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|Molar mass||394.89 g/mol|
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EPI-001 is a novel experimental non-steroidal antiandrogen that is under investigation for the treatment of prostate cancer. 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). 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. 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.
As of 2016, EPI-001's successor, EPI-506, is under clinical investigation in a phase I/II study.
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. 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. Importantly, if the AR lacks an LBD, the receptor will be nuclear and constitutively-active. Constitutively active splice variants of the AR that lack the C-terminal LBD are correlated to CRPC and poor survival. EPI-001 is an inhibitor of constitutively active splice variant of ARs that lack the C-terminal LBD. 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, whereas EPI-001 does not cause the AR to become nuclear. 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. Unlike antiandrogens such as bicalutamide, EPI-001 does not cause the AR to bind to androgen response elements on the DNA of target genes.
EPI-001 has also been found to act as a selective PPARγ modulator (SPPARM), with both agonistic and antagonistic actions on the PPARγ. 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.
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. EPI-001 has specificity to the AR (aside from the PPARγ) and has excellent anti-tumor activity in vivo with xenografts of CRPC.
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