Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOJWV3F)

• DOT Name: HCLS1-associated protein X-1 (HAX1)
• Synonyms: HS1-associating protein X-1; HAX-1; HS1-binding protein 1; HSP1BP-1
• Gene Name: HAX1
• Related Disease: Kostmann syndrome
• UniProt ID: HAX1_HUMAN
• Sequence:
  MSLFDLFRGFFGFPGPRSHRDPFFGGMTRDEDDDEEEEEEGGSWGRGNPRFHSPQHPPEE
  FGFGFSFSPGGGIRFHDNFGFDDLVRDFNSIFSDMGAWTLPSHPPELPGPESETPGERLR
  EGQTLRDSMLKYPDSHQPRIFGGVLESDARSESPQPAPDWGSQRPFHRFDDVWPMDPHPR
  TREDNDLDSQVSQEGLGPVLQPQPKSYFKSISVTKITKPDGIVEERRTVVDSEGRTETTV
  TRHEADSSPRGDPESPRPPALDDAFSILDLFLGRWFRSR
• Function: Recruits the Arp2/3 complex to the cell cortex and regulates reorganization of the cortical actin cytoskeleton via its interaction with KCNC3 and the Arp2/3 complex. Slows down the rate of inactivation of KCNC3 channels. Promotes GNA13-mediated cell migration. Involved in the clathrin-mediated endocytosis pathway. May be involved in internalization of ABC transporters such as ABCB11. May inhibit CASP9 and CASP3. Promotes cell survival. May regulate intracellular calcium pools.
• Tissue Specificity: Ubiquitous. Up-regulated in oral cancers.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Kostmann syndrome	DISDR6N8	Definitive	Autosomal recessive	[1]

15 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 HCLS1-associated protein X-1 (HAX1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of HCLS1-associated protein X-1 (HAX1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of HCLS1-associated protein X-1 (HAX1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of HCLS1-associated protein X-1 (HAX1).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of HCLS1-associated protein X-1 (HAX1).	[6]
Marinol	DM70IK5	Approved	Marinol decreases the expression of HCLS1-associated protein X-1 (HAX1).	[7]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of HCLS1-associated protein X-1 (HAX1).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of HCLS1-associated protein X-1 (HAX1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of HCLS1-associated protein X-1 (HAX1).	[10]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of HCLS1-associated protein X-1 (HAX1).	[11]
MG-132	DMKA2YS	Preclinical	MG-132 affects the expression of HCLS1-associated protein X-1 (HAX1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of HCLS1-associated protein X-1 (HAX1).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of HCLS1-associated protein X-1 (HAX1).	[14]
AM251	DMTAWHL	Investigative	AM251 increases the expression of HCLS1-associated protein X-1 (HAX1).	[15]
BAY11-7082	DMQNOFA	Investigative	BAY11-7082 decreases the expression of HCLS1-associated protein X-1 (HAX1).	[16]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] 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.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] 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.
• [7] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [8] 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.
• [9] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [10] 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.
• [11] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [12] Novel mitochondrial substrates of omi indicate a new regulatory role in neurodegenerative disorders. PLoS One. 2009 Sep 18;4(9):e7100. doi: 10.1371/journal.pone.0007100.
• [13] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.
• [16] N(alpha)-tosyl-L-phenylalanine chloromethyl ketone induces caspase-dependent apoptosis in transformed human B cell lines with transcriptional down-regulation of anti-apoptotic HS1-associated protein X-1. J Biol Chem. 2009 Oct 9;284(41):27827-27837. doi: 10.1074/jbc.M109.027912. Epub 2009 Aug 13.