Details of Drug Off-Target (DOT)

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

• DOT Name: Retinoblastoma-associated protein (RB1)
• Synonyms: p105-Rb; p110-RB1; pRb; Rb; pp110
• Gene Name: RB1
• Related Disease:
  Hereditary retinoblastoma
  Retinoblastoma
  Melanoma
• UniProt ID: RB_HUMAN
• PDB ID: 1AD6; 1GH6; 1GUX; 1H25; 1N4M; 1O9K; 1PJM; 2AZE; 2QDJ; 2R7G; 3N5U; 3POM; 4CRI; 4ELJ; 4ELL
• Pfam ID: PF11934 ; PF01858 ; PF01857 ; PF08934
• Sequence:
  MPPKTPRKTAATAAAAAAEPPAPPPPPPPEEDPEQDSGPEDLPLVRLEFEETEEPDFTAL
  CQKLKIPDHVRERAWLTWEKVSSVDGVLGGYIQKKKELWGICIFIAAVDLDEMSFTFTEL
  QKNIEISVHKFFNLLKEIDTSTKVDNAMSRLLKKYDVLFALFSKLERTCELIYLTQPSSS
  ISTEINSALVLKVSWITFLLAKGEVLQMEDDLVISFQLMLCVLDYFIKLSPPMLLKEPYK
  TAVIPINGSPRTPRRGQNRSARIAKQLENDTRIIEVLCKEHECNIDEVKNVYFKNFIPFM
  NSLGLVTSNGLPEVENLSKRYEEIYLKNKDLDARLFLDHDKTLQTDSIDSFETQRTPRKS
  NLDEEVNVIPPHTPVRTVMNTIQQLMMILNSASDQPSENLISYFNNCTVNPKESILKRVK
  DIGYIFKEKFAKAVGQGCVEIGSQRYKLGVRLYYRVMESMLKSEEERLSIQNFSKLLNDN
  IFHMSLLACALEVVMATYSRSTSQNLDSGTDLSFPWILNVLNLKAFDFYKVIESFIKAEG
  NLTREMIKHLERCEHRIMESLAWLSDSPLFDLIKQSKDREGPTDHLESACPLNLPLQNNH
  TAADMYLSPVRSPKKKGSTTRVNSTANAETQATSAFQTQKPLKSTSLSLFYKKVYRLAYL
  RLNTLCERLLSEHPELEHIIWTLFQHTLQNEYELMRDRHLDQIMMCSMYGICKVKNIDLK
  FKIIVTAYKDLPHAVQETFKRVLIKEEEYDSIIVFYNSVFMQRLKTNILQYASTRPPTLS
  PIPHIPRSPYKFPSSPLRIPGGNIYISPLKSPYKISEGLPTPTKMTPRSRILVSIGESFG
  TSEKFQKINQMVCNSDRVLKRSAEGSNPPKPLKKLRFDIEGSDEADGSKHLPGESKFQQK
  LAEMTSTRTRMQKQKMNDSMDTSNKEEK
• Function: Tumor suppressor that is a key regulator of the G1/S transition of the cell cycle. The hypophosphorylated form binds transcription regulators of the E2F family, preventing transcription of E2F-responsive genes. Both physically blocks E2Fs transactivating domain and recruits chromatin-modifying enzymes that actively repress transcription. Cyclin and CDK-dependent phosphorylation of RB1 induces its dissociation from E2Fs, thereby activating transcription of E2F responsive genes and triggering entry into S phase. RB1 also promotes the G0-G1 transition upon phosphorylation and activation by CDK3/cyclin-C. Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation. Recruits and targets histone methyltransferases SUV39H1, KMT5B and KMT5C, leading to epigenetic transcriptional repression. Controls histone H4 'Lys-20' trimethylation. Inhibits the intrinsic kinase activity of TAF1. Mediates transcriptional repression by SMARCA4/BRG1 by recruiting a histone deacetylase (HDAC) complex to the c-FOS promoter. In resting neurons, transcription of the c-FOS promoter is inhibited by BRG1-dependent recruitment of a phospho-RB1-HDAC1 repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex; (Microbial infection) In case of viral infections, interactions with SV40 large T antigen, HPV E7 protein or adenovirus E1A protein induce the disassembly of RB1-E2F1 complex thereby disrupting RB1's activity.
• Tissue Specificity: Expressed in the retina. Expressed in foreskin keratinocytes (at protein level) .
