Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT26PHO)

• DTT Name: Mineralocorticoid receptor (MR)
• Synonyms: Nuclear receptor subfamily 3 group C member 2; Mineralocorticoid receptor; MLR; MCR; Inner ear mineralocorticoid receptor; Delta
• Gene Name: NR3C2
• DTT Type: Successful target; [1]
• Related Disease:
  Adrenocortical insufficiency [ICD-11: 5A74]
  Contraceptive management [ICD-11: QA21]
  Heart failure [ICD-11: BD10-BD1Z]
  Hypertension [ICD-11: BA00-BA04]
  Hypo-osmolality/hyponatraemia [ICD-11: 5C72]
• BioChemical Class: Nuclear hormone receptor
• UniProt ID: MCR_HUMAN
• TTD ID: T72168
• Sequence:
  METKGYHSLPEGLDMERRWGQVSQAVERSSLGPTERTDENNYMEIVNVSCVSGAIPNNST
  QGSSKEKQELLPCLQQDNNRPGILTSDIKTELESKELSATVAESMGLYMDSVRDADYSYE
  QQNQQGSMSPAKIYQNVEQLVKFYKGNGHRPSTLSCVNTPLRSFMSDSGSSVNGGVMRAV
  VKSPIMCHEKSPSVCSPLNMTSSVCSPAGINSVSSTTASFGSFPVHSPITQGTPLTCSPN
  VENRGSRSHSPAHASNVGSPLSSPLSSMKSSISSPPSHCSVKSPVSSPNNVTLRSSVSSP
  ANINNSRCSVSSPSNTNNRSTLSSPAASTVGSICSPVNNAFSYTASGTSAGSSTLRDVVP
  SPDTQEKGAQEVPFPKTEEVESAISNGVTGQLNIVQYIKPEPDGAFSSSCLGGNSKINSD
  SSFSVPIKQESTKHSCSGTSFKGNPTVNPFPFMDGSYFSFMDDKDYYSLSGILGPPVPGF
  DGNCEGSGFPVGIKQEPDDGSYYPEASIPSSAIVGVNSGGQSFHYRIGAQGTISLSRSAR
  DQSFQHLSSFPPVNTLVESWKSHGDLSSRRSDGYPVLEYIPENVSSSTLRSVSTGSSRPS
  KICLVCGDEASGCHYGVVTCGSCKVFFKRAVEGQHNYLCAGRNDCIIDKIRRKNCPACRL
  QKCLQAGMNLGARKSKKLGKLKGIHEEQPQQQQPPPPPPPPQSPEEGTTYIAPAKEPSVN
  TALVPQLSTISRALTPSPVMVLENIEPEIVYAGYDSSKPDTAENLLSTLNRLAGKQMIQV
  VKWAKVLPGFKNLPLEDQITLIQYSWMCLSSFALSWRSYKHTNSQFLYFAPDLVFNEEKM
  HQSAMYELCQGMHQISLQFVRLQLTFEEYTIMKVLLLLSTIPKDGLKSQAAFEEMRTNYI
  KELRKMVTKCPNNSGQSWQRFYQLTKLLDSMHDLVSDLLEFCFYTFRESHALKVEFPAML
  VEIISDQLPKVESGNAKPLYFHRK
• Function: Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels. Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol.
• Reactome Pathway:
  Nuclear Receptor transcription pathway (R-HSA-383280)
  SUMOylation of intracellular receptors (R-HSA-4090294)
  HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)

Molecular Interaction Atlas (MIA) of This DTT

7 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aldosterone	DM9S2JW	Hypertension	BA00-BA04	Approved	[2]
Desoxycorticosterone acetate	DMS0AFE	Discovery agent	N.A.	Approved	[3]
Desoxycorticosterone pivalate	DMSA4B3	Addison disease	5A74.0	Approved	[4]
Drospirenone	DM1A9W3	Contraception	QA21	Approved	[5]
Eplerenone	DMF0NQR	Heart failure	BD10-BD13	Approved	[3]
Fludrocortisone	DMUDIR8	Cerebral salt-wasting syndrome	5C72	Approved	[1], [6]
Spironolactone	DM2AQ5N	Congestive heart failure	BD10	Approved	[3]

