Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4YZG2N)

• DOT Name: Low-density lipoprotein receptor-related protein 1B (LRP1B)
• Synonyms: LRP-1B; Low-density lipoprotein receptor-related protein-deleted in tumor; LRP-DIT
• Gene Name: LRP1B
• Related Disease:
  Alzheimer disease
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Esophageal squamous cell carcinoma
  Melanoma
  Motion sickness
  Neoplasm
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Ovarian cancer
  Papillary renal cell carcinoma
  Prostate neoplasm
  Renal cell carcinoma
  Squamous cell carcinoma
  Systemic lupus erythematosus
  Adult glioblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Glioblastoma multiforme
  Lung adenocarcinoma
  Pure red-cell aplasia
  Lung cancer
  Lung carcinoma
  Obesity
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Uveal Melanoma
• UniProt ID: LRP1B_HUMAN
• Pfam ID: PF12662 ; PF16472 ; PF00008 ; PF07645 ; PF14670 ; PF00057 ; PF00058
• Sequence:
  MSEFLLALLTLSGLLPIARVLTVGADRDQQLCDPGEFLCHDHVTCVSQSWLCDGDPDCPD
  DSDESLDTCPEEVEIKCPLNHIACLGTNKCVHLSQLCNGVLDCPDGYDEGVHCQELLSNC
  QQLNCQYKCTMVRNSTRCYCEDGFEITEDGRSCKDQDECAVYGTCSQTCRNTHGSYTCSC
  VEGYLMQPDNRSCKAKIEPTDRPPILLIANFETIEVFYLNGSKMATLSSVNGNEIHTLDF
  IYNEDMICWIESRESSNQLKCIQITKAGGLTDEWTINILQSFHNVQQMAIDWLTRNLYFV
  DHVGDRIFVCNSNGSVCVTLIDLELHNPKAIAVDPIAGKLFFTDYGNVAKVERCDMDGMN
  RTRIIDSKTEQPAALALDLVNKLVYWVDLYLDYVGVVDYQGKNRHTVIQGRQVRHLYGIT
  VFEDYLYATNSDNYNIVRINRFNGTDIHSLIKIENAWGIRIYQKRTQPTVRSHACEVDPY
  GMPGGCSHICLLSSSYKTRTCRCRTGFNLGSDGRSCKRPKNELFLFYGKGRPGIVRGMDL
  NTKIADEYMIPIENLVNPRALDFHAETNYIYFADTTSFLIGRQKIDGTERETILKDDLDN
  VEGIAVDWIGNNLYWTNDGHRKTINVARLEKASQSRKTLLEGEMSHPRGIVVDPVNGWMY
  WTDWEEDEIDDSVGRIEKAWMDGFNRQIFVTSKMLWPNGLTLDFHTNTLYWCDAYYDHIE
  KVFLNGTHRKIVYSGRELNHPFGLSHHGNYVFWTDYMNGSIFQLDLITSEVTLLRHERPP
  LFGLQIYDPRKQQGDNMCRVNNGGCSTLCLAIPGGRVCACADNQLLDENGTTCTFNPGEA
  LPHICKAGEFRCKNRHCIQARWKCDGDDDCLDGSDEDSVNCFNHSCPDDQFKCQNNRCIP
  KRWLCDGANDCGSNEDESNQTCTARTCQVDQFSCGNGRCIPRAWLCDREDDCGDQTDEMA
  SCEFPTCEPLTQFVCKSGRCISSKWHCDSDDDCGDGSDEVGCVHSCFDNQFRCSSGRCIP
  GHWACDGDNDCGDFSDEAQINCTKEEIHSPAGCNGNEFQCHPDGNCVPDLWRCDGEKDCE
  DGSDEKGCNGTIRLCDHKTKFSCWSTGRCINKAWVCDGDIDCEDQSDEDDCDSFLCGPPK
  HPCANDTSVCLQPEKLCNGKKDCPDGSDEGYLCDECSLNNGGCSNHCSVVPGRGIVCSCP
  EGLQLNKDNKTCEIVDYCSNHLKCSQVCEQHKHTVKCSCYEGWKLDVDGESCTSVDPFEA
  FIIFSIRHEIRRIDLHKRDYSLLVPGLRNTIALDFHFNQSLLYWTDVVEDRIYRGKLSES
  GGVSAIEVVVEHGLATPEGLTVDWIAGNIYWIDSNLDQIEVAKLDGSLRTTLIAGAMEHP
  RAIALDPRYGILFWTDWDANFPRIESASMSGAGRKTIYKDMKTGAWPNGLTVDHFEKRIV
  WTDARSDAIYSALYDGTNMIEIIRGHEYLSHPFAVSLYGSEVYWTDWRTNTLSKANKWTG
  QNVSVIQKTSAQPFDLQIYHPSRQPQAPNPCAANDGKGPCSHMCLINHNRSAACACPHLM
  KLSSDKKTCYEMKKFLLYARRSEIRGVDIDNPYFNFITAFTVPDIDDVTVIDFDASEERL
  YWTDIKTQTIKRAFINGTGLETVISRDIQSIRGLAVDWVSRNLYWISSEFDETQINVARL
  DGSLKTSIIHGIDKPQCLAAHPVRGKLYWTDGNTINMANMDGSNSKILFQNQKEPVGLSI