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  Cell cycle (hsa04110)
  Cellular senescence (hsa04218)
  Cushing syndrome (hsa04934)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Pancreatic cancer (hsa05212)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Melanoma (hsa05218)
  Bladder cancer (hsa05219)
  Chronic myeloid leukemia (hsa05220)
  Small cell lung cancer (hsa05222)
  Non-small cell lung cancer (hsa05223)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  APC/C (R-HSA-174178)
  Condensation of Prophase Chromosomes (R-HSA-2299718)
  Formation of Senescence-Associated Heterochromatin Foci (SAHF) (R-HSA-2559584)
  Oncogene Induced Senescence (R-HSA-2559585)
  Phosphorylation of proteins involved in G1/S transition by active Cyclin E (R-HSA-69200)
  Cyclin E associated events during G1/S transition (R-HSA-69202)
  Cyclin D associated events in G1 (R-HSA-69231)
  Cyclin A (R-HSA-69656)
  RUNX2 regulates osteoblast differentiation (R-HSA-8940973)
  Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) (R-HSA-9661069)
  Defective translocation of RB1 mutants to the nucleus (R-HSA-9661070)
  Replication of the SARS-CoV-1 genome (R-HSA-9682706)
  Aberrant regulation of mitotic exit in cancer due to RB1 defects (R-HSA-9687136)
  Replication of the SARS-CoV-2 genome (R-HSA-9694686)
  Inhibition of replication initiation of damaged DNA by RB1/E2F1 (R-HSA-113501)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary retinoblastoma	DISPBIDE	Definitive	Autosomal dominant	[1]
Retinoblastoma	DISVPNPB	Definitive	Autosomal dominant	[2]
Melanoma	DIS1RRCY	Moderate	Autosomal dominant	[1]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Retinoblastoma-associated protein (RB1) affects the response to substance of Cisplatin.	[95]
Bortezomib	DMNO38U	Approved	Retinoblastoma-associated protein (RB1) increases the response to substance of Bortezomib.	[96]
Palbociclib	DMD7L94	Approved	Retinoblastoma-associated protein (RB1) decreases the response to substance of Palbociclib.	[97]
BMS-754807	DMPK32V	Phase 1	Retinoblastoma-associated protein (RB1) decreases the response to substance of BMS-754807.	[98]

50 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 Retinoblastoma-associated protein (RB1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the phosphorylation of Retinoblastoma-associated protein (RB1).	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the phosphorylation of Retinoblastoma-associated protein (RB1).	[17]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[18]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the phosphorylation of Retinoblastoma-associated protein (RB1).	[19]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[22]
Etoposide	DMNH3PG	Approved	Etoposide decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[24]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the phosphorylation of Retinoblastoma-associated protein (RB1).	[26]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[30]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[33]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[36]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the phosphorylation of Retinoblastoma-associated protein (RB1).	[39]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[36]
Lovastatin	DM9OZWQ	Approved	Lovastatin decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[45]
Orlistat	DMRJSP8	Approved	Orlistat decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[46]
Romidepsin	DMT5GNL	Approved	Romidepsin decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[48]
Amodiaquine	DME4RA8	Approved	Amodiaquine affects the phosphorylation of Retinoblastoma-associated protein (RB1).	[49]
Masoprocol	DMMVNZ0	Approved	Masoprocol decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[50]
Amlodipine	DMBDAZV	Approved	Amlodipine decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[54]
Lopinavir	DMITQS0	Approved	Lopinavir affects the phosphorylation of Retinoblastoma-associated protein (RB1).	[55]
Trametinib	DM2JGQ3	Approved	Trametinib decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[56]
Dicumarol	DMFQCB1	Approved	Dicumarol increases the phosphorylation of Retinoblastoma-associated protein (RB1).	[59]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[61]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[62]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[64]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the phosphorylation of Retinoblastoma-associated protein (RB1).	[66]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[67]
HMPL-004	DM29XGY	Phase 3	HMPL-004 decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[68]
Peretinoin	DMESAZK	Phase 3	Peretinoin decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[69]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[70]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[71]
BAICALEIN	DM4C7E6	Phase 2	BAICALEIN decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[72]
Amsilarotene	DMOB01U	Phase 2	Amsilarotene increases the phosphorylation of Retinoblastoma-associated protein (RB1).	[76]
Salirasib	DMRSU4X	Phase 2	Salirasib decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[77]
Inecalcitol oral	DMU5SZP	Phase 2	Inecalcitol oral decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[78]
Indisulam	DM9SX6Y	Phase 2	Indisulam decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[79]
2-hydroxyoleic acid	DMCLKA4	Phase 1/2	2-hydroxyoleic acid decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[80]
TAK-114	DMTXE19	Phase 1	TAK-114 decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[83]
Adaphostin	DM16QSG	Phase 1	Adaphostin decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[84]
L-Cysteine	DMCMOS8	Clinical trial	L-Cysteine decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[85]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[87]
PMID26560530-Compound-35	DMO36RL	Patented	PMID26560530-Compound-35 decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[90]
