Target Information
| Target General Information | Top | |||||
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| Target ID |
T94085
(Former ID: TTDS00073)
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| Target Name |
Retinoic acid receptor alpha (RARA)
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| Synonyms |
RAR-alpha; RAR alpha; Nuclear receptor subfamily 1 group B member 1; NR1B1
Click to Show/Hide
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| Gene Name |
RARA
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Mature T-cell lymphoma [ICD-11: 2A90] | |||||
| 2 | Alzheimer disease [ICD-11: 8A20] | |||||
| Function |
Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function. Receptor for retinoic acid.
Click to Show/Hide
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| BioChemical Class |
Nuclear hormone receptor
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| UniProt ID | ||||||
| Sequence |
MASNSSSCPTPGGGHLNGYPVPPYAFFFPPMLGGLSPPGALTTLQHQLPVSGYSTPSPAT
IETQSSSSEEIVPSPPSPPPLPRIYKPCFVCQDKSSGYHYGVSACEGCKGFFRRSIQKNM VYTCHRDKNCIINKVTRNRCQYCRLQKCFEVGMSKESVRNDRNKKKKEVPKPECSESYTL TPEVGELIEKVRKAHQETFPALCQLGKYTTNNSSEQRVSLDIDLWDKFSELSTKCIIKTV EFAKQLPGFTTLTIADQITLLKAACLDILILRICTRYTPEQDTMTFSDGLTLNRTQMHNA GFGPLTDLVFAFANQLLPLEMDDAETGLLSAICLICGDRQDLEQPDRVDMLQEPLLEALK VYVRKRRPSRPHMFPKMLMKITDLRSISAKGAERVITLKMEIPGSMPPLIQEMLENSEGL DTLSGQPGGGGRDGGGLAPPPGSCSPSLSPSSNRSSPATHSP Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| ADReCS ID | BADD_A02162 | |||||
| HIT2.0 ID | T46E53 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | Tamibarotene | Drug Info | Phase 3 | T-cell leukaemia | [2] | |
| 2 | IRX-5183 | Drug Info | Phase 1 | Solid tumour/cancer | [3] | |
| 3 | SY-1425 | Drug Info | Phase 1 | Acute myeloid leukaemia | [3] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | LG100268 | Drug Info | Discontinued in Phase 1 | Acquired immune deficiency syndrome | [4], [5] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | Tamibarotene | Drug Info | [6], [7] | |||
| Agonist | [+] 10 Agonist drugs | + | ||||
| 1 | IRX-5183 | Drug Info | [8], [9] | |||
| 2 | SY-1425 | Drug Info | [3] | |||
| 3 | PMID27336223-Compound-4 | Drug Info | [10] | |||
| 4 | PMID27336223-Compound-5 | Drug Info | [10] | |||
| 5 | LG100268 | Drug Info | [11] | |||
| 6 | AGN193836 | Drug Info | [13] | |||
| 7 | BMS753 | Drug Info | [15] | |||
| 8 | CD666 | Drug Info | [16] | |||
| 9 | Ro 40-6055 | Drug Info | [17] | |||
| 10 | Ro-40-0655 | Drug Info | [9] | |||
| Antagonist | [+] 3 Antagonist drugs | + | ||||
| 1 | AGN193109 | Drug Info | [12] | |||
| 2 | BMS614 | Drug Info | [14] | |||
| 3 | Ro 41-5253 | Drug Info | [18] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Tretinoin | Ligand Info | |||||
| Structure Description | Crystal structure of a mixed agonist-bound RAR-alpha and antagonist-bound RXR-alpha heterodimer ligand binding domains | PDB:3A9E | ||||
| Method | X-ray diffraction | Resolution | 2.75 Å | Mutation | No | [19] |
| PDB Sequence |
SYTLTPEVGE
186 LIEKVRKAHQ196 ETFPALCQLG206 KYTTNNSSEQ216 RVSLDIDLWD226 KFSELSTKCI 236 IKTVEFAKQL246 PGFTTLTIAD256 QITLLKAACL266 DILILRICTR276 YTPEQDTMTF 286 SDGLTLNRTQ296 MHNAGFGPLT306 DLVFAFANQL316 LPLEMDDAET326 GLLSAICLIC 336 GDRQDLEQPD346 RVDMLQEPLL356 EALKVYVRKR366 RPSRPHMFPK376 MLMKITDLRS 386 ISAKGAERVI396 TLKMEIPGSM406 PPLIQEMLE
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PHE199
3.704
TRP225
4.135
PHE228
3.301
LEU231
3.805
SER232
3.977
CYS235
3.518
LEU266
4.048
LEU269
3.616
ILE270
3.984
ARG272
4.684
ILE273
3.745
ARG276
3.637
PHE286
3.294
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| Ligand Name: PMID27336223-Compound-5 | Ligand Info | |||||
| Structure Description | Crystal structure of RARalpha ligand binding domain in complex with an agonist ligand (Am580) and a coactivator fragment | PDB:3KMR | ||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | No | [20] |
| PDB Sequence |
PEVGELIEKV
191 RKAHQETFPA201 LCQLGKYTTN211 NSSEQRVSLD221 IDLWDKFSEL231 STKCIIKTVE 241 FAKQLPGFTT251 LTIADQITLL261 KAACLDILIL271 RICTRYTPEQ281 DTMTFSDGLT 291 LNRTQMHNAG301 FGPLTDLVFA311 FANQLLPLEM321 DDAETGLLSA331 ICLICGDRQD 341 LEQPDRVDML351 QEPLLEALKV361 YVRKRRPSRP371 HMFPKMLMKI381 TDLRSISAKG 391 AERVITLKME401 IPGSMPPLIQ411 EMLE
