Table 2. Human enigmatic orphans.
| Enigmatic-Orphans | ||||||||
|---|---|---|---|---|---|---|---|---|
|
NR1F1 (RORα) RAR-Related-Orphan-Receptor-α |
15 | 11 12 11 |
NP_599023 NP_599022 NP_002934 |
523 556 548 |
66-160 99-193 91-185 |
272-523 305-544 297-536 |
ATRA (PUBCHEM: 444795)(end.agonist) Stehlin-Gaon C et al, Nat Struct Biol (2003)10: 820-5. Melatonin (PUBCHEM:896)(end.agonist) Dai J et al, Mol Cell Endocrinol (2001)176:111-20 SR1078 (PUBCHEM:17980288)(synth. agonist) Kojetin D et al, ACS Chem Biol (2011) 6:131-4 SR1001 (PUBCHEM:44241473)(synth.antagonist) Solt LA et al, Nature(2011)472: 491-4 |
Onco-suppressive action ER− tumors |
|
NR1F2 (RORβ) RAR-Related-Orphan-Receptor-β |
9 | 10 | NP_008845 | 459 | 3-97 | 210-450 | Unknown end. agonists N-[5-(2-chloro-benzoyl)-4-(3-chlorophenyl)-thiazol-2-yl]-2-(4-ethanesulfonyl-phenyl)-acetamide (PUBCHEM:8813095)(synth. reverse agonist) Gege C et al Bioorg Med Chem Lett (2014)24:5265-7 |
Unknown |
|
NR1F3 (RORγ) RAR-Related-Orphan-Receptor-γ |
1 | 10 11 |
NP_001001523 NP_005051 |
497 518 |
4-97 24-118 |
247-485 268-506 |
7β,27-dihydroxycholesterol (PUBCHEM:24895774)(end.agonist) Soroosh P et al, Proc Natl Acad Sci U S A (2014)111:12163-8. SR2211 (PUBCHEM:51035449)(synth. antagonist) Kumar N et al, ACS Chem Biol (2012) 7:672-7 N-[5-(2-chloro-benzoyl)-4-(3-chlorophenyl)-thiazol-2-yl]-2-(4-ethanesulfonyl-phenyl)-acetamide (PUBCHEM:8813095)(synth. reverse agonist) Gege C et al Bioorg Med Chem Lett (2014)24:5265-7 |
Oncogenic Action ER− tumors |
|
NR1I3 (CAR) Constitutive-Androstane-Receptor |
1 | 9 9 9 9 8 8 8 8 8 8 8 7 7 |
NP_005113 NP_001070950 NP_001070948 NP_001070937 NP_001070940 NP_001070949 NP_001070947 NP_001070939 NP_001070942 NP_001070944 NP_001070945 NP_001070938 NP_001070943 |
348 357 352 340 324 314 319 309 296 311 306 280 267 |
11-82 11-82 11-82 11-82 7-53 11-82 7-53 11-82 11-82 7-53 7-53 7-53 7-53 |
106-346 106-355 106-350 106-311 77-322 106-312 77-317 106-307 106-267 77-282 77-277 77-278 77-238 |
Androstenol (PUBCHEM:101989)(end. antagonist) Makinen J et al, Biochem J (2003) 376:465-72 CITCO (PUBCHEM:9600409)(synth. agonist) Maglich JM et al, J Biol Chem (2003) 278:17277-83. TCPOBOP (PUBCHEM:5382)(synth. agonist) Yamamoto Y et al, PLoS One (2010) 5:e10121 BDBM50422490 (CHEMBL141998) (synth. antagonist) Jyrkkarinne J et al, J Med Chem (2003) 46: 4687-95. |
Unknown |
|
NR2A1 (HNF4α) Hepatocyte-Nuclear-Factor-4α |
20 | 10 11 10 8 10 10 8 |
NP_001245284 NP_001274112 NP_849180 NP_849181 NP_787110 NP_001025174 NP_001274113 |
467 449 464 417 452 442 395 |
53-128 35-110 60-135 60-135 38-113 38-113 35-110 |
144-366 126-348 151-373 151-373 129-351 129-351 126-348 |
Linoleic-acid (PUBCHEM:5280450)(end. agonist) Yuan X et al, PLoS One (2009) 4:e5609. | Onco-suppressive action |
|
NR2A2 (HNF4γ) Hepatocyte-Nuclear-Factor-4γ |
8 | 10 | NP_004124 | 445 | 49-124 | 140-361 | Fatty-acids (end. agonists) Sladek F, Mol Cell (2002) 10:219-21 | Unknown |
|
NR3B1 (ESRRα) Estrogen-Related-Receptor-α |
11 | 7 | NP_001269379 | 423 | 73-168 | 197-420 | Diethylstilbestrol (PUBCHEM:448537)(end. agonist) Ariazi EA and Jordan VC, Curr Top Med Chem (2006) 6:203-15 SR16388 (PUBCHEM:54612678)(synth. antagonist) Duellman SJ et al, Biochem Pharmacol (2010) 80:819-26 XCT790 (PUBCHEM:6918788)(synth. antagonist) Lanvin O et al, J Biol Chem (2007) 282:28328-34 |
Oncogenic Action Her2 tumors Basal tumors |
|
NR3B2 (ESRRβ) Estrogen-Related-Receptor-β |
