Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4B7CPF)

• DOT Name: High mobility group protein B1 (HMGB1)
• Synonyms: High mobility group protein 1; HMG-1
• Gene Name: HMGB1
• UniProt ID: HMGB1_HUMAN
• PDB ID: 2LY4; 2RTU; 2YRQ; 6CG0; 6CIJ; 6CIK; 6CIL; 6CIM; 6OEM; 6OEN; 6OEO
• Pfam ID: PF00505 ; PF09011
• Sequence:
  MGKGDPKKPRGKMSSYAFFVQTCREEHKKKHPDASVNFSEFSKKCSERWKTMSAKEKGKF
  EDMAKADKARYEREMKTYIPPKGETKKKFKDPNAPKRPPSAFFLFCSEYRPKIKGEHPGL
  SIGDVAKKLGEMWNNTAADDKQPYEKKAAKLKEKYEKDIAAYRAKGKPDAAKKGVVKAEK
  SKKKKEEEEDEEDEEDEEEEEDEEDEDEEEDDDDE
• Function: Multifunctional redox sensitive protein with various roles in different cellular compartments. In the nucleus is one of the major chromatin-associated non-histone proteins and acts as a DNA chaperone involved in replication, transcription, chromatin remodeling, V(D)J recombination, DNA repair and genome stability. Proposed to be an universal biosensor for nucleic acids. Promotes host inflammatory response to sterile and infectious signals and is involved in the coordination and integration of innate and adaptive immune responses. In the cytoplasm functions as a sensor and/or chaperone for immunogenic nucleic acids implicating the activation of TLR9-mediated immune responses, and mediates autophagy. Acts as a danger-associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury. Released to the extracellular environment can bind DNA, nucleosomes, IL-1 beta, CXCL12, AGER isoform 2/sRAGE, lipopolysaccharide (LPS) and lipoteichoic acid (LTA), and activates cells through engagement of multiple surface receptors. In the extracellular compartment fully reduced HMGB1 (released by necrosis) acts as a chemokine, disulfide HMGB1 (actively secreted) as a cytokine, and sulfonyl HMGB1 (released from apoptotic cells) promotes immunological tolerance. Has proangiogdenic activity. May be involved in platelet activation. Binds to phosphatidylserine and phosphatidylethanolamide. Bound to RAGE mediates signaling for neuronal outgrowth. May play a role in accumulation of expanded polyglutamine (polyQ) proteins such as huntingtin (HTT) or TBP ; Nuclear functions are attributed to fully reduced HGMB1. Associates with chromatin and binds DNA with a preference to non-canonical DNA structures such as single-stranded DNA, DNA-containing cruciforms or bent structures, supercoiled DNA and ZDNA. Can bent DNA and enhance DNA flexibility by looping thus providing a mechanism to promote activities on various gene promoters by enhancing transcription factor binding and/or bringing distant regulatory sequences into close proximity. May have an enhancing role in nucleotide excision repair (NER). However, effects in NER using in vitro systems have been reported conflictingly. May be involved in mismatch repair (MMR) and base excision repair (BER) pathways. May be involved in double strand break repair such as non-homologous end joining (NHEJ). Involved in V(D)J recombination by acting as a cofactor of the RAG complex: acts by stimulating cleavage and RAG protein binding at the 23 bp spacer of conserved recombination signal sequences (RSS). In vitro can displace histone H1 from highly bent DNA. Can restructure the canonical nucleosome leading to relaxation of structural constraints for transcription factor-binding. Enhances binding of sterol regulatory element-binding proteins (SREBPs) such as SREBF1 to their cognate DNA sequences and increases their transcriptional activities. Facilitates binding of TP53 to DNA. Proposed to be involved in mitochondrial quality control and autophagy in a transcription-dependent fashion implicating HSPB1; however, this function has been questioned. Can modulate the activity of the telomerase complex and may be involved in telomere maintenance; In the cytoplasm proposed to dissociate the BECN1:BCL2 complex via competitive interaction with BECN1 leading to autophagy activation. Involved in oxidative stress-mediated autophagy. Can protect BECN1 and ATG5 from calpain-mediated cleavage and thus proposed to control their proautophagic and proapoptotic functions and to regulate the extent and severity of inflammation-associated cellular injury. In myeloid cells has a protective role against endotoxemia and bacterial infection by promoting autophagy. Involved in endosomal translocation and activation of TLR9 in response to CpG-DNA in macrophages; In the extracellular compartment (following either active secretion or passive release) involved in regulation of the inflammatory response. Fully reduced HGMB1 (which subsequently gets oxidized after release) in association with CXCL12 mediates the recruitment of inflammatory cells during the initial phase of tissue injury; the CXCL12:HMGB1 complex triggers CXCR4 homodimerization. Induces the migration of monocyte-derived immature dendritic cells and seems to regulate adhesive and migratory functions of neutrophils implicating AGER/RAGE and ITGAM. Can bind to various types of DNA and RNA including microbial unmethylated CpG-DNA to enhance the innate immune response to nucleic acids. Proposed to act in promiscuous DNA/RNA sensing which cooperates with subsequent discriminative sensing by specific pattern recognition receptors. Promotes extracellular DNA-induced AIM2 inflammasome activation implicating AGER/RAGE. Disulfide HMGB1 binds to transmembrane receptors, such as AGER/RAGE, TLR2, TLR4 and probably TREM1, thus activating their signal transduction pathways. Mediates the release of cytokines/chemokines such as TNF, IL-1, IL-6, IL-8, CCL2, CCL3, CCL4 and CXCL10. Promotes secretion of interferon-gamma by macrophage-stimulated natural killer (NK) cells in concert with other cytokines like IL-2 or IL-12. TLR4 is proposed to be the primary receptor promoting macrophage activation and signaling through TLR4 seems to implicate LY96/MD-2. In bacterial LPS- or LTA-mediated inflammatory responses binds to the endotoxins and transfers them to CD14 for signaling to the respective TLR4:LY96 and TLR2 complexes. Contributes to tumor proliferation by association with ACER/RAGE. Can bind to IL1-beta and signals through the IL1R1:IL1RAP receptor complex. Binding to class A CpG activates cytokine production in plasmacytoid dendritic cells implicating TLR9, MYD88 and AGER/RAGE and can activate autoreactive B cells. Via HMGB1-containing chromatin immune complexes may also promote B cell responses to endogenous TLR9 ligands through a B-cell receptor (BCR)-dependent and ACER/RAGE-independent mechanism. Inhibits phagocytosis of apoptotic cells by macrophages; the function is dependent on poly-ADP-ribosylation and involves binding to phosphatidylserine on the cell surface of apoptotic cells. In adaptive immunity may be involved in enhancing immunity through activation of effector T cells and suppression of regulatory T (TReg) cells. In contrast, without implicating effector or regulatory T-cells, required for tumor infiltration and activation of T-cells expressing the lymphotoxin LTA:LTB heterotrimer thus promoting tumor malignant progression. Also reported to limit proliferation of T-cells. Released HMGB1:nucleosome complexes formed during apoptosis can signal through TLR2 to induce cytokine production. Involved in induction of immunological tolerance by apoptotic cells; its pro-inflammatory activities when released by apoptotic cells are neutralized by reactive oxygen species (ROS)-dependent oxidation specifically on Cys-106. During macrophage activation by activated lymphocyte-derived self apoptotic DNA (ALD-DNA) promotes recruitment of ALD-DNA to endosomes; (Microbial infection) Critical for entry of human coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus NL63/HCoV-NL63. Regulates the expression of the pro-viral genes ACE2 and CTSL through chromatin modulation. Required for SARS-CoV-2 ORF3A-induced reticulophagy which induces endoplasmic reticulum stress and inflammatory responses and facilitates viral infection ; (Microbial infection) Associates with the influenza A viral protein NP in the nucleus of infected cells, promoting viral growth and enhancing the activity of the viral polymerase; (Microbial infection) Promotes Epstein-Barr virus (EBV) latent-to-lytic switch by sustaining the expression of the viral transcription factor BZLF1 that acts as a molecular switch to induce the transition from the latent to the lytic or productive phase of the virus cycle. Mechanistically, participates in EBV reactivation through the NLRP3 inflammasome; (Microbial infection) Facilitates dengue virus propagation via interaction with the untranslated regions of viral genome. In turn, this interaction with viral RNA may regulate secondary structure of dengue RNA thus facilitating its recognition by the replication complex.
• Tissue Specificity: Ubiquitous. Expressed in platelets .
