Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGY5D5J)

• DOT Name: Sequestosome-1 (SQSTM1)
• Synonyms: EBI3-associated protein of 60 kDa; EBIAP; p60; Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa; Ubiquitin-binding protein p62
• Gene Name: SQSTM1
• Related Disease:
  Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset
  Frontotemporal dementia and/or amyotrophic lateral sclerosis 3
  Osteosarcoma
  Paget disease of bone 3
  Amyotrophic lateral sclerosis
  Behavioral variant of frontotemporal dementia
  Frontotemporal dementia with motor neuron disease
• UniProt ID: SQSTM_HUMAN
• PDB ID: 1Q02; 2JY7; 2JY8; 2K0B; 2KNV; 4MJS; 4UF8; 4UF9; 5YP7; 5YP8; 5YPA; 5YPB; 5YPC; 5YPE; 5YPF; 5YPG; 5YPH; 6JM4; 6KHZ; 6MJ7; 6TGY; 6TH3; 7R1O
• Pfam ID: PF00564 ; PF16577 ; PF00569
• Sequence:
  MASLTVKAYLLGKEDAAREIRRFSFCCSPEPEAEAEAAAGPGPCERLLSRVAALFPALRP
  GGFQAHYRDEDGDLVAFSSDEELTMAMSYVKDDIFRIYIKEKKECRRDHRPPCAQEAPRN
  MVHPNVICDGCNGPVVGTRYKCSVCPDYDLCSVCEGKGLHRGHTKLAFPSPFGHLSEGFS
  HSRWLRKVKHGHFGWPGWEMGPPGNWSPRPPRAGEARPGPTAESASGPSEDPSVNFLKNV
  GESVAAALSPLGIEVDIDVEHGGKRSRLTPVSPESSSTEEKSSSQPSSCCSDPSKPGGNV
  EGATQSLAEQMRKIALESEGRPEEQMESDNCSGGDDDWTHLSSKEVDPSTGELQSLQMPE
  SEGPSSLDPSQEGPTGLKEAALYPHLPPEADPRLIESLSQMLSMGFSDEGGWLTRLLQTK
  NYDIGAALDTIQYSKHPPPL
• Function: Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a a bridge between polyubiquitinated proteins and autophagosomes. Promotes the recruitment of ubiquitinated cargo proteins to autophagosomes via multiple domains that bridge proteins and organelles in different steps. SQSTM1 first mediates the assembly and removal of ubiquitinated proteins by undergoing liquid-liquid phase separation upon binding to ubiquitinated proteins via its UBA domain, leading to the formation of insoluble cytoplasmic inclusions, known as p62 bodies. SQSTM1 then interacts with ATG8 family proteins on autophagosomes via its LIR motif, leading to p62 body recruitment to autophagosomes, followed by autophagic clearance of ubiquitinated proteins. SQSTM1 is itself degraded along with its ubiquitinated cargos. Also required to recruit ubiquitinated proteins to PML bodies in the nucleus. Also involved in autophagy of peroxisomes (pexophagy) in response to reactive oxygen species (ROS) by acting as a bridge between ubiquitinated PEX5 receptor and autophagosomes. Acts as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: interaction inactivates the BCR(KEAP1) complex by sequestering the complex in inclusion bodies, promoting nuclear accumulation of NFE2L2/NRF2 and subsequent expression of cytoprotective genes. Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes. Involved in endosome organization by retaining vesicles in the perinuclear cloud: following ubiquitination by RNF26, attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport. Sequesters tensin TNS2 into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal degradation. May regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. Adapter that mediates the interaction between TRAF6 and CYLD.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Mitophagy - animal (hsa04137)
  Autophagy - animal (hsa04140)
  Necroptosis (hsa04217)
  Cellular senescence (hsa04218)
  Osteoclast differentiation (hsa04380)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Shigellosis (hsa05131)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  p75NTR recruits signalling complexes (R-HSA-209543)
  NF-kB is activated and signals survival (R-HSA-209560)
  PINK1-PRKN Mediated Mitophagy (R-HSA-5205685)
  Neddylation (R-HSA-8951664)
  Interleukin-1 signaling (R-HSA-9020702)
  Pexophagy (R-HSA-9664873)
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  Nuclear events mediated by NFE2L2 (R-HSA-9759194)
  NRIF signals cell death from the nucleus (R-HSA-205043)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset	DISE9VTC	Definitive	Autosomal recessive	[1]
Frontotemporal dementia and/or amyotrophic lateral sclerosis 3	DISYMV4O	Strong	Autosomal dominant	[2]
Osteosarcoma	DISLQ7E2	Strong	Autosomal dominant	[3]
Paget disease of bone 3	DISZ9LUZ	Strong	Autosomal dominant	[3]
Amyotrophic lateral sclerosis	DISF7HVM	Supportive	Autosomal dominant	[4]
Behavioral variant of frontotemporal dementia	DISQHX2V	Supportive	Autosomal dominant	[5]
