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Clinical data
Drug classNonsteroidal antiandrogen
ATC code
  • None
PubChem CID
CompTox Dashboard (EPA)
Chemical and physical data
Molar mass394.89 g·mol−1
3D model (JSmol)

EPI-001 is the first inhibitor of the androgen receptor amino-terminal domain. The single stereoisomer of EPI-001, EPI-002, is a first-in-class drug that the USAN council assigned a new stem class "-aniten" and the generic name "ralaniten". This distinguishes the anitens novel molecular mechanism from anti androgens that bind the C-terminus ligand-binding domain and have the stem class "lutamide" (such as flutamide, nilutamide, bicalutamide, enzalutamide, etc.). EPI-001 and its stereoisomers and analogues were discovered by Dr. Marianne Sadar and Dr. Raymond Andersen who co-founded the pharmaceutical company ESSA Pharma Inc (Vancouver, Canada) for the clinical development of anitens for the treatment of castration-resistant prostate cancer (CRPC).

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 type compounds may prove to be effective in the treatment of advanced prostate cancer resistant to conventional antiandrogens such as enzalutamide.[1]

EPI-001's successor, ralaniten acetate (EPI-506), a prodrug of ralaniten (EPI-002), one of the four stereoisomers of EPI-001, was under clinical investigation in a phase I study.[3] EPI-506 was the first drug that directly binds to an intrinsically disordered region to be tested in humans and marks a leap in drug development from folded drug targets.



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 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 at extremely high concentrations of 50 to 200 uM 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]

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[edit]


  1. ^ a b c 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. ^ a b c d e f g 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. ^ "Safety and Anti-Tumor Study of Oral EPI-506 for Patients With Metastatic Castration-Resistant Prostate Cancer - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-02-27.
  4. ^ a b 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. PMC 3132148. PMID 21285252.
  5. ^ a b 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.
  6. ^ 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. PMC 2672822. PMID 19244107.
  7. ^ 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. PMC 2614301. PMID 19117982.
  8. ^ 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. PMC 2912187. PMID 20644256.
  9. ^ 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. PMC 3729216. PMID 21748469.
  10. ^ 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. PMC 3084247. PMID 21552559.
  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. PMC 3219707. PMID 22114732.
  12. ^ a b 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 (Mar 2012). "ARN-509: a novel antiandrogen for prostate cancer treatment". Cancer Res. 72 (6): 1494–503. doi:10.1158/0008-5472.CAN-11-3948. PMC 3306502. PMID 22266222.
  13. ^ Sadar MD (Jun 2012). "Advances in small molecule inhibitors of androgen receptor for the treatment of advanced prostate cancer". World J Urol. 30 (3): 311–8. doi:10.1007/s00345-011-0745-5. PMID 21833557.
  14. ^ Masiello D, Cheng S, Bubley GJ, Lu ML, Balk SP (Jul 2002). "Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor". J Biol Chem. 277 (29): 26321–6. doi:10.1074/jbc.M203310200. PMID 12015321.
  15. ^ a b 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.