82I	Strong	Genetic Variation	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Coagulation defect	DIS9X3H6	Strong	Biomarker	[7]
Colitis	DISAF7DD	Strong	Genetic Variation	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[9]
Griscelli syndrome	DISTHCOQ	Strong	Genetic Variation	[10]
Hantavirus infection	DISZFTMH	Strong	Genetic Variation	[11]
Hermansky-Pudlak syndrome	DISCY0HQ	Strong	Biomarker	[12]
Hermansky-Pudlak syndrome 4	DISV59JX	Strong	Biomarker	[13]
Hypopigmentation of the skin	DIS39YKC	Strong	Altered Expression	[14]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[15]
Limb-girdle muscular dystrophy	DISI9Y1Z	Strong	Biomarker	[16]
Nephropathy	DISXWP4P	Strong	Biomarker	[14]
Ocular albinism	DIS5IHK1	Strong	Biomarker	[17]
Platelet storage pool deficiency	DISHODOH	Strong	Biomarker	[18]
Polyp	DISRSLYF	Strong	Biomarker	[9]
Pulmonary disease	DIS6060I	Strong	Genetic Variation	[19]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[20]
Usher syndrome type 1B	DISWTUHR	Strong	Genetic Variation	[10]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[21]
Bartter disease type 3	DISJJPTS	moderate	Biomarker	[22]
Bartter syndrome	DIS7D44B	moderate	Genetic Variation	[22]
Hemophagocytic syndrome	DIS3TMN4	moderate	Biomarker	[23]
Nephrocalcinosis	DIS5ZVJP	moderate	Biomarker	[22]
Hermansky-Pudlak syndrome with pulmonary fibrosis	DISHOVR0	Supportive	Autosomal recessive	[24]
Hermansky-Pudlak syndrome 3	DIS7GFO2	Disputed	Biomarker	[25]

2 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 BLOC-3 complex member HPS1 (HPS1).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of BLOC-3 complex member HPS1 (HPS1).	[33]

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-3 complex member HPS1 (HPS1).	[27]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BLOC-3 complex member HPS1 (HPS1).	[28]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of BLOC-3 complex member HPS1 (HPS1).	[29]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of BLOC-3 complex member HPS1 (HPS1).	[30]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of BLOC-3 complex member HPS1 (HPS1).	[31]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of BLOC-3 complex member HPS1 (HPS1).	[32]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of BLOC-3 complex member HPS1 (HPS1).	[30]

References

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• [12] The BLOC-3 subunit HPS4 is required for activation of Rab32/38 GTPases in melanogenesis, but its Rab9 activity is dispensable for melanogenesis.J Biol Chem. 2019 Apr 26;294(17):6912-6922. doi: 10.1074/jbc.RA119.007345. Epub 2019 Mar 5.
• [13] Galectin-3 Interacts with the CHI3L1 Axis and Contributes to Hermansky-Pudlak Syndrome Lung Disease.J Immunol. 2018 Mar 15;200(6):2140-2153. doi: 10.4049/jimmunol.1701442. Epub 2018 Feb 2.
• [14] Characterizing renal involvement in Hermansky-Pudlak Syndrome in a zebrafish model.Sci Rep. 2019 Nov 27;9(1):17718. doi: 10.1038/s41598-019-54058-5.
• [15] Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome).N Engl J Med. 1998 Apr 30;338(18):1258-64. doi: 10.1056/NEJM199804303381803.
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• [17] Clinical and molecular findings of FRMD7 related congenital nystagmus as adifferential diagnosis of ocular albinism.Ophthalmic Genet. 2019 Apr;40(2):161-164. doi: 10.1080/13816810.2019.1592201. Epub 2019 Apr 3.
• [18] Iris phenotypes and pigment dispersion caused by genes influencing pigmentation.Pigment Cell Melanoma Res. 2008 Oct;21(5):565-78. doi: 10.1111/j.1755-148X.2008.00482.x. Epub 2007 Jun 28.
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• [20] An association study of the Hermansky-Pudlak syndrome type 4 gene in schizophrenic patients.Psychiatr Genet. 2013 Aug;23(4):163-73. doi: 10.1097/YPG.0b013e32836130a9.
• [21] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [22] Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome.J Am Soc Nephrol. 2000 Aug;11(8):1449-1459. doi: 10.1681/ASN.V1181449.
• [23] Nontuberculous Mycobacterium infection complicated with Haemophagocytic syndrome: a case report and literature review.BMC Infect Dis. 2019 May 9;19(1):399. doi: 10.1186/s12879-019-4061-9.
• [24] 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.
• [25] A new genetic isolate with a unique phenotype of syndromic oculocutaneous albinism: clinical, molecular, and cellular characteristics.Hum Mutat. 2006 Nov;27(11):1158. doi: 10.1002/humu.9463.
• [26] 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.
• [27] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
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• [29] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [30] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [31] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [32] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [33] 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.