Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWCI7ZA)

• DOT Name: HUWE1-associated protein modifying stress responses 1 (HAPSTR1)
• Synonyms: Telomere attrition and p53 response 1 protein
• Gene Name: HAPSTR1
• UniProt ID: HAPR1_HUMAN
• Pfam ID: PF15251
• Sequence:
  MEERKEEGEAEIQEHGPEHWFSKWERQCLAEAEQDEQLPPELQEEAAAAAQPEHKQQKLW
  HLFQNSATAVAQLYKDRVCQQPGLSLWVPFQNAATAVTNLYKESVDTHQRSFDIGIQIGY
  QRRNKDVLAWVKKRRRTIRREDLISFLCGKVPPPRNSRAPPRLTVVSPNRATSTETSSSV
  ETDLQPFREAIALHGLSGAMASISVRSSTPGSPTHVSSGSNASRRRNGLHDVDLNTFISE
  EMALHLDNGGTRKRTSAQCGDVITDSPTHKRNRMI
• Function: Acts as a central player within a network of stress response pathways promoting cellular adaptability. The E3 ligase HUWE1 assists HAPSTR1 in controlling stress signaling and in turn, HUWE1 feeds back to promote the degradation of HAPSTR1. HAPSTR1 represents a central coordination mechanism for stress response programs. Functions as a negative regulator of TP53/P53 in the cellular response to telomere erosion and probably also DNA damage. May attenuate p53/TP53 activation through the E3 ubiquitin ligase HUWE1.

Molecular Interaction Atlas (MIA) of This DOT

3 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 HUWE1-associated protein modifying stress responses 1 (HAPSTR1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of HUWE1-associated protein modifying stress responses 1 (HAPSTR1).	[8]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of HUWE1-associated protein modifying stress responses 1 (HAPSTR1).	[9]

8 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 HUWE1-associated protein modifying stress responses 1 (HAPSTR1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of HUWE1-associated protein modifying stress responses 1 (HAPSTR1).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of HUWE1-associated protein modifying stress responses 1 (HAPSTR1).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of HUWE1-associated protein modifying stress responses 1 (HAPSTR1).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of HUWE1-associated protein modifying stress responses 1 (HAPSTR1).	[6]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of HUWE1-associated protein modifying stress responses 1 (HAPSTR1).	[7]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of HUWE1-associated protein modifying stress responses 1 (HAPSTR1).	[10]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of HUWE1-associated protein modifying stress responses 1 (HAPSTR1).	[11]

References

• [1] 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.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [5] 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.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [8] 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.
• [9] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [10] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [11] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.