  DYVENKLYWISSGNGTINRCNLDGGNLEVIESMKEELTKATALTIMDKKLWWADQNLAQL
  GTCSKRDGRNPTILRNKTSGVVHMKVYDKEAQQGSNSCQLNNGGCSQLCLPTSETTRTCM
  CTVGYYLQKNRMSCQGIESFLMYSVHEGIRGIPLEPSDKMDALMPISGTSFAVGIDFHAE
  NDTIYWTDMGFNKISRAKRDQTWKEDIITNGLGRVEGIAVDWIAGNIYWTDHGFNLIEVA
  RLNGSFRYVIISQGLDQPRSIAVHPEKGLLFWTEWGQMPCIGKARLDGSEKVVLVSMGIA
  WPNGISIDYEENKLYWCDARTDKIERIDLETGGNREMVLSGSNVDMFSVAVFGAYIYWSD
  RAHANGSVRRGHKNDATETITMRTGLGVNLKEVKIFNRVREKGTNVCARDNGGCKQLCLY
  RGNSRRTCACAHGYLAEDGVTCLRHEGYLLYSGRTILKSIHLSDETNLNSPIRPYENPRY
  FKNVIALAFDYNQRRKGTNRIFYSDAHFGNIQLIKDNWEDRQVIVENVGSVEGLAYHRAW
  DTLYWTSSTTSSITRHTVDQTRPGAFDREAVITMSEDDHPHVLALDECQNLMFWTNWNEQ
  HPSIMRSTLTGKNAQVVVSTDILTPNGLTIDYRAEKLYFSDGSLGKIERCEYDGSQRHVI
  VKSGPGTFLSLAVYDNYIFWSDWGRRAILRSNKYTGGDTKILRSDIPHQPMGIIAVANDT
  NSCELSPCALLNGGCHDLCLLTPNGRVNCSCRGDRILLEDNRCVTKNSSCNAYSEFECGN
  GECIDYQLTCDGIPHCKDKSDEKLLYCENRSCRRGFKPCYNRRCIPHGKLCDGENDCGDN
  SDELDCKVSTCATVEFRCADGTCIPRSARCNQNIDCADASDEKNCNNTDCTHFYKLGVKT
  TGFIRCNSTSLCVLPTWICDGSNDCGDYSDELKCPVQNKHKCEENYFSCPSGRCILNTWI
  CDGQKDCEDGRDEFHCDSSCSWNQFACSAQKCISKHWICDGEDDCGDGLDESDSICGAIT
  CAADMFSCQGSRACVPRHWLCDGERDCPDGSDELSTAGCAPNNTCDENAFMCHNKVCIPK
  QFVCDHDDDCGDGSDESPQCGYRQCGTEEFSCADGRCLLNTQWQCDGDFDCPDHSDEAPL
  NPKCKSAEQSCNSSFFMCKNGRCIPSGGLCDNKDDCGDGSDERNCHINECLSKKVSGCSQ
  DCQDLPVSYKCKCWPGFQLKDDGKTCVDIDECSSGFPCSQQCINTYGTYKCLCTDGYEIQ
  PDNPNGCKSLSDEEPFLILADHHEIRKISTDGSNYTLLKQGLNNVIAIDFDYREEFIYWI
  DSSRPNGSRINRMCLNGSDIKVVHNTAVPNALAVDWIGKNLYWSDTEKRIIEVSKLNGLY
  PTILVSKRLKFPRDLSLDPQAGYLYWIDCCEYPHIGRVGMDGTNQSVVIETKISRPMALT
  IDYVNRRLYWADENHIEFSNMDGSHRHKVPNQDIPGVIALTLFEDYIYWTDGKTKSLSRA
  HKTSGADRLSLIYSWHAITDIQVYHSYRQPDVSKHLCMINNGGCSHLCLLAPGKTHTCAC
  PTNFYLAADNRTCLSNCTASQFRCKTDKCIPFWWKCDTVDDCGDGSDEPDDCPEFRCQPG
  RFQCGTGLCALPAFICDGENDCGDNSDELNCDTHVCLSGQFKCTKNQKCIPVNLRCNGQD
  DCGDEEDERDCPENSCSPDYFQCKTTKHCISKLWVCDEDPDCADASDEANCDKKTCGPHE
  FQCKNNNCIPDHWRCDSQNDCSDNSDEENCKPQTCTLKDFLCANGDCVSSRFWCDGDFDC
  ADGSDERNCETSCSKDQFRCSNGQCIPAKWKCDGHEDCKYGEDEKSCEPASPTCSSREYI
  CASDGCISASLKCNGEYDCADGSDEMDCVTECKEDQFRCKNKAHCIPIRWLCDGIHDCVD
  GSDEENCERGGNICRADEFLCNNSLCKLHFWVCDGEDDCGDNSDEAPDMCVKFLCPSTRP
  HRCRNNRICLQSEQMCNGIDECGDNSDEDHCGGKLTYKARPCKKDEFACSNKKCIPMDLQ
  CDRLDDCGDGSDEQGCRIAPTEYTCEDNVNPCGDDAYCNQIKTSVFCRCKPGFQRNMKNR
  QCEDLNECLVFGTCSHQCINVEGSYKCVCDQNFQERNNTCIAEGSEDQVLYIANDTDILG
  FIYPFNYSGDHQQISHIEHNSRITGMDVYYQRDMIIWSTQFNPGGIFYKRIHGREKRQAN
  SGLICPEFKRPRDIAVDWVAGNIYWTDHSRMHWFSYYTTHWTSLRYSINVGQLNGPNCTR
  LLTNMAGEPYAIAVNPKRGMMYWTVVGDHSHIEEAAMDGTLRRILVQKNLQRPTGLAVDY
  FSERIYWADFELSIIGSVLYDGSNSVVSVSSKQGLLHPHRIDIFEDYIYGAGPKNGVFRV
  QKFGHGSVEYLALNIDKTKGVLISHRYKQLDLPNPCLDLACEFLCLLNPSGATCVCPEGK
  YLINGTCNDDSLLDDSCKLTCENGGRCILNEKGDLRCHCWPSYSGERCEVNHCSNYCQNG
  GTCVPSVLGRPTCSCALGFTGPNCGKTVCEDFCQNGGTCIVTAGNQPYCHCQPEYTGDRC
  QYYVCHHYCVNSESCTIGDDGSVECVCPTRYEGPKCEVDKCVRCHGGHCIINKDSEDIFC
