Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTOZRK6)

• DTT Name: Glucocorticoid receptor messenger RNA (GCR mRNA)
• Synonyms: Nuclear receptor subfamily 3 group C member 1 (mRNA); Glucocorticoid receptor (mRNA); GRL (mRNA); GR (mRNA); Alpha-A (mRNA)
• Gene Name: NR3C1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: mRNA target
• UniProt ID: GCR_HUMAN
• TTD ID: T30687
• Sequence:
  MDSKESLTPGREENPSSVLAQERGDVMDFYKTLRGGATVKVSASSPSLAVASQSDSKQRR
  LLVDFPKGSVSNAQQPDLSKAVSLSMGLYMGETETKVMGNDLGFPQQGQISLSSGETDLK
  LLEESIANLNRSTSVPENPKSSASTAVSAAPTEKEFPKTHSDVSSEQQHLKGQTGTNGGN
  VKLYTTDQSTFDILQDLEFSSGSPGKETNESPWRSDLLIDENCLLSPLAGEDDSFLLEGN
  SNEDCKPLILPDTKPKIKDNGDLVLSSPSNVTLPQVKTEKEDFIELCTPGVIKQEKLGTV
  YCQASFPGANIIGNKMSAISVHGVSTSGGQMYHYDMNTASLSQQQDQKPIFNVIPPIPVG
  SENWNRCQGSGDDNLTSLGTLNFPGRTVFSNGYSSPSMRPDVSSPPSSSSTATTGPPPKL
  CLVCSDEASGCHYGVLTCGSCKVFFKRAVEGQHNYLCAGRNDCIIDKIRRKNCPACRYRK
  CLQAGMNLEARKTKKKIKGIQQATTGVSQETSENPGNKTIVPATLPQLTPTLVSLLEVIE
  PEVLYAGYDSSVPDSTWRIMTTLNMLGGRQVIAAVKWAKAIPGFRNLHLDDQMTLLQYSW
  MFLMAFALGWRSYRQSSANLLCFAPDLIINEQRMTLPCMYDQCKHMLYVSSELHRLQVSY
  EEYLCMKTLLLLSSVPKDGLKSQELFDEIRMTYIKELGKAIVKREGNSSQNWQRFYQLTK
  LLDSMHEVVENLLNYCFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGNIKKLLFHQK
• Function: Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Involved in chromatin remodeling. Plays a role in rapid mRNA degradation by binding to the 5' UTR of target mRNAs and interacting with PNRC2 in a ligand-dependent manner which recruits the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Receptor for glucocorticoids (GC).
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway: BMAL1 (R-HSA-1368108)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Vamorolone	DM047HI	Duchenne muscular dystrophy	8C70.1	Approved	[1]

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CORT125281	DMHBOUX	Prostate cancer	2C82.0	Phase 2	[2]
ISIS-GCCR	DMICMNU	Diabetic complication	5A2Y	Phase 2	[3]
A-348441	DM25CBW	Type-2 diabetes	5A11	Phase 1	[4]
AZD9567	DMAXHC0	Rheumatoid arthritis	FA20	Phase 1	[1]
ORIC-101	DMR12S0	Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]

