Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0I83YS)

• DOT Name: Heat shock protein beta-8 (HSPB8)
• Synonyms: HspB8; Alpha-crystallin C chain; E2-induced gene 1 protein; Protein kinase H11; Small stress protein-like protein HSP22
• Gene Name: HSPB8
• Related Disease:
  Neuronopathy, distal hereditary motor, autosomal dominant
  Charcot-Marie-Tooth disease axonal type 2L
  Neuronopathy, distal hereditary motor, type 2A
  Autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome
  Distal hereditary motor neuropathy type 2
• UniProt ID: HSPB8_HUMAN
• Pfam ID: PF00011
• Sequence:
  MADGQMPFSCHYPSRLRRDPFRDSPLSSRLLDDGFGMDPFPDDLTASWPDWALPRLSSAW
  PGTLRSGMVPRGPTATARFGVPAEGRTPPPFPGEPWKVCVNVHSFKPEELMVKTKDGYVE
  VSGKHEEKQQEGGIVSKNFTKKIQLPAEVDPVTVFASLSPEGLLIIEAPQVPPYSTFGES
  SFNNELPQDSQEVTCT
• Function: Displays temperature-dependent chaperone activity.
• Tissue Specificity: Predominantly expressed in skeletal muscle and heart.
• Reactome Pathway: HSF1-dependent transactivation (R-HSA-3371571)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuronopathy, distal hereditary motor, autosomal dominant	DIS4M3WN	Definitive	Autosomal dominant	[1]
Charcot-Marie-Tooth disease axonal type 2L	DISO472Y	Strong	Autosomal dominant	[2]
Neuronopathy, distal hereditary motor, type 2A	DIS89MRX	Strong	Autosomal dominant	[3]
Autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome	DISJ9NDI	Supportive	Autosomal dominant	[4]
Distal hereditary motor neuropathy type 2	DIS162V1	Supportive	Autosomal dominant	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Heat shock protein beta-8 (HSPB8) decreases the response to substance of Afimoxifene.	[23]

26 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 Heat shock protein beta-8 (HSPB8).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Heat shock protein beta-8 (HSPB8).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Heat shock protein beta-8 (HSPB8).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Heat shock protein beta-8 (HSPB8).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Heat shock protein beta-8 (HSPB8).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Heat shock protein beta-8 (HSPB8).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Heat shock protein beta-8 (HSPB8).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Heat shock protein beta-8 (HSPB8).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Heat shock protein beta-8 (HSPB8).	[13]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Heat shock protein beta-8 (HSPB8).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Heat shock protein beta-8 (HSPB8).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Heat shock protein beta-8 (HSPB8).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Heat shock protein beta-8 (HSPB8).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Heat shock protein beta-8 (HSPB8).	[16]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Heat shock protein beta-8 (HSPB8).	[17]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Heat shock protein beta-8 (HSPB8).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Heat shock protein beta-8 (HSPB8).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Heat shock protein beta-8 (HSPB8).	[20]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Heat shock protein beta-8 (HSPB8).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Heat shock protein beta-8 (HSPB8).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Heat shock protein beta-8 (HSPB8).	[6]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the expression of Heat shock protein beta-8 (HSPB8).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Heat shock protein beta-8 (HSPB8).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Heat shock protein beta-8 (HSPB8).	[25]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the expression of Heat shock protein beta-8 (HSPB8).	[23]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Heat shock protein beta-8 (HSPB8).	[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] A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L) maps to chromosome 12q24. Hum Genet. 2004 May;114(6):527-33. doi: 10.1007/s00439-004-1102-1. Epub 2004 Mar 12.
• [3] Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet. 2004 Jun;36(6):597-601. doi: 10.1038/ng1328. Epub 2004 May 2.
• [4] Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy. Neurology. 2016 Jan 26;86(4):391-8. doi: 10.1212/WNL.0000000000002324. Epub 2015 Dec 30.
• [5] 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.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [11] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [12] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [15] Gene expression profiling of rheumatoid arthritis synovial cells treated with antirheumatic drugs. J Biomol Screen. 2007 Apr;12(3):328-40. doi: 10.1177/1087057107299261. Epub 2007 Mar 22.
• [16] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [17] Transcriptional profiling of MCF7 breast cancer cells in response to 5-Fluorouracil: relationship with cell cycle changes and apoptosis, and identification of novel targets of p53. Int J Cancer. 2006 Sep 1;119(5):1164-75.
• [18] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] Regulation of lipocalin-2 gene by the cancer chemopreventive retinoid 4-HPR. Int J Cancer. 2006 Oct 1;119(7):1599-606.
• [22] Effects of triclocarban on the transcription of estrogen, androgen and aryl hydrocarbon receptor responsive genes in human breast cancer cells. Toxicol In Vitro. 2013 Aug;27(5):1467-75.
• [23] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [24] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.