• KEGG Pathway:
  Base excision repair (hsa03410)
  Autophagy - animal (hsa04140)
  Necroptosis (hsa04217)
  Neutrophil extracellular trap formation (hsa04613)
• Reactome Pathway:
  Apoptosis induced DNA fragmentation (R-HSA-140342)
  MyD88 (R-HSA-166058)
  TAK1-dependent IKK and NF-kappa-B activation (R-HSA-445989)
  MyD88 deficiency (TLR2/4) (R-HSA-5602498)
  IRAK4 deficiency (TLR2/4) (R-HSA-5603041)
  Pyroptosis (R-HSA-5620971)
  Regulation of TLR by endogenous ligand (R-HSA-5686938)
  Neutrophil degranulation (R-HSA-6798695)
  Advanced glycosylation endproduct receptor signaling (R-HSA-879415)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  ER-Phagosome pathway (R-HSA-1236974)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	High mobility group protein B1 (HMGB1) affects the response to substance of Paclitaxel.	[39]
Topotecan	DMP6G8T	Approved	High mobility group protein B1 (HMGB1) affects the response to substance of Topotecan.	[39]
Vinblastine	DM5TVS3	Approved	High mobility group protein B1 (HMGB1) affects the response to substance of Vinblastine.	[39]

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 High mobility group protein B1 (HMGB1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of High mobility group protein B1 (HMGB1).	[22]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of High mobility group protein B1 (HMGB1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of High mobility group protein B1 (HMGB1).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of High mobility group protein B1 (HMGB1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of High mobility group protein B1 (HMGB1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of High mobility group protein B1 (HMGB1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of High mobility group protein B1 (HMGB1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of High mobility group protein B1 (HMGB1).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of High mobility group protein B1 (HMGB1).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of High mobility group protein B1 (HMGB1).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of High mobility group protein B1 (HMGB1).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of High mobility group protein B1 (HMGB1).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of High mobility group protein B1 (HMGB1).	[13]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of High mobility group protein B1 (HMGB1).	[14]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of High mobility group protein B1 (HMGB1).	[12]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of High mobility group protein B1 (HMGB1).	[16]
Sorafenib	DMS8IFC	Approved	Sorafenib increases the expression of High mobility group protein B1 (HMGB1).	[17]
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin increases the expression of High mobility group protein B1 (HMGB1).	[19]
Romiplostim	DM3U7SZ	Approved	Romiplostim increases the expression of High mobility group protein B1 (HMGB1).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of High mobility group protein B1 (HMGB1).	[21]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of High mobility group protein B1 (HMGB1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of High mobility group protein B1 (HMGB1).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of High mobility group protein B1 (HMGB1).	[25]
Acteoside	DM0YHKB	Terminated	Acteoside decreases the expression of High mobility group protein B1 (HMGB1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of High mobility group protein B1 (HMGB1).	[27]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of High mobility group protein B1 (HMGB1).	[28]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of High mobility group protein B1 (HMGB1).	[29]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of High mobility group protein B1 (HMGB1).	[30]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of High mobility group protein B1 (HMGB1).	[31]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of High mobility group protein B1 (HMGB1).	[32]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of High mobility group protein B1 (HMGB1).	[33]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of High mobility group protein B1 (HMGB1).	[34]
acrolein	DMAMCSR	Investigative	acrolein increases the expression of High mobility group protein B1 (HMGB1).	[35]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of High mobility group protein B1 (HMGB1).	[36]
OLEANOLIC_ACID	DMWDMJ3	Investigative	OLEANOLIC_ACID decreases the expression of High mobility group protein B1 (HMGB1).	[37]

8 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the secretion of High mobility group protein B1 (HMGB1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the secretion of High mobility group protein B1 (HMGB1).	[5]
Ethanol	DMDRQZU	Approved	Ethanol increases the secretion of High mobility group protein B1 (HMGB1).	[15]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the secretion of High mobility group protein B1 (HMGB1).	[3]
Etoposide	DMNH3PG	Approved	Etoposide increases the secretion of High mobility group protein B1 (HMGB1).	[3]
Gefitinib	DM15F0X	Approved	Gefitinib increases the secretion of High mobility group protein B1 (HMGB1).	[18]
Flucloxacillin	DMNUWST	Approved	Flucloxacillin increases the secretion of High mobility group protein B1 (HMGB1).	[20]
MANGOSTIN	DMYQGDV	Investigative	MANGOSTIN decreases the secretion of High mobility group protein B1 (HMGB1).	[38]

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