EPI-001

EPI-001
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
Molar mass 394.89 g/mol

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]

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.[3] 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.[4] Importantly, if the AR lacks an LBD, the receptor will be nuclear and constitutively-active.[4] Constitutively active splice variants of the AR that lack the C-terminal LBD are correlated to CRPC and poor survival.[5][6][7][8][9][10] 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,[3][11][12] 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,[11][13] 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.[14] 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.[14]

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 2 3 4 Agarwal, N.; Di Lorenzo, G.; Sonpavde, G.; Bellmunt, J. (2014). "New agents for prostate cancer". Annals of Oncology 25 (9): 1700–1709. doi:10.1093/annonc/mdu038. ISSN 0923-7534. PMID 24658665.
  2. 1 2 3 4 5 6 7 Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, Myung JK, Watt K, Tam T, Yang YC; et al. (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. doi:10.1016/j.ccr.2010.04.027. PMID 20541699.
  3. 1 2 Sadar MD (2011). "Small Molecules Targeting the "Achilles" Heel of Androgen Receptor Activity". Cancer Research 71 (4): 1208–13. doi:10.1158/0008-5472.CAN_10-3398. PMID 21285252.
  4. 1 2 Jenster, Guido (1991). "Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization". Molecular Endocrinology 5 (10): 1396–404. doi:10.1210/mend-5-10-1396. PMID 1775129.
  5. ↑ Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J; et al. (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. doi:10.1158/0008-5472.can-08-3795.
  6. ↑ Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, Han M, Partin AW, Vessella RL; et al. (2009). "Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer". Cancer Res 69: 16–22. doi:10.1158/0008-5472.can-08-2764.
  7. ↑ Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, Page ST, Coleman IM, Nguyen HM; et al. (2010). "Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant". J Clin Invest 120: 2715–30. doi:10.1172/jci41824.
  8. ↑ Haile S, Sadar MD (2011). "Androgen receptor and its splice variants in prostate cancer". Cell Mol Life Sci. 68 (24): 3971–81. doi:10.1007/s00018-011-0766-7. PMID 21748469.
  9. ↑ 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. doi:10.1371/journal.pone.0019059. PMID 21552559.
  10. ↑ 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.
  11. 1 2 "ARN-509: a novel antiandrogen for prostate cancer treatment.". Cancer Res 72 (6): 1494–503. Mar 2012. doi:10.1158/0008-5472.CAN-11-3948. PMC 3306502. PMID 22266222.
  12. ↑ "Advances in small molecule inhibitors of androgen receptor for the treatment of advanced prostate cancer.". World J Urol 30 (3): 311–8. Jun 2012. doi:10.1007/s00345-011-0745-5. PMID 21833557.
  13. ↑ "Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor.". J Biol Chem 277 (29): 26321–6. Jul 2002. doi:10.1074/jbc.M203310200. PMID 12015321.
  14. 1 2 Brand LJ, Olson ME, Ravindranathan P, Guo H, Kempema AM, Andrews TE, Chen X, Raj GV, Harki DA, Dehm SM (2015). "EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer". Oncotarget 6 (6): 3811–24. doi:10.18632/oncotarget.2924. PMC 4414155. PMID 25669987.
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