Ferulic Acid	DMJC7NF	Patented	Ferulic Acid decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[91]
SCH 727965	DMCJLD1	Discontinued in Phase 3	SCH 727965 decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[92]
Lexacalcitol	DMJ3ZT8	Discontinued in Phase 2	Lexacalcitol decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[67]
TNP-470	DMT0QK8	Discontinued in Phase 2	TNP-470 decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[93]
ERA-923	DM6NTAS	Discontinued in Phase 2	ERA-923 decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[94]
LG100268	DM41RK2	Discontinued in Phase 1	LG100268 decreases the phosphorylation of Retinoblastoma-associated protein (RB1).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Retinoblastoma-associated protein (RB1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Retinoblastoma-associated protein (RB1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Retinoblastoma-associated protein (RB1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Retinoblastoma-associated protein (RB1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Retinoblastoma-associated protein (RB1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Retinoblastoma-associated protein (RB1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Retinoblastoma-associated protein (RB1).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Retinoblastoma-associated protein (RB1).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Retinoblastoma-associated protein (RB1).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Retinoblastoma-associated protein (RB1).	[7]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Retinoblastoma-associated protein (RB1).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Retinoblastoma-associated protein (RB1).	[20]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Retinoblastoma-associated protein (RB1).	[21]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Retinoblastoma-associated protein (RB1).	[23]
Irinotecan	DMP6SC2	Approved	Irinotecan affects the expression of Retinoblastoma-associated protein (RB1).	[25]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Retinoblastoma-associated protein (RB1).	[14]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Retinoblastoma-associated protein (RB1).	[27]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Retinoblastoma-associated protein (RB1).	[28]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Retinoblastoma-associated protein (RB1).	[29]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Retinoblastoma-associated protein (RB1).	[31]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Retinoblastoma-associated protein (RB1).	[32]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the activity of Retinoblastoma-associated protein (RB1).	[34]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Retinoblastoma-associated protein (RB1).	[35]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of Retinoblastoma-associated protein (RB1).	[37]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of Retinoblastoma-associated protein (RB1).	[38]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Retinoblastoma-associated protein (RB1).	[38]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the expression of Retinoblastoma-associated protein (RB1).	[40]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid decreases the expression of Retinoblastoma-associated protein (RB1).	[41]
Gefitinib	DM15F0X	Approved	Gefitinib decreases the expression of Retinoblastoma-associated protein (RB1).	[42]
Ritonavir	DMU764S	Approved	Ritonavir increases the expression of Retinoblastoma-associated protein (RB1).	[43]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol increases the expression of Retinoblastoma-associated protein (RB1).	[44]
Ximelegatran	DMU8ANS	Approved	Ximelegatran decreases the expression of Retinoblastoma-associated protein (RB1).	[47]
Teriflunomide	DMQ2FKJ	Approved	Teriflunomide decreases the expression of Retinoblastoma-associated protein (RB1).	[51]
LY2835219	DM93VBZ	Approved	LY2835219 decreases the expression of Retinoblastoma-associated protein (RB1).	[52]
Salbutamol	DMN9CWF	Approved	Salbutamol decreases the expression of Retinoblastoma-associated protein (RB1).	[53]
Thiazolidinedione	DMC1NBW	Approved	Thiazolidinedione decreases the expression of Retinoblastoma-associated protein (RB1).	[57]
Talazoparib	DM1KS78	Approved	Talazoparib affects the expression of Retinoblastoma-associated protein (RB1).	[58]
Levamisole	DM5EN79	Approved	Levamisole decreases the expression of Retinoblastoma-associated protein (RB1).	[60]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Retinoblastoma-associated protein (RB1).	[63]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Retinoblastoma-associated protein (RB1).	[65]
Flavopiridol	DMKSUOI	Phase 2	Flavopiridol decreases the activity of Retinoblastoma-associated protein (RB1).	[73]
BEZ235	DMKBRDL	Phase 2	BEZ235 decreases the expression of Retinoblastoma-associated protein (RB1).	[74]
R-roscovitine	DMSH108	Phase 2	R-roscovitine increases the expression of Retinoblastoma-associated protein (RB1).	[75]
UCN-01	DMUNJZB	Phase 2	UCN-01 increases the expression of Retinoblastoma-associated protein (RB1).	[75]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Retinoblastoma-associated protein (RB1).	[81]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Retinoblastoma-associated protein (RB1).	[82]
BETULINIC ACID	DMBUI2A	Phase 1	BETULINIC ACID decreases the expression of Retinoblastoma-associated protein (RB1).	[42]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Retinoblastoma-associated protein (RB1).	[86]
Eugenol	DM7US1H	Patented	Eugenol decreases the expression of Retinoblastoma-associated protein (RB1).	[88]
PMID26394986-Compound-22	DM43Z1G	Patented	PMID26394986-Compound-22 increases the expression of Retinoblastoma-associated protein (RB1).	[89]

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