EPI-001

From Infogalactic: the planetary knowledge core
Jump to: navigation, search
EPI-001.svg
Systematic (IUPAC) name
3-(4-{2-[4-(3-Chloro-2-hydroxypropoxy)phenyl]-2-propanyl}phenoxy)-1,2-propanediol
Clinical data
Legal status
  • Investigational
Identifiers
PubChem CID: 4166922
ChemSpider 3378517
Chemical data
Formula C21H27ClO5
Molecular mass 394.89 g/mol
  • ClCC(O)COc1ccc(cc1)C(c2ccc(OCC(O)CO)cc2)(C)C
  • InChI=1S/C21H27ClO5/c1-21(2,15-3-7-19(8-4-15)26-13-17(24)11-22)16-5-9-20(10-6-16)27-14-18(25)12-23/h3-10,17-18,23-25H,11-14H2,1-2H3
  • Key:HDTYUHNZRYZEEB-UHFFFAOYSA-N

EPI-001 is a novel experimental non-steroidal antiandrogen that is under investigation for the treatment of prostate cancer.[1] The drug is being developed by the pharmaceutical company ESSA Pharma Inc (Vancouver, Canada) for the treatment of castration-resistant prostate cancer (CRPC) and is currently in pre-clinical development.

EPI-001 is an antagonist of the androgen receptor (AR) that acts by binding covalently to the N-terminal domain (NTD) of the AR and blocking protein-protein interactions required for transcriptional activity of the AR and its splice variants (IC50 for inhibition of AR NTD transactivation ≈ 6 µM).[1][2] This is different from all currently-used antiandrogens, which, conversely, bind to the C-terminal ligand-binding domain (LBD) of the AR and competitively block binding and activation of the receptor by androgens.[1] Due to its unique mechanism of action, EPI-001 may prove to be effective in the treatment of advanced prostate cancer resistant to conventional antiandrogens such as enzalutamide.[1]

As of 2016, EPI-001's successor, EPI-506, is under clinical investigation in a phase I/II study.[3]

Discovery

EPI-001 was discovered by Marianne Sadar at the British Columbia Cancer Agency and Raymond Andersen at the University of British Columbia. It was derived from bisphenol A diglycidyl ether (BADGE), a known antiandrogenic endocrine disruptor of the bisphenol family.

Mechanism of action

EPI-001 is a mixture of four stereoisomers. EPI-001 binds to the activation function-1 (AF-1) region in the NTD of the AR, as opposed to virtually all other AR antagonists, which bind to the C-terminal LBD.[4] A functional AF-1 is essential for the AR to have transcriptional activity. If AF-1 is deleted or mutated, the AR will still bind androgens, but will have no transcriptional activity.[5] Importantly, if the AR lacks an LBD, the receptor will be nuclear and constitutively-active.[5] Constitutively active splice variants of the AR that lack the C-terminal LBD are correlated to CRPC and poor survival.[6][7][8][9][10][11] EPI-001 is an inhibitor of constitutively active splice variant of ARs that lack the C-terminal LBD.[2] Conventional antiandrogens do not inhibit constitutively-active variants of AR that have a truncated or deleted C-terminal LBD.

In the absence of androgen, all known antiandrogens cause translocation of AR from the cytoplasm to the nucleus,[4][12][13] whereas EPI-001 does not cause the AR to become nuclear.[2] Binding of EPI-001 to the NTD of the AR blocks protein-protein interactions that are essential for its transcriptional activity. Specifically, EPI-001 blocks AR interactions with CREB-binding protein, RAP74, and between the NTD and C-terminal domain (termed N/C interaction) required for antiparallel dimer formation of AR.[2] Unlike antiandrogens such as bicalutamide,[12][14] EPI-001 does not cause the AR to bind to androgen response elements on the DNA of target genes.[2]

EPI-001 has also been found to act as a selective PPARγ modulator (SPPARM), with both agonistic and antagonistic actions on the PPARγ.[15] Via PPARγ activation, EPI-001 has been found to inhibit AR expression and activity in prostate cancer cells, indicating at least one AR-independent action by which EPI-001 exhibits antiandrogen properties in the prostate.[15]

Specificity and efficacy

EPI-001 inhibits AR-dependent proliferation of human prostate cancer cells while having no significant effects on cells that do not require the AR for growth and survival.[2] EPI-001 has specificity to the AR (aside from the PPARγ) and has excellent anti-tumor activity in vivo with xenografts of CRPC.[2]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.0 4.1 Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ 5.0 5.1 Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ 12.0 12.1 Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ 15.0 15.1 Lua error in package.lua at line 80: module 'strict' not found.
Retrieved from "https://infogalactic.com/w/index.php?title=EPI-001&oldid=722243845"