  NCTNGKIASSCQLCDGYCYNGGTCQLDPETNVPVCLCSTNWSGTQCERPAPKSSKSDHIS
  TRSIAIIVPLVLLVTLITTLVIGLVLCKRKRRTKTIRRQPIINGGINVEIGNPSYNMYEV
  DHDHNDGGLLDPGFMIDPTKARYIGGGPSAFKLPHTAPPIYLNSDLKGPLTAGPTNYSNP
  VYAKLYMDGQNCRNSLGSVDERKELLPKKIEIGIRETVA
• Function: Potential cell surface proteins that bind and internalize ligands in the process of receptor-mediated endocytosis.
• Tissue Specificity: Expressed in thyroid gland and in salivary gland, as well as in adult and fetal brain.

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Posttranslational Modification	[4]
Melanoma	DIS1RRCY	Strong	Biomarker	[5]
Motion sickness	DISZ2WZW	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[9]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[10]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[2]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[11]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[2]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[4]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[12]
Adult glioblastoma	DISVP4LU	moderate	Genetic Variation	[13]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[14]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[15]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[15]
Carcinoma	DISH9F1N	moderate	Biomarker	[15]
Glioblastoma multiforme	DISK8246	moderate	Genetic Variation	[13]
Lung adenocarcinoma	DISD51WR	moderate	Genetic Variation	[16]
Pure red-cell aplasia	DIST91OT	moderate	Genetic Variation	[17]
Lung cancer	DISCM4YA	Limited	Biomarker	[18]
Lung carcinoma	DISTR26C	Limited	Biomarker	[18]
Obesity	DIS47Y1K	Limited	Biomarker	[19]
Prostate cancer	DISF190Y	Limited	Genetic Variation	[20]
Prostate carcinoma	DISMJPLE	Limited	Genetic Variation	[21]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[22]
Uveal Melanoma	DISA7ZGL	Limited	Genetic Variation	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Low-density lipoprotein receptor-related protein 1B (LRP1B).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Low-density lipoprotein receptor-related protein 1B (LRP1B).	[24]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Low-density lipoprotein receptor-related protein 1B (LRP1B).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Low-density lipoprotein receptor-related protein 1B (LRP1B).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Low-density lipoprotein receptor-related protein 1B (LRP1B).	[26]

References

• [1] Genome-wide haplotype association study identify TNFRSF1A, CASP7, LRP1B, CDH1 and TG genes associated with Alzheimer's disease in Caribbean Hispanic individuals.Oncotarget. 2015 Dec 15;6(40):42504-14. doi: 10.18632/oncotarget.6391.
• [2] Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma.Nat Genet. 2011 Dec 4;44(1):17-9. doi: 10.1038/ng.1014.
