Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBTW01J)

• DOT Name: BLOC-3 complex member HPS4 (HPS4)
• Synonyms: Hermansky-Pudlak syndrome 4 protein; Light-ear protein homolog
• Gene Name: HPS4
• Related Disease:
  Hermansky-Pudlak syndrome 4
  Albinism
  Coagulation defect
  Colitis
  Hantavirus infection
  Hermansky-Pudlak syndrome
  Pulmonary disease
  Pulmonary fibrosis
  Schizophrenia
  Hermansky-Pudlak syndrome with pulmonary fibrosis
  Oculocutaneous albinism
  Respiratory failure
  Platelet storage pool deficiency
• UniProt ID: HPS4_HUMAN
• Pfam ID: PF19031 ; PF19033
• Sequence:
  MATSTSTEAKSASWWNYFFLYDGSKVKEEGDPTRAGICYFYPSQTLLDQQELLCGQIAGV
  VRCVSDISDSPPTLVRLRKLKFAIKVDGDYLWVLGCAVELPDVSCKRFLDQLVGFFNFYN
  GPVSLAYENCSQEELSTEWDTFIEQILKNTSDLHKIFNSLWNLDQTKVEPLLLLKAARIL
  QTCQRSPHILAGCILYKGLIVSTQLPPSLTAKVLLHRTAPQEQRLPTGEDAPQEHGAALP
  PNVQIIPVFVTKEEAISLHEFPVEQMTRSLASPAGLQDGSAQHHPKGGSTSALKENATGH
  VESMAWTTPDPTSPDEACPDGRKENGCLSGHDLESIRPAGLHNSARGEVLGLSSSLGKEL
  VFLQEELDLSEIHIPEAQEVEMASGHFAFLHVPVPDGRAPYCKASLSASSSLEPTPPEDT
  AISSLRPPSAPEMLTQHGAQEQLEDHPGHSSQAPIPRADPLPRRTRRPLLLPRLDPGQRG
  NKLPTGEQGLDEDVDGVCESHAAPGLECSSGSANCQGAGPSADGISSRLTPAESCMGLVR
  MNLYTHCVKGLVLSLLAEEPLLGDSAAIEEVYHSSLASLNGLEVHLKETLPRDEAASTSS
  TYNFTHYDRIQSLLMANLPQVATPQDRRFLQAVSLMHSEFAQLPALYEMTVRNASTAVYA
  CCNPIQETYFQQLAPAARSSGFPNPQDGAFSLSGKAKQKLLKHGVNLL
• 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.
• Reactome Pathway: RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hermansky-Pudlak syndrome 4	DISV59JX	Definitive	Autosomal recessive	[1]
Albinism	DIS5D82I	Strong	Genetic Variation	[2]
Coagulation defect	DIS9X3H6	Strong	Biomarker	[3]
Colitis	DISAF7DD	Strong	Biomarker	[4]
Hantavirus infection	DISZFTMH	Strong	Genetic Variation	[5]
Hermansky-Pudlak syndrome	DISCY0HQ	Strong	Biomarker	[6]
Pulmonary disease	DIS6060I	Strong	Biomarker	[7]
Pulmonary fibrosis	DISQKVLA	moderate	Genetic Variation	[5]
Schizophrenia	DISSRV2N	moderate	Biomarker	[8]
Hermansky-Pudlak syndrome with pulmonary fibrosis	DISHOVR0	Supportive	Autosomal recessive	[9]
Oculocutaneous albinism	DISJS7CU	Disputed	Genetic Variation	[5]
Respiratory failure	DISVMYJO	Disputed	Biomarker	[5]
Platelet storage pool deficiency	DISHODOH	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of BLOC-3 complex member HPS4 (HPS4).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of BLOC-3 complex member HPS4 (HPS4).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BLOC-3 complex member HPS4 (HPS4).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of BLOC-3 complex member HPS4 (HPS4).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of BLOC-3 complex member HPS4 (HPS4).	[16]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of BLOC-3 complex member HPS4 (HPS4).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of BLOC-3 complex member HPS4 (HPS4).	[19]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of BLOC-3 complex member HPS4 (HPS4).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of BLOC-3 complex member HPS4 (HPS4).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of BLOC-3 complex member HPS4 (HPS4).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of BLOC-3 complex member HPS4 (HPS4).	[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] A deletion in the Hermansky-Pudlak syndrome 4 (Hps4) gene appears to be responsible for albinism in channel catfish.Mol Genet Genomics. 2017 Jun;292(3):663-670. doi: 10.1007/s00438-017-1302-8. Epub 2017 Mar 13.
• [3] Hermansky-Pudlak syndrome type 1 in patients of Indian descent.Mol Genet Metab. 2009 Jul;97(3):227-33. doi: 10.1016/j.ymgme.2009.03.011. Epub 2009 Apr 2.
• [4] Hermansky-Pudlak syndrome type 4 (HPS-4): clinical and molecular characteristics. Hum Genet. 2003 Jul;113(1):10-7. doi: 10.1007/s00439-003-0933-5. Epub 2003 Mar 27.
• [5] A novel mutation causes Hermansky-Pudlak syndrome type 4 with pulmonary fibrosis in 2 siblings from China.Medicine (Baltimore). 2019 Aug;98(33):e16899. doi: 10.1097/MD.0000000000016899.
• [6] 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.
• [7] Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene.Nat Genet. 2002 Mar;30(3):321-4. doi: 10.1038/ng835. Epub 2002 Feb 11.
• [8] 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.
• [9] 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.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] 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.
• [13] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [14] 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.
• [15] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [16] 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.
• [17] 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.
• [18] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.