Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTKPW01)

• DTT Name: Androgen receptor messenger RNA (AR mRNA)
• Synonyms: Testosterone receptor (mRNA); Nuclear receptor subfamily 3 group C member 4 (mRNA); NR3C4 (mRNA); Dihydrotestosterone receptor (mRNA); DHTR (mRNA); Androgen receptor (mRNA)
• Gene Name: AR
• DTT Type: Clinical trial target; [1]
• BioChemical Class: mRNA target
• UniProt ID: ANDR_HUMAN
• TTD ID: T46521
• Sequence:
  MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQ
  QQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQ
  SALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSAD
  LKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELC
  KAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAG
  KSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQ
  SRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAA
  GPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAP
  YGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRL
  ETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRN
  DCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKLQEEGEASSTTSPTEETTQKL
  TVSHIEGYECQPIFLNVLEAIEPGVVCAGHDNNQPDSFAALLSSLNELGERQLVHVVKWA
  KALPGFRNLHVDDQMAVIQYSWMGLMVFAMGWRSFTNVNSRMLYFAPDLVFNEYRMHKSR
  MYSQCVRMRHLSQEFGWLQITPQEFLCMKALLLFSIIPVDGLKNQKFFDELRMNYIKELD
  RIIACKRKNPTSCSRRFYQLTKLLDSVQPIARELHQFTFDLLIKSHMVSVDFPEMMAEII
  SVQVPKILSGKVKPIYFHTQ
• Function: Transcription factor activity is modulated by bound coactivator and corepressor proteins like ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation. Transcription activation is also down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3. Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues.
• KEGG Pathway:
  Oocyte meiosis (hsa04114)
  Pathways in cancer (hsa05200)
  Prostate cancer (hsa05215)
• Reactome Pathway:
  Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 (R-HSA-5625886)
  Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dihydrotestosterone	DM3S8XC	Prostate hyperplasia	GA90	Phase 4	[1]

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BAY 86-5044	DMRZLU4	Breast cancer	2C60-2C65	Phase 2	[2]
IONIS-AR-2.5Rx	DMF2DMS	Prostate cancer	2C82.0	Phase 1/2	[3]
TRC-253	DMXI8CD	Prostate cancer	2C82.0	Phase 1/2	[4]
EZN-4176	DMNPS59	Prostate cancer	2C82.0	Phase 1	[5]
ISIS-AR	DM8P3N5	Prostate cancer	2C82.0	Phase 1	[6]

1 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
EUGENOL	DM7US1H	Discovery agent	N.A.	Patented	[7]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
RU-58841	DMMEAZ2	Acne vulgaris	ED80	Discontinued in Phase 1	[8]