• [3] Down-regulation of LRP1B in colon cancer promoted the growth and migration of cancer cells.Exp Cell Res. 2017 Aug 1;357(1):1-8. doi: 10.1016/j.yexcr.2017.04.010. Epub 2017 Apr 11.
• [4] Genetic or epigenetic silencing of low density lipoprotein receptor-related protein 1B expression in oral squamous cell carcinoma.Cancer Sci. 2006 Oct;97(10):1070-4. doi: 10.1111/j.1349-7006.2006.00283.x.
• [5] Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma.Nat Genet. 2011 Dec 25;44(2):133-9. doi: 10.1038/ng.1026.
• [6] Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis.Hum Mol Genet. 2015 May 1;24(9):2700-8. doi: 10.1093/hmg/ddv028. Epub 2015 Jan 26.
• [7] Sleeping Beauty transposon mutagenesis identifies genes that cooperate with mutant Smad4 in gastric cancer development.Proc Natl Acad Sci U S A. 2016 Apr 5;113(14):E2057-65. doi: 10.1073/pnas.1603223113. Epub 2016 Mar 22.
• [8] Genome-wide association study of coronary artery calcified atherosclerotic plaque in African Americans with type 2 diabetes.BMC Genet. 2017 Dec 8;18(1):105. doi: 10.1186/s12863-017-0572-9.
• [9] Association of LRP1B Mutation With Tumor Mutation Burden and Outcomes in Melanoma and Non-small Cell Lung Cancer Patients Treated With Immune Check-Point Blockades.Front Immunol. 2019 May 21;10:1113. doi: 10.3389/fimmu.2019.01113. eCollection 2019.
• [10] LRP1B deletion in high-grade serous ovarian cancers is associated with acquired chemotherapy resistance to liposomal doxorubicin.Cancer Res. 2012 Aug 15;72(16):4060-73. doi: 10.1158/0008-5472.CAN-12-0203.
• [11] Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.Nat Genet. 2018 May;50(5):682-692. doi: 10.1038/s41588-018-0086-z. Epub 2018 Apr 16.
• [12] Genome-wide analysis of histone H3 lysine 4 trimethylation by ChIP-chip in peripheral blood mononuclear cells of systemic lupus erythematosus patients.Clin Exp Rheumatol. 2010 Mar-Apr;28(2):158-68. Epub 2010 May 13.
• [13] LRP1B deletion is associated with poor outcome for glioblastoma patients.J Neurol Sci. 2015 Nov 15;358(1-2):440-3. doi: 10.1016/j.jns.2015.09.345. Epub 2015 Sep 11.
• [14] Expression of a recombinant full-length LRP1B receptor in human non-small cell lung cancer cells confirms the postulated growth-suppressing function of this large LDL receptor family member.Oncotarget. 2016 Oct 18;7(42):68721-68733. doi: 10.18632/oncotarget.11897.
• [15] Nuclear localization of LDL receptor-related protein 1B in mammary gland carcinogenesis.J Mol Med (Berl). 2019 Feb;97(2):257-268. doi: 10.1007/s00109-018-01732-2. Epub 2019 Jan 3.
• [16] Targeted Sequencing Analysis of Pulmonary Adenocarcinoma with Multiple Synchronous Ground-Glass/Lepidic Nodules.J Thorac Oncol. 2018 Nov;13(11):1776-1783. doi: 10.1016/j.jtho.2018.07.097. Epub 2018 Aug 16.
• [17] Identification of mutations in patients with acquired pure red cell aplasia.Acta Biochim Biophys Sin (Shanghai). 2018 Jul 1;50(7):685-692. doi: 10.1093/abbs/gmy052.
• [18] Integrative analysis of genomic sequencing data reveals higher prevalence of LRP1B mutations in lung adenocarcinoma patients with COPD.Sci Rep. 2017 May 18;7(1):2121. doi: 10.1038/s41598-017-02405-9.
• [19] The genetic and epigenetic association of LDL Receptor Related Protein 1B (LRP1B) gene with childhood obesity.Sci Rep. 2019 Feb 12;9(1):1815. doi: 10.1038/s41598-019-38538-2.
• [20] Pembrolizumab in men with heavily treated metastatic castrate-resistant prostate cancer.Cancer Med. 2019 Aug;8(10):4644-4655. doi: 10.1002/cam4.2375. Epub 2019 Jul 3.
• [21] Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy.J Natl Cancer Inst. 2020 Feb 1;112(2):179-190. doi: 10.1093/jnci/djz075.
• [22] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [23] Genome-wide study on uveal melanoma patients finds association to DNA repair gene TDP1.Melanoma Res. 2020 Apr;30(2):166-172. doi: 10.1097/CMR.0000000000000641.
• [24] 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.
• [25] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [26] 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.
• [27] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.