EPI-001: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
Declining submission: see comment therein (AFCH)
No edit summary
Line 6: Line 6:


==Mechanism of Action==
==Mechanism of Action==
EPI-001 is a mixture of four stereoisomers. EPI-001 binds to the activation function-1 (AF-1) region in the amino-terminus of androgen receptor (AR) as opposed to the antiandrogens that bind to the C-terminus ligand-binding domain (Sadar 2012). A functional AF-1 is essential for the androgen receptor to have transcriptional activity. If AF-1 is deleted or mutated, the androgen receptor will still bind androgen, but will have no transcriptional activity (Jenster et al., 1991). Importantly, if the androgen receptor lacks a ligand-binding domain, the receptor will be nuclear and constitutively active (Jenster et al., 1991). Constitutively active splice variants of the androgen receptor that lack ligand-binding domain are correlated to castration-resistant prostate cancer and poor survival (Guo et al., 2009; Hu et al., 2009, Sun et al., 2010; Haile & Sadar 2011; Hornberg et al., 2011; Zhang et al., 2011).
EPI-001 is a mixture of four stereoisomers. EPI-001 binds to the activation function-1 (AF-1) region in the amino-terminus of androgen receptor (AR) as opposed to the antiandrogens that bind to the C-terminus ligand-binding domain <ref name="Sadar 2011">{{cite journal|last=Sadar|first=Marianne|journal=Cancer Research|year=2011|pmid=21285252}}</ref>. A functional AF-1 is essential for the androgen receptor to have transcriptional activity. If AF-1 is deleted or mutated, the androgen receptor will still bind androgen, but will have no transcriptional activity <ref name="Jenster et al 1991">{{cite journal|last=Jenster|first=Guido|journal=Molecular Endocrinology|year=1991|volume=5|issue=10|pages=1396|pmid=1775129}}</ref>. Importantly, if the androgen receptor lacks a ligand-binding domain, the receptor will be nuclear and constitutively active <ref name="Jenster et al 1991">{{cite journal|last=Jenster|first=Guido|journal=Molecular Endocrinology|year=1991|volume=5|issue=10|pages=1396|pmid=1775129}}</ref>. Constitutively active splice variants of the androgen receptor that lack ligand-binding domain are correlated to castration-resistant prostate cancer and poor survival <ref name="Guo et al 2009">{{cite journal|last=Guo|first=Z|journal=Cancer Research|year=2009|volume=69|pages=2305|pmid=19244107}}</ref> <ref name="Hu et al 2009">{{cite journal|last=Hu|journal=Cancer Research|year=2009|volume=69|pages=16|pmid=19117982}}</ref> <ref name="Sun et al 2010">{{cite journal|last=Sun|journal=Journal of Clinical Investigation|year=2010|volume=120|pages=2715|pmid=20644256}}</ref> <ref name="Haile & Sadar 2011">{{cite journal|last=Haile|coauthors=Sadar|journal=Cell Mol Life Sci|year=2011|volume=68|issue=24|pages=3971|pmid=21748469}}</ref> <ref name="Hornberg et al 2011">{{cite journal|last=Hornberg|journal=PLoS One|year=2011|volume=6|pmid=21552559}}</ref> <ref name="Zhang et al 2011">{{cite journal|last=Zhang|journal=PLoS One|year=2011|volume=6|pmid=22114732}}</ref>.
EPI-001 is the first and currently only inhibitor of constitutively active splice variant of androgen receptor that lack the C-terminal ligand-binding domain (Andersen et al 2010). Antiandrogens do not inhibit constitutively active variants of androgen receptor that have truncated or deleted ligand-binding domain.
EPI-001 is the first and currently only inhibitor of constitutively active splice variant of androgen receptor that lack the C-terminal ligand-binding domain <ref name="Andersen et al 2010">{{cite journal|last=Andersen|journal=Cancer Cell|year=2010|volume=17|issue=6|pages=535|pmid=20541699}}</ref>. Antiandrogens do not inhibit constitutively active variants of androgen receptor that have truncated or deleted ligand-binding domain.