57 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane	DMDJYHK	Discovery agent	N.A.	Investigative	[9]
2'-Hydroxy-3-methoxy-biphenyl-4-carbonitrile	DM5QV19	Discovery agent	N.A.	Investigative	[8]
2-chloro-4-(o-tolyloxy)benzonitrile	DMTPKU8	Discovery agent	N.A.	Investigative	[10]
2-methoxy-4-(2-methoxyphenylthio)benzonitrile	DMF8E5L	Discovery agent	N.A.	Investigative	[11]
2-methoxy-4-(m-tolyloxy)benzonitrile	DM1MGQ6	Discovery agent	N.A.	Investigative	[11]
2-methoxy-4-(o-tolyloxy)benzonitrile	DMT7YR3	Discovery agent	N.A.	Investigative	[11]
2-methoxy-4-(p-tolyloxy)benzonitrile	DMR5YZG	Discovery agent	N.A.	Investigative	[11]
2-methoxy-4-(propylthio)benzonitrile	DMXGP2I	Discovery agent	N.A.	Investigative	[11]
3,2'-bis-trifluoromethyl-biphenyl-4-carbonitrile	DMD0Z3U	Discovery agent	N.A.	Investigative	[12]
3-chloro-4-(o-tolyloxy)benzonitrile	DMNQF03	Discovery agent	N.A.	Investigative	[10]
3-chloro-4-(o-tolylthio)benzonitrile	DM6Z3I8	Discovery agent	N.A.	Investigative	[11]
3-methoxy-4-(m-tolyloxy)benzonitrile	DM2QD45	Discovery agent	N.A.	Investigative	[11]
3-methoxy-4-(o-tolyloxy)benzonitrile	DMEGF58	Discovery agent	N.A.	Investigative	[11]
3-methoxy-4-(p-tolyloxy)benzonitrile	DM37QE8	Discovery agent	N.A.	Investigative	[11]
4-(2,6-dimethylphenylthio)-2-methoxybenzonitrile	DMPLG9Q	Discovery agent	N.A.	Investigative	[11]
4-(butylthio)-2-(trifluoromethyl)benzonitrile	DM6SIA4	Discovery agent	N.A.	Investigative	[11]
4-(butylthio)-2-methoxybenzonitrile	DMH1AZV	Discovery agent	N.A.	Investigative	[11]
4-(cyclobutylmethylthio)-2-methoxybenzonitrile	DMR69K2	Discovery agent	N.A.	Investigative	[11]
4-(cyclopropylmethylthio)-2-methoxybenzonitrile	DM43Z2J	Discovery agent	N.A.	Investigative	[11]
4-(isopentylthio)-2-(trifluoromethyl)benzonitrile	DMGSZB2	Discovery agent	N.A.	Investigative	[11]
4-(isopentylthio)-2-methoxybenzonitrile	DML1G9S	Discovery agent	N.A.	Investigative	[11]
4-(isopropylthio)-2-(trifluoromethyl)benzonitrile	DMVDHX1	Discovery agent	N.A.	Investigative	[11]
4-(isopropylthio)-2-methoxybenzonitrile	DMR5HNI	Discovery agent	N.A.	Investigative	[11]
4-(m-tolyloxy)-2-(trifluoromethyl)benzonitrile	DM8BWZO	Discovery agent	N.A.	Investigative	[10]
4-(mesityloxy)-2-(trifluoromethyl)benzonitrile	DMQG57D	Discovery agent	N.A.	Investigative	[10]
4-(mesitylthio)-2-(trifluoromethyl)benzonitrile	DMAI3NZ	Discovery agent	N.A.	Investigative	[11]
4-(mesitylthio)-2-methoxybenzonitrile	DM1XK68	Discovery agent	N.A.	Investigative	[11]
4-(o-tolyloxy)-2-(trifluoromethyl)benzonitrile	DM8I4B9	Discovery agent	N.A.	Investigative	[10]
4-(o-tolylthio)-2-(trifluoromethyl)benzonitrile	DM85XP6	Discovery agent	N.A.	Investigative	[11]
4-(p-tolyloxy)-2-(trifluoromethyl)benzonitrile	DMXK56P	Discovery agent	N.A.	Investigative	[10]
4-(propylthio)-2-(trifluoromethyl)benzonitrile	DM8BZQ3	Discovery agent	N.A.	Investigative	[11]
5-Methoxyflavone	DMQX3V9	Discovery agent	N.A.	Investigative	[13]
6-amino-4-trifluoromethylquinolin-2(1H)-one	DMC5M76	Discovery agent	N.A.	Investigative	[14]
6-Hydroxyflavanone	DM6FNVC	Discovery agent	N.A.	Investigative	[13]
6-N-propyl -4-trifluoromethylquinolin-2(1H)-one	DMDPA2T	Discovery agent	N.A.	Investigative	[14]
AL-43	DMLEDHR	Discovery agent	N.A.	Investigative	[15]
andarine	DMX4P5A	Discovery agent	N.A.	Investigative	[16]
APIGENIN	DMI3491	Discovery agent	N.A.	Investigative	[13]
bisphenol A	DM2ZLD7	Discovery agent	N.A.	Investigative	[17]
BMS-564929	DMILMHZ	Discovery agent	N.A.	Investigative	[18]
CP-394531	DMDPH3W	Discovery agent	N.A.	Investigative	[19]
CP-409069	DM1U6P7	Discovery agent	N.A.	Investigative	[19]
Epierenone	DMVZW92	Discovery agent	N.A.	Investigative	[20]
flavone	DMEQH6J	Discovery agent	N.A.	Investigative	[13]
KAEMPFEROL	DMHEMUB	Discovery agent	N.A.	Investigative	[13]
LG-120838	DMG1UOR	Discovery agent	N.A.	Investigative	[21]
LG-121071	DMMHYQ4	Discovery agent	N.A.	Investigative	[22]
LGD-2226	DMKRSZY	Discovery agent	N.A.	Investigative	[23]
LGD-5552	DM67KWM	Discovery agent	N.A.	Investigative	[24]
NSC-26745	DMNX245	Discovery agent	N.A.	Investigative	[13]
PF-0998425	DMBM7LU	Discovery agent	N.A.	Investigative	[8]
RU-43044	DMY9P85	Discovery agent	N.A.	Investigative	[19]
RU-56187	DMO3WEG	Discovery agent	N.A.	Investigative	[25]
WAY-255348	DMSLNWA	Solid tumour/cancer	2A00-2F9Z	Investigative	[26]
YM-175735	DMMW3L1	Discovery agent	N.A.	Investigative	[27]
[3H]methyltrienolone	DMTSGOW	Discovery agent	N.A.	Investigative	[1]
[3H]mibolerone	DM6HDKQ	Discovery agent	N.A.	Investigative	[1]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Prostate cancer	2C82	Prostate	4.81E-01	-0.23	-0.29