21 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE	DMTPQ84	Discovery agent	N.A.	Investigative	[5]
1-(2,3-DICHLOROPHENYL)-2,2,2-TRIFLUORO-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)ETHANOL (ENANTIOMERIC MIX)	DM1Q0TM	Discovery agent	N.A.	Investigative	[6]
1-(3-CHLORO-4-FLUOROPHENYL)-2,2,2-TRIFLUORO-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)ETHANOL (ENANTIOMERIC MIX)	DMJXOUK	Discovery agent	N.A.	Investigative	[6]
1-Methoxy-6-phenyl-6H-benzo[c]chromen-8-ylamine	DM8YQ2O	Discovery agent	N.A.	Investigative	[7]
1-Methoxy-6-phenyl-6H-benzo[c]chromene	DM2D5HB	Discovery agent	N.A.	Investigative	[7]
2,2,2-TRIFLUORO-1-(4-FLUOROPHENYL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)ETHANOL (DIASTEREOMERIC MIX)	DMBLXOG	Discovery agent	N.A.	Investigative	[6]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one	DMM9X0G	Discovery agent	N.A.	Investigative	[8]
AL-43	DMLEDHR	Discovery agent	N.A.	Investigative	[9]
CP-394531	DMDPH3W	Discovery agent	N.A.	Investigative	[10]
CP-409069	DM1U6P7	Discovery agent	N.A.	Investigative	[10]
deoxycorticosterone	DMW6YLS	Discovery agent	N.A.	Investigative	[5]
DI-O-METHYLENDIANDRIN A	DM5G4O7	Discovery agent	N.A.	Investigative	[11]
ENDIANDRIN A	DM7RDGH	Discovery agent	N.A.	Investigative	[11]
Epierenone	DMVZW92	Discovery agent	N.A.	Investigative	[12]
LG-120838	DMG1UOR	Discovery agent	N.A.	Investigative	[13]
LGD-5552	DM67KWM	Discovery agent	N.A.	Investigative	[14]
OXDEX	DMMEDJT	Discovery agent	N.A.	Investigative	[15]
RU-43044	DMY9P85	Discovery agent	N.A.	Investigative	[10]
RU26988	DMA7URH	Discovery agent	N.A.	Investigative	[16]
RU28362	DMAOJ0E	Discovery agent	N.A.	Investigative	[16]
WAY-214950	DM8ODI7	Discovery agent	N.A.	Investigative	[17]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Type 2 diabetes	5A11	Liver tissue	3.19E-02	0.54	1.67

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Clinical pipeline report, company report or official report of ISIS Pharmaceuticals (2011).
• [4] Synthesis and activity of novel bile-acid conjugated glucocorticoid receptor antagonists. Bioorg Med Chem Lett. 2006 Dec 1;16(23):6086-90.
• [5] Functional probing of the human glucocorticoid receptor steroid-interacting surface by site-directed mutagenesis. Gln-642 plays an important role in steroid recognition and binding. J Biol Chem. 2000Jun 23;275(25):19041-9.
• [6] 5-Functionalized indazoles as glucocorticoid receptor agonists. Bioorg Med Chem Lett. 2010 May 15;20(10):3017-20.
• [7] Synthesis and biological evaluation of novel, selective, nonsteroidal glucocorticoid receptor antagonists. Bioorg Med Chem Lett. 2004 May 3;14(9):2079-82.
• [8] Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 rec... J Med Chem. 2010 Sep 9;53(17):6386-97.
• [9] Differentiation of in vitro transcriptional repression and activation profiles of selective glucocorticoid modulators. Bioorg Med Chem Lett. 2004 Apr 5;14(7):1721-7.
• [10] Virtual screening for the identification of novel nonsteroidal glucocorticoid modulators. J Med Chem. 2010 Apr 22;53(8):3065-74.
• [11] Endiandrin A, a potent glucocorticoid receptor binder isolated from the Australian plant Endiandra anthropophagorum. J Nat Prod. 2007 Jul;70(7):1118-21.
• [12] (S)-N-{3-[1-cyclopropyl-1-(2,4-difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide: a potent, nonsteroidal, functional antagonist of the mine... J Med Chem. 2007 Dec 27;50(26):6443-5.
• [13] 5-Benzylidene 1,2-dihydrochromeno[3,4-f]quinolines, a novel class of nonsteroidal human progesterone receptor agonists. J Med Chem. 1998 Oct 22;41(22):4354-9.
• [14] Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein-protein interaction profile. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19244-9.
• [15] Investigation of the relative cellular permeability of DNA-binding pyrrole-imidazole polyamides. J Med Chem. 2009 Aug 13;52(15):4604-12.
• [16] 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. (Target id: 625).
• [17] Indazole-based liver X receptor (LXR) modulators with maintained atherosclerotic lesion reduction activity but diminished stimulation of hepatic tr... J Med Chem. 2008 Nov 27;51(22):7161-8.