14 | 10 | NP_004443 | 508 | 98-193 | 212-431 | Diethylstilbestrol (PUBCHEM:448537)(end. agonist) Ariazi EA and Jordan VC, Curr Top Med Chem (2006) 6:203-15 DY131 (PUBCHEM:5497124)(synth. agonist) Yu DD and Forman BM, Bioorg Med Chem Lett (2005) 15:1311-3 |
Onco-suppressive action |
|
NR3B3 (ESRRγ) Estrogen-Related-Receptor-γ |
1 | 9 8 7 8 |
NP_001230448 NP_001230447 NP_001429 NP_001230436 |
435 470 458 396 |
99-195 127-223 122-218 99-156 |
214-433 249-468 237-456 175-394 |
Diethylstilbestrol (PUBCHEM:448537)(end. agonist) Ariazi EA and Jordan VC, Curr Top Med Chem (2006) 6:203-15 GSK4716 (PUBCHEM:5331325)(synth. agonist) Zuercher WJ et al, J Med Chem (2005) 48: 3107-9 GSK9089 (PUBCHEM:5497124)(synth. agonist) Zuercher WJ et al, J Med Chem (2005) 48: 3107-9 |
Onco-suppressive action |
|
NR5A1 (SF-1) Steroidogenic-Factor-1 |
9 | 7 | NP_004950 | 461 | 13-105 | 223-459 | phosphatidic-acid (PUBCHEM: 5283523)(end. agonist) Krylova IN et al, Cell (2005) 120:343-55 phosphatidyl-choline (PUBCHEM: 5287971)(end. agonist) Sablin EP et al, Mol Endocrinol (2009) 23: 25-34 GSK8470 (PUBCHEM:10883540)(synth. agonist) Whitby RJ et al, J Med Chem (2006) 49: 6652-5 AC-45594 (PUBCHEM:25641)(synth. antagonist) Del Tredici AL et al, Mol Pharmacol (2008) 73: 900-8 |
Unknown |
|
NR5A2 (LRH-1) Liver-Receptor-Homolog-1 |
1 | 8 7 7 |
NP_995582 NP_001263393 NP_003813 |
541 469 495 |
86-178 14-106 40-132 |
342-390 229-469 255-495 |
phosphatidic-acid (PUBCHEM: 5283523)(end. agonist) Krylova IN et al, Cell (2005) 120:343-55 GSK8470 (PUBCHEM:10883540)(synth. agonist) Whitby RJ et al, J Med Chem (2006) 49: 6652-5 |
Oncogenic action |
The table contains basic information on the Enigmatic-Orphans group of nuclear receptors (NRs). The first column lists the human NRs considered in the review article. The official symbol of each NR is indicated in italics, while the original alias of each protein product is indicated in parenthesis. The full name of each NR is indicated underneath in italics. The second column from the left lists the human chromosome (Chr) each NR maps to. The number of exons encoding the transcripts giving rise to the corresponding NR protein-variant is indicated in the third column. The fourth column lists the accession number of each NR protein-variant. The amino acid (aa) length of each NR protein variant, the position of the DNA-binding domain (DBD) and the ligand-binding domain (LBD) are indicated in columns five, six and seven, respectively. Column eight contains a list of representative endogenous (end.) and synthetic (synth.) agonists, antagonists and reverse agonists for each NR along with an appropriate reference. The chemical structures of the listed molecules can be found in the PUBCHEM database with the use of the PUBCHEM-CID accession numbers provided. The structure of the NR1I3 antagonist, BDBM50422490, is available in the CHEMBL database as indicated. When possible, the predicted onco-suppressive (bold) or oncogenic (black-boxed) action of the corresponding NR is indicated in the last column on the right. Synthetic agonists and antagonists of potential therapeutic interested targeting onco-suppressive and oncogenic NRs, respectively, are marked in bold and boxed in black. Finally, in the few cases where supportive data are available, the type of breast-cancer which is predicted to represent a preferential target of the NR is listed in the last column.