Frontotemporal dementia with motor neuron disease	DISPZM6A	Supportive	Autosomal dominant	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Sequestosome-1 (SQSTM1).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Sequestosome-1 (SQSTM1).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Sequestosome-1 (SQSTM1).	[78]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Sequestosome-1 (SQSTM1).	[87]

93 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 Sequestosome-1 (SQSTM1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sequestosome-1 (SQSTM1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sequestosome-1 (SQSTM1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Sequestosome-1 (SQSTM1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sequestosome-1 (SQSTM1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sequestosome-1 (SQSTM1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sequestosome-1 (SQSTM1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sequestosome-1 (SQSTM1).	[14]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sequestosome-1 (SQSTM1).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Sequestosome-1 (SQSTM1).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Sequestosome-1 (SQSTM1).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Sequestosome-1 (SQSTM1).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Sequestosome-1 (SQSTM1).	[20]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Sequestosome-1 (SQSTM1).	[21]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Sequestosome-1 (SQSTM1).	[22]
Marinol	DM70IK5	Approved	Marinol increases the expression of Sequestosome-1 (SQSTM1).	[23]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Sequestosome-1 (SQSTM1).	[24]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Sequestosome-1 (SQSTM1).	[25]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Sequestosome-1 (SQSTM1).	[26]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Sequestosome-1 (SQSTM1).	[27]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Sequestosome-1 (SQSTM1).	[28]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Sequestosome-1 (SQSTM1).	[29]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Sequestosome-1 (SQSTM1).	[30]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Sequestosome-1 (SQSTM1).	[31]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Sequestosome-1 (SQSTM1).	[32]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Sequestosome-1 (SQSTM1).	[33]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Sequestosome-1 (SQSTM1).	[34]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Sequestosome-1 (SQSTM1).	[35]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Sequestosome-1 (SQSTM1).	[36]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Sequestosome-1 (SQSTM1).	[37]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Sequestosome-1 (SQSTM1).	[38]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Sequestosome-1 (SQSTM1).	[39]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Sequestosome-1 (SQSTM1).	[40]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Sequestosome-1 (SQSTM1).	[41]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Sequestosome-1 (SQSTM1).	[42]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Sequestosome-1 (SQSTM1).	[43]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the expression of Sequestosome-1 (SQSTM1).	[44]
Gefitinib	DM15F0X	Approved	Gefitinib decreases the expression of Sequestosome-1 (SQSTM1).	[45]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate increases the expression of Sequestosome-1 (SQSTM1).	[46]
Imatinib	DM7RJXL	Approved	Imatinib increases the expression of Sequestosome-1 (SQSTM1).	[47]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Sequestosome-1 (SQSTM1).	[48]
Nefazodone	DM4ZS8M	Approved	Nefazodone increases the expression of Sequestosome-1 (SQSTM1).	[49]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol decreases the expression of Sequestosome-1 (SQSTM1).	[50]
Artesunate	DMR27C8	Approved	Artesunate decreases the expression of Sequestosome-1 (SQSTM1).	[51]
Sevoflurane	DMC9O43	Approved	Sevoflurane decreases the expression of Sequestosome-1 (SQSTM1).	[52]
Atazanavir	DMSYRBX	Approved	Atazanavir increases the expression of Sequestosome-1 (SQSTM1).	[49]
Hydroxychloroquine	DMSIVND	Approved	Hydroxychloroquine increases the expression of Sequestosome-1 (SQSTM1).	[53]
Reserpine	DM6VM38	Approved	Reserpine increases the expression of Sequestosome-1 (SQSTM1).	[42]
