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 Marianne Sadