Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ71YV2)

• DOT Name: Low-density lipoprotein receptor-related protein 8 (LRP8)
• Synonyms: LRP-8; Apolipoprotein E receptor 2
• Gene Name: LRP8
• Related Disease:
  Advanced cancer
  Alcohol dependence
  Amyloidosis
  Autism
  Autoimmune polyendocrinopathy
  Bone disease
  Breast cancer
  Breast carcinoma
  Cardiovascular disease
  Cognitive impairment
  Coronary heart disease
  Dementia
  Familial Alzheimer disease
  Hyperlipidemia
  Major depressive disorder
  Melanoma
  Myocardial infarction
  Phospholipid syndrome
  Psychotic disorder
  Triple negative breast cancer
  Vascular disease
  Arteriosclerosis
  Atherosclerosis
  Fetal growth restriction
  Neurodegenerative disease
  Coronary atherosclerosis
  Neoplasm
  Neuroblastoma
  Tourette syndrome
• UniProt ID: LRP8_HUMAN
• PDB ID: 3A7Q; 5B4X; 5B4Y; 7UCX
• Pfam ID: PF07645 ; PF14670 ; PF00057 ; PF00058
• Sequence:
  MGLPEPGPLRLLALLLLLLLLLLLQLQHLAAAAADPLLGGQGPAKDCEKDQFQCRNERCI
  PSVWRCDEDDDCLDHSDEDDCPKKTCADSDFTCDNGHCIHERWKCDGEEECPDGSDESEA
  TCTKQVCPAEKLSCGPTSHKCVPASWRCDGEKDCEGGADEAGCATLCAPHEFQCGNRSCL
  AAVFVCDGDDDCGDGSDERGCADPACGPREFRCGGDGGGACIPERWVCDRQFDCEDRSDE
  AAELCGRPGPGATSAPAACATASQFACRSGECVHLGWRCDGDRDCKDKSDEADCPLGTCR
  GDEFQCGDGTCVLAIKHCNQEQDCPDGSDEAGCLQGLNECLHNNGGCSHICTDLKIGFEC
  TCPAGFQLLDQKTCGDIDECKDPDACSQICVNYKGYFKCECYPGYEMDLLTKNCKAAAGK
  SPSLIFTNRHEVRRIDLVKRNYSRLIPMLKNVVALDVEVATNRIYWCDLSYRKIYSAYMD
  KASDPKEQEVLIDEQLHSPEGLAVDWVHKHIYWTDSGNKTISVATVDGGRRRTLFSRNLS
  EPRAIAVDPLRGFMYWSDWGDQAKIEKSGLNGVDRQTLVSDNIEWPNGITLDLLSQRLYW
  VDSKLHQLSSIDFSGGNRKTLISSTDFLSHPFGIAVFEDKVFWTDLENEAIFSANRLNGL
  EISILAENLNNPHDIVIFHELKQPRAPDACELSVQPNGGCEYLCLPAPQISSHSPKYTCA
  CPDTMWLGPDMKRCYRAPQSTSTTTLASTMTRTVPATTRAPGTTVHRSTYQNHSTETPSL
  TAAVPSSVSVPRAPSISPSTLSPATSNHSQHYANEDSKMGSTVTAAVIGIIVPIVVIALL
  CMSGYLIWRNWKRKNTKSMNFDNPVYRKTTEEEDEDELHIGRTAQIGHVYPAAISSFDRP
  LWAEPCLGETREPEDPAPALKELFVLPGEPRSQLHQLPKNPLSELPVVKSKRVALSLEDD
  GLP
• Function: Cell surface receptor for Reelin (RELN) and apolipoprotein E (apoE)-containing ligands. LRP8 participates in transmitting the extracellular Reelin signal to intracellular signaling processes, by binding to DAB1 on its cytoplasmic tail. Reelin acts via both the VLDL receptor (VLDLR) and LRP8 to regulate DAB1 tyrosine phosphorylation and microtubule function in neurons. LRP8 has higher affinity for Reelin than VLDLR. LRP8 is thus a key component of the Reelin pathway which governs neuronal layering of the forebrain during embryonic brain development. Binds the endoplasmic reticulum resident receptor-associated protein (RAP). Binds dimers of beta 2-glycoprotein I and may be involved in the suppression of platelet aggregation in the vasculature. Highly expressed in the initial segment of the epididymis, where it affects the functional expression of clusterin and phospholipid hydroperoxide glutathione peroxidase (PHGPx), two proteins required for sperm maturation. May also function as an endocytic receptor. Not required for endocytic uptake of SEPP1 in the kidney which is mediated by LRP2. Together with its ligand, apolipoprotein E (apoE), may indirectly play a role in the suppression of the innate immune response by controlling the survival of myeloid-derived suppressor cells; (Microbial infection) Acts as a receptor for Semliki Forest virus.
• Tissue Specificity: Expressed mainly in brain and placenta. Also expressed in platelets and megakaryocytic cells. Not expressed in the liver.
• Reactome Pathway:
  Retinoid metabolism and transport (R-HSA-975634)
  Platelet sensitization by LDL (R-HSA-432142)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Alcohol dependence	DIS4ZSCO	Strong	Genetic Variation	[2]
Amyloidosis	DISHTAI2	Strong	Altered Expression	[3]
Autism	DISV4V1Z	Strong	Biomarker	[4]
Autoimmune polyendocrinopathy	DISOLDB2	Strong	Biomarker	[5]
Bone disease	DISE1F82	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[7]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[7]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[8]
Cognitive impairment	DISH2ERD	Strong	Altered Expression	[9]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[10]
Dementia	DISXL1WY	Strong	Genetic Variation	[11]
Familial Alzheimer disease	DISE75U4	Strong	Genetic Variation	[12]
Hyperlipidemia	DIS61J3S	Strong	Altered Expression	[13]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[14]
Melanoma	DIS1RRCY	Strong	Biomarker	[15]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[16]
Phospholipid syndrome	DISPI49U	Strong	Biomarker	[5]
Psychotic disorder	DIS4UQOT	Strong	Genetic Variation	[17]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[7]
Vascular disease	DISVS67S	Strong	Biomarker	[8]
Arteriosclerosis	DISK5QGC	moderate	Biomarker	[8]
Atherosclerosis	DISMN9J3	moderate	Biomarker	[8]
Fetal growth restriction	DIS5WEJ5	moderate	Biomarker	[18]
Neurodegenerative disease	DISM20FF	moderate	Biomarker	[19]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[10]
Neoplasm	DISZKGEW	Limited	Altered Expression	[7]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[20]
Tourette syndrome	DISX9D54	No Known	Unknown	[21]

22 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 Low-density lipoprotein receptor-related protein 8 (LRP8).	[22]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[26]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[27]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[28]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[30]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[31]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[32]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[33]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[34]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[37]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[38]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[39]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[40]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[41]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Low-density lipoprotein receptor-related protein 8 (LRP8).	[42]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Low-density lipoprotein receptor-related protein 8 (LRP8).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Low-density lipoprotein receptor-related protein 8 (LRP8).	[36]

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