Ropivacaine	DMSPJG2	Approved	Ropivacaine decreases the expression of Sequestosome-1 (SQSTM1).	[54]
Osimertinib	DMRJLAT	Approved	Osimertinib decreases the expression of Sequestosome-1 (SQSTM1).	[55]
Miconazole	DMPMYE8	Approved	Miconazole increases the expression of Sequestosome-1 (SQSTM1).	[56]
Promethazine	DM6I5GR	Approved	Promethazine increases the expression of Sequestosome-1 (SQSTM1).	[57]
Trametinib	DM2JGQ3	Approved	Trametinib decreases the expression of Sequestosome-1 (SQSTM1).	[58]
AZD5363	DM9SKW8	Approved	AZD5363 affects the expression of Sequestosome-1 (SQSTM1).	[59]
Benzocaine	DMI18HW	Approved	Benzocaine decreases the expression of Sequestosome-1 (SQSTM1).	[60]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sequestosome-1 (SQSTM1).	[61]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Sequestosome-1 (SQSTM1).	[62]
Isoflavone	DM7U58J	Phase 4	Isoflavone increases the expression of Sequestosome-1 (SQSTM1).	[63]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Sequestosome-1 (SQSTM1).	[64]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Sequestosome-1 (SQSTM1).	[65]
Rigosertib	DMOSTXF	Phase 3	Rigosertib affects the expression of Sequestosome-1 (SQSTM1).	[67]
HMPL-004	DM29XGY	Phase 3	HMPL-004 decreases the expression of Sequestosome-1 (SQSTM1).	[68]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the expression of Sequestosome-1 (SQSTM1).	[68]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine increases the expression of Sequestosome-1 (SQSTM1).	[44]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Sequestosome-1 (SQSTM1).	[13]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Sequestosome-1 (SQSTM1).	[69]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Sequestosome-1 (SQSTM1).	[42]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Sequestosome-1 (SQSTM1).	[42]
ANW-32821	DMMJOZD	Phase 2	ANW-32821 increases the expression of Sequestosome-1 (SQSTM1).	[70]
CERC-801	DM3SZ7P	Phase 2	CERC-801 increases the expression of Sequestosome-1 (SQSTM1).	[71]
BEZ235	DMKBRDL	Phase 2	BEZ235 decreases the expression of Sequestosome-1 (SQSTM1).	[72]
Apilimod dimesylate	DM4N2O0	Phase 2	Apilimod dimesylate increases the expression of Sequestosome-1 (SQSTM1).	[73]
Ym155	DM5Q1W4	Phase 2	Ym155 decreases the expression of Sequestosome-1 (SQSTM1).	[74]
Azd2014	DMOEARH	Phase 2	Azd2014 affects the expression of Sequestosome-1 (SQSTM1).	[59]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Sequestosome-1 (SQSTM1).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Sequestosome-1 (SQSTM1).	[76]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Sequestosome-1 (SQSTM1).	[77]
AMEP	DMFELMQ	Phase 1	AMEP increases the expression of Sequestosome-1 (SQSTM1).	[79]
Tetrandrine	DMAOJBX	Phase 1	Tetrandrine decreases the expression of Sequestosome-1 (SQSTM1).	[80]
GSK618334	DMJPXZ4	Phase 1	GSK618334 decreases the expression of Sequestosome-1 (SQSTM1).	[81]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Sequestosome-1 (SQSTM1).	[82]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Sequestosome-1 (SQSTM1).	[42]
Clioquinol	DM746BZ	Withdrawn from market	Clioquinol decreases the expression of Sequestosome-1 (SQSTM1).	[83]
E-64D	DMCVXBE	Preclinical	E-64D increases the expression of Sequestosome-1 (SQSTM1).	[48]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sequestosome-1 (SQSTM1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Sequestosome-1 (SQSTM1).	[85]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Sequestosome-1 (SQSTM1).	[86]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Sequestosome-1 (SQSTM1).	[88]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Sequestosome-1 (SQSTM1).	[68]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Sequestosome-1 (SQSTM1).	[89]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Sequestosome-1 (SQSTM1).	[90]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Sequestosome-1 (SQSTM1).	[91]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Sequestosome-1 (SQSTM1).	[92]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the degradation of Sequestosome-1 (SQSTM1).	[66]
SEN-196	DMLDBQ5	Phase 2	SEN-196 decreases the degradation of Sequestosome-1 (SQSTM1).	[75]
EMBELIN	DMFZO4Y	Terminated	EMBELIN increases the degradation of Sequestosome-1 (SQSTM1).	[84]

References

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