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PHE199
4.778
TRP225
3.894
PHE228
3.433
SER229
4.915
LEU231
3.645
SER232
3.186
CYS235
3.808
LEU266
3.872
LEU269
3.262
ILE270
3.780
ARG272
4.441
ILE273
3.623
ARG276
2.961
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Th17 cell differentiation | hsa04659 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Estrogen signaling pathway | hsa04915 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 19 | Degree centrality | 2.04E-03 | Betweenness centrality | 2.48E-04 |
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| Closeness centrality | 2.40E-01 | Radiality | 1.42E+01 | Clustering coefficient | 2.92E-01 |
| Neighborhood connectivity | 4.09E+01 | Topological coefficient | 9.56E-02 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Drug Resistance Mutation (DRM) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Pathways in cancer | |||||
| 2 | Transcriptional misregulation in cancer | |||||
| 3 | Acute myeloid leukemia | |||||
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | Retinoic acid receptors-mediated signaling | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Nuclear Receptor transcription pathway | |||||
| WikiPathways | [+] 5 WikiPathways | + | ||||
| 1 | Vitamin A and Carotenoid Metabolism | |||||
| 2 | Nuclear Receptors in Lipid Metabolism and Toxicity | |||||
| 3 | Integrated Pancreatic Cancer Pathway | |||||
| 4 | Adipogenesis | |||||
| 5 | Nuclear Receptors | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):30-4. | |||||
| REF 2 | ClinicalTrials.gov (NCT04797780) SY-1425 Plus Azacitidine in Participants With Newly Diagnosed RARA-positive Higher-Risk Myelodysplastic Syndrome. U.S. National Institutes of Health. | |||||
| REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 4 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2808). | |||||
| REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010920) | |||||
| REF 6 | Tamibarotene: a candidate retinoid drug for Alzheimer's disease. Biol Pharm Bull. 2012;35(8):1206-12. | |||||
| REF 7 | A retinoic acid receptor agonist tamibarotene suppresses iron accumulation in the liver.Obesity (Silver Spring).2013 Jan;21(1):E22-5. | |||||
| REF 8 | Retinoic acid receptor alpha and retinoid X receptor specific agonists reduce renal injury in established chronic glomerulonephritis of the rat. J Mol Med (Berl). 2004 Feb;82(2):116-25. | |||||
| REF 9 | Tamibarotene. Drugs Today (Barc). 2007 Aug;43(8):563-8. | |||||
| REF 10 | Therapeutic use of selective synthetic ligands for retinoic acid receptors: a patent review.Expert Opin Ther Pat. 2016 Aug;26(8):957-71. | |||||
| REF 11 | Placental steroidogenesis in rats is independent of signaling pathways induced by retinoic acids. Gen Comp Endocrinol. 2009 Sep 15;163(3):285-91. | |||||
| REF 12 | Therapeutic applications for ligands of retinoid receptors. Curr Pharm Des. 2000 Jan;6(1):25-58. | |||||
| REF 13 | Synthesis and biological activity of retinoic acid receptor-alpha specific amides. Bioorg Med Chem Lett. 2002 Nov 4;12(21):3145-8. | |||||
| REF 14 | Co-regulator recruitment and the mechanism of retinoic acid receptor synergy. Nature. 2002 Jan 10;415(6868):187-92. | |||||
| REF 15 | Structural basis for engineering of retinoic acid receptor isotype-selective agonists and antagonists. Chem Biol. 1999 Aug;6(8):519-29. | |||||
| REF 16 | Identification of synthetic retinoids with selectivity for human nuclear retinoic acid receptor gamma. Biochem Biophys Res Commun. 1992 Jul 31;186(2):977-83. | |||||
| REF 17 | Selective high affinity retinoic acid receptor alpha or beta-gamma ligands. Mol Pharmacol. 1991 Oct;40(4):556-62. | |||||
| REF 18 | A retinoic acid receptor alpha antagonist selectively counteracts retinoic acid effects. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7129-33. | |||||
| REF 19 | The "Phantom Effect" of the Rexinoid LG100754: structural and functional insights. PLoS One. 2010 Nov 30;5(11):e15119. | |||||
| REF 20 | A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor. Nat Struct Mol Biol. 2010 Jul;17(7):801-7. | |||||
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