In the absence of androgen, all known antiandrogens cause translocation of androgen receptor from the cytoplasm to the nucleus (Clegg et al. 2012; Sadar 2011; Sadar 2012), whereas EPI-001 does not cause androgen receptor to become nuclear (Andersen et al., 2010). Binding of EPI-001 to the amino-terminus domain of the androgen receptor blocks protein-protein interactions that are essential for its transcriptional activity. Specifically, EPI-001 blocks androgen receptor interactions with CREB-binding protein, RAP74, and between the N-terminal domain and C-terminal domain (termed N/C interaction) required for antiparallel dimer formation of androgen receptor (Andersen et al., 2010). Unlike antiandrogens such as bicalutamide (Masiello et al., 2002; Clegg et al., 2012), EPI-001 does not cause androgen receptor to bind to androgen response elements on the DNA of target genes (Andersen et al., 2010).
In the absence of androgen, all known antiandrogens cause translocation of androgen receptor from the cytoplasm to the nucleus <ref name="Clegg et al 2012">{{cite journal|last=Clegg|journal=Cancer Research|year=2012|volume=72|issue=6|pages=1494|pmid=22266222}}</ref> <ref name="Sadar 2011">{{cite journal|last=Sadar|journal=Cancer Research|year=2011|volume=71|issue=4|pages=1208|pmid=21285252}}</ref> <ref name="Sadar 2012">{{cite journal|last=Sadar|journal=World J Urol|year=2012|volume=30|issue=3|pages=311|pmid=21833557}}</ref>, whereas EPI-001 does not cause androgen receptor to become nuclear (Andersen et al., 2010). Binding of EPI-001 to the amino-terminus domain of the androgen receptor blocks protein-protein interactions that are essential for its transcriptional activity. Specifically, EPI-001 blocks androgen receptor interactions with CREB-binding protein, RAP74, and between the N-terminal domain and C-terminal domain (termed N/C interaction) required for antiparallel dimer formation of androgen receptor <ref name="Andersen et al 2010">{{cite journal|last=Andersen|journal=Cancer Cell|year=2010|volume=17|issue=6|pages=535|pmid=20541699}}</ref>. Unlike antiandrogens such as bicalutamide <ref name="Masiello et al 2002">{{cite journal|last=Masiello|journal=J Biol Chem|year=2002|volume=277|issue=29|pages=26321|pmid=12015321}}</ref> <ref name="Clegg et al 2012">{{cite journal|last=Clegg|journal=Cancer Research|year=2012|volume=72|issue=6|pages=1494|pmid=22266222}}</ref>, EPI-001 does not cause androgen receptor to bind to androgen response elements on the DNA of target genes <ref name="Andersen et al 2010">{{cite journal|last=Andersen|journal=Cancer Cell|year=2010|volume=17|issue=6|pages=535|pmid=20541699}}</ref>.


==Specificity and Efficacy==
==Specificity and Efficacy==
EPI-001 inhibits androgen receptor-dependent proliferation of human prostate cancer cells while having no significant effects on cells that do not require androgen receptor for growth and survival (Andersen et al., 2010). EPI-001 has specificity to the androgen receptor and has excellent antitumour activity in vivo with xenografts of castration resistant prostate cancer (Andersen et al., 2010).
EPI-001 inhibits androgen receptor-dependent proliferation of human prostate cancer cells while having no significant effects on cells that do not require androgen receptor for growth and survival <ref name="Andersen et al 2010">{{cite journal|last=Andersen|journal=Cancer Cell|year=2010|volume=17|issue=6|pages=535|pmid=20541699}}</ref>. EPI-001 has specificity to the androgen receptor and has excellent antitumour activity in vivo with xenografts of castration resistant prostate cancer <ref name="Andersen et al 2010">{{cite journal|last=Andersen|journal=Cancer Cell|year=2010|volume=17|issue=6|pages=535|pmid=20541699}}</ref>.


==References==
==References==

Revision as of 20:46, 4 March 2013

EPI-001‬‬‬‬‬‬‬‬‬ is the first experimental drug that is antagonist to the intrinsically disordered amino-terminus domain of the androgen receptor. EPI-001 is being developed by the pharmaceutical company ESSA Pharma Inc (Vancouver, Canada) for the treatment of castration-resistant prostate cancer and is currently in pre-clinical development.

Discovery

EPI-001 was discovered by Dr. Marianne D Sadar at the British Columbia Cancer Agency and Dr. Raymond J Andersen at the University of British Columbia.

Mechanism of Action

EPI-001 is a mixture of four stereoisomers. EPI-001 binds to the activation function-1 (AF-1) region in the amino-terminus of androgen receptor (AR) as opposed to the antiandrogens that bind to the C-terminus ligand-binding domain [1]. A functional AF-1 is essential for the androgen receptor to have transcriptional activity. If AF-1 is deleted or mutated, the androgen receptor will still bind androgen, but will have no transcriptional activity [2]. Importantly, if the androgen receptor lacks a ligand-binding domain, the receptor will be nuclear and constitutively active [2]. Constitutively active splice variants of the androgen receptor that lack ligand-binding domain are correlated to castration-resistant prostate cancer and poor survival [3] [4] [5] [6] [7] [8]. EPI-001 is the first and currently only inhibitor of constitutively active splice variant of androgen receptor that lack the C-terminal ligand-binding domain [9]. Antiandrogens do not inhibit constitutively active variants of androgen receptor that have truncated or deleted ligand-binding domain.

In the absence of androgen, all known antiandrogens cause translocation of androgen receptor from the cytoplasm to the nucleus [10] [1] [11], whereas EPI-001 does not cause androgen receptor to become nuclear (Andersen et al., 2010). Binding of EPI-001 to the amino-terminus domain of the androgen receptor blocks protein-protein interactions that are essential for its transcriptional activity. Specifically, EPI-001 blocks androgen receptor interactions with CREB-binding protein, RAP74, and between the N-terminal domain and C-terminal domain (termed N/C interaction) required for antiparallel dimer formation of androgen receptor [9]. Unlike antiandrogens such as bicalutamide [12] [10], EPI-001 does not cause androgen receptor to bind to androgen response elements on the DNA of target genes [9].

Specificity and Efficacy

EPI-001 inhibits androgen receptor-dependent proliferation of human prostate cancer cells while having no significant effects on cells that do not require androgen receptor for growth and survival [9]. EPI-001 has specificity to the androgen receptor and has excellent antitumour activity in vivo with xenografts of castration resistant prostate cancer [9].

References

  1. Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, Myung JK, Watt K, Tam T, Yang YC, Banuelos AC, Williams DE, McEwan IJ, Wang YZ, Sadar MD. (2010) Regression of castrate-recurrent prostate cancer by a small molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell 17(6)535-46.
  2. Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, Chen Y, Grillot K, Bischoff ED, Cai L, Aparicio A, Dorow S, Arora V, Shao G, Qian J, Zhao H, Yang G, Cao C, Sensintaffar J, Wasielewska T, Herbert MR, Bonnefous C, Darimont B, Scher HI, Smith-Jones P, Klang M, Smith ND, De Stanchina E, Wu N, Ouerfelli O, Rix PJ, Heyman RA, Jung ME, Sawyers CL, Hager JH. (2012) ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 72(6):1494-503. PMID:22266222
  3. Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, Kung HJ, Brodie AM, Edwards J, Qiu Y (2009) A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res 69:2305-13.
  4. Haile S, Sadar MD. (2011) Androgen receptor and its splice variants in prostate cancer. Cell Mol Life Sci. 68(24):3971-81.
  5. Hörnberg E, Ylitalo EB, Crnalic S, Antti H, Stattin P, Widmark A, Bergh A, Wikström P (2011) Expression of Androgen Receptor Splice Variants in Prostate Cancer Bone Metastases is Associated with Castration-Resistance and Short Survival. PLoS One 6:e19059.
  6. Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, Han M, Partin AW, Vessella RL, Isaacs WB, Bova GS, Luo J (2009) Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res 69:16-22.
  7. Masiello D, Cheng S, Bubley GJ, Lu ML, Balk SP. (2002) Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor. J Biol Chem. 277(29):26321-6. PMID:12015321
  8. Sadar MD. (2011) Small Molecules Targeting the “Achilles” Heel of Androgen Receptor Activity. Cancer Research. 71(4):1208-13.
  9. Sadar MD. (2011) Advances in Small Molecule Inhibitors of Androgen Receptor for the Treatment of Advanced Prostate Cancer. World J Urol. 30(3):311-8. PMID:21833557
  10. Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, Page ST, Coleman IM, Nguyen HM, Sun H, Nelson PS, Plymate SR (2010) Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest 120:2715-30.
  11. Zhang X, Morrissey C, Sun S, Ketchandji M, Nelson PS, True LD, Vakar-Lopez F, Vessella RL, Plymate SR. (2011) Androgen receptor variants occur frequently in castration resistant prostate cancer metastases. PLoS One. 6(11):e27970. doi: 10.1371/journal.pone.0027970. PMID: 22114732
  1. ^ a b Sadar, Marianne (2011). Cancer Research. PMID 21285252. {{cite journal}}: Missing or empty |title= (help) Cite error: The named reference "Sadar 2011" was defined multiple times with different content (see the help page).
  2. ^ a b Jenster, Guido (1991). Molecular Endocrinology. 5 (10): 1396. PMID 1775129. {{cite journal}}: Missing or empty |title= (help)
  3. ^ Guo, Z (2009). Cancer Research. 69: 2305. PMID 19244107. {{cite journal}}: Missing or empty |title= (help)
  4. ^ Hu (2009). Cancer Research. 69: 16. PMID 19117982. {{cite journal}}: Missing or empty |title= (help)
  5. ^ Sun (2010). Journal of Clinical Investigation. 120: 2715. PMID 20644256. {{cite journal}}: Missing or empty |title= (help)
  6. ^ Haile (2011). Cell Mol Life Sci. 68 (24): 3971. PMID 21748469. {{cite journal}}: Missing or empty |title= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  7. ^ Hornberg (2011). PLoS One. 6. PMID 21552559. {{cite journal}}: Missing or empty |title= (help)
  8. ^ Zhang (2011). PLoS One. 6. PMID 22114732. {{cite journal}}: Missing or empty |title= (help)
  9. ^ a b c d e Andersen (2010). Cancer Cell. 17 (6): 535. PMID 20541699. {{cite journal}}: Missing or empty |title= (help)
  10. ^ a b Clegg (2012). Cancer Research. 72 (6): 1494. PMID 22266222. {{cite journal}}: Missing or empty |title= (help)
  11. ^ Sadar (2012). World J Urol. 30 (3): 311. PMID 21833557. {{cite journal}}: Missing or empty |title= (help)
  12. ^ Masiello (2002). J Biol Chem. 277 (29): 26321. PMID 12015321. {{cite journal}}: Missing or empty |title= (help)
Retrieved from "https://en.wikipedia.org/w/index.php?title=EPI-001&oldid=542098770"