References

• [1] 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: 628).
• [2] Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist. J Med Chem. 2000 Dec 28;43(26):5010-6.
• [3] Perspectives on the current and emerging chemical androgen receptor antagonists for the treatment of prostate cancer. Expert Opin Pharmacother. 2019 Feb;20(2):163-172.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] 2011 Pipeline of Santaris Pharma.
• [6] Clinical pipeline report, company report or official report of ISIS Pharmaceuticals.
• [7] Effect of essential oils, such as raspberry ketone and its derivatives, on antiandrogenic activity based on in vitro reporter gene assay. Bioorg Med Chem Lett. 2010 Apr 1;20(7):2111-4.
• [8] Rational design and synthesis of 4-((1R,2R)-2-hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile (PF-998425), a novel, nonsteroidal androgen recepto... J Med Chem. 2008 Nov 13;51(21):7010-4.
• [9] Identification of the brominated flame retardant 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane as an androgen agonist. J Med Chem. 2006 Dec 14;49(25):7366-72.
• [10] Diphenyl ethers as androgen receptor antagonists for the topical suppression of sebum production. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2176-8.
• [11] 4-(Alkylthio)- and 4-(arylthio)-benzonitrile derivatives as androgen receptor antagonists for the topical suppression of sebum production. Bioorg Med Chem Lett. 2009 Mar 1;19(5):1310-3.
• [12] Preparation of 4-aryl-2-trifluoromethylbenzonitrile derivatives as androgen receptor antagonists for topical suppression of sebum production. Bioorg Med Chem Lett. 2007 Oct 15;17(20):5529-32.
• [13] Effect of flavonoids on androgen and glucocorticoid receptors based on in vitro reporter gene assay. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4706-10.
• [14] Discovery of 6-N,N-bis(2,2,2-trifluoroethyl)amino- 4-trifluoromethylquinolin-2(1H)-one as a novel selective androgen receptor modulator. J Med Chem. 2006 Oct 19;49(21):6143-6.
• [15] 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.
• [16] Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. J Med Chem. 2009 Jun 25;52(12):3597-617.
• [17] Structure-activity relationships of bisphenol A analogs at estrogen receptors (ERs): discovery of an ERalpha-selective antagonist. Bioorg Med Chem Lett. 2013 Jul 15;23(14):4031-6.
• [18] N-aryl-oxazolidin-2-imine muscle selective androgen receptor modulators enhance potency through pharmacophore reorientation. J Med Chem. 2009 May 14;52(9):2794-8.
• [19] Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists. J Med Chem. 2002 Jun 6;45(12):2417-24.
• [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] Novel series of potent, nonsteroidal, selective androgen receptor modulators based on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. J Med Chem. 2007 May 17;50(10):2486-96.
• [23] Novel selective androgen receptor modulators: SAR studies on 6-bisalkylamino-2-quinolinones. Bioorg Med Chem Lett. 2007 Mar 15;17(6):1527-31.
• [24] 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.
• [25] Structure-activity relationships of bioisosteric replacement of the carboxylic acid in novel androgen receptor pure antagonists. Bioorg Med Chem. 2010 May 1;18(9):3159-68.
• [26] 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.
• [27] (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3- yl]piperazine-1-carboxamide (YM580) as an orally po... J Med Chem. 2006 Jan 26;49(2):716-26.