8 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Finerenone	DMM4FJ3	Diabetic nephropathy	GB61.Z	Phase 3	[7]
BR-4628	DMNFKVW	Heart failure	BD10-BD13	Phase 2	[8]
LY-2623091	DMFGNB4	Chronic kidney disease	GB61	Phase 2	[9]
MT-3995	DMXSZA4	Diabetic nephropathy	GB61.Z	Phase 2	[9]
Nerenone	DMBJ3GL	Diabetic nephropathy	GB61.Z	Phase 2	[8]
ZK-91587	DMJ94L0	Cardiovascular disease	BA00-BE2Z	Phase 2	[10], [11]
KBP-5074	DMI9FXE	Hypertension	BA00-BA04	Phase 1/2	[12]
XL550	DMY93SW	Type-2 diabetes	5A11	Phase 1	[13]

6 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID27551786-Compound-106	DM5OQBR	N. A.	N. A.	Patented	[14]
PMID27551786-Compound-138	DM4IZUH	N. A.	N. A.	Patented	[14]
PMID27551786-Compound-I	DMA7H63	N. A.	N. A.	Patented	[14]
PMID27551786-Compound-II	DMJADXV	N. A.	N. A.	Patented	[14]
PMID27551786-Compound-III	DMBQ981	N. A.	N. A.	Patented	[14]
PMID27551786-Compound-IV	DM7IB8L	N. A.	N. A.	Patented	[14]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PF-03882845	DMOS9NZ	Diabetic nephropathy	GB61.Z	Terminated	[15]

10 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	[16]
AL-43	DMLEDHR	Discovery agent	N.A.	Investigative	[17]
B-Octylglucoside	DMMO75G	Discovery agent	N.A.	Investigative	[18]
CB-1922	DMSFXZU	Human immunodeficiency virus infection	1C62	Investigative	[8]
Deoxycorticosterone	DMW6YLS	Discovery agent	N.A.	Investigative	[19]
Epierenone	DMVZW92	Discovery agent	N.A.	Investigative	[20]
LG-120838	DMG1UOR	Discovery agent	N.A.	Investigative	[21]
LGD-5552	DM67KWM	Discovery agent	N.A.	Investigative	[22]
RU28318	DMN049T	Discovery agent	N.A.	Investigative	[8]
WAY-255348	DMSLNWA	Solid tumour/cancer	2A00-2F9Z	Investigative	[23]

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	7.31E-01	-5.31E-04	-1.53E-03

References

• [1] Mineralocorticoid receptor-mediated inhibition of the hypothalamic-pituitary-adrenal axis in aged humans. J Gerontol A Biol Sci Med Sci. 2003 Oct;58(10):B900-5.
• [2] Stimulation of testosterone production in rat Leydig cells by aldosterone is mineralocorticoid receptor mediated. Mol Cell Endocrinol. 2005 Nov 24;243(1-2):35-42.
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [4] Characterization of rat brain aldosterone receptors reveals high affinity for corticosterone. Endocrinology. 1983 Dec;113(6):2043-51.
• [5] Biochemical mechanisms of New Molecular Entities (NMEs) approved by United States FDA during 2001-2004: mechanisms leading to optimal efficacy and ... Curr Top Med Chem. 2006;6(5):461-78.
• [6] Addison's disease. BMJ. 2009 Jul 2;339:b2385.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] 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: 626).
• [9] Nonsteroidal antagonists of the mineralocorticoid receptor. Curr Opin Nephrol Hypertens. 2015 Sep;24(5):417-24.
• [10] ZK91587: a novel synthetic antimineralocorticoid displays high affinity for corticosterone (type I) receptors in the rat hippocampus. Life Sci. 1988;43(19):1537-43.
• [11] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [12] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [13] Clinical pipeline report, company report or official report of Exelixis (2011).
• [14] Mineralocorticoid receptor antagonists: a patent evaluation of US20150284376A1.Expert Opin Ther Pat. 2016 Sep 14:1-4.
• [15] Discovery of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g] indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy.J Med Chem.2010 Aug 26;53(16):5979-6002.
• [16] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [17] Nonsteroidal selective glucocorticoid modulators: the effect of C-10 substitution on receptor selectivity and functional potency of 5-allyl-2,5-dih... J Med Chem. 2003 Mar 13;46(6):1016-30.
• [18] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [19] Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands. Eur J Pharmacol. 1993 Oct 15;247(2):145-54.
• [20] (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.
• [21] 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.
• [22] 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.
• [23] Design, synthesis, and SAR of new pyrrole-oxindole progesterone receptor modulators leading to 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-... J Med Chem. 2008 Mar 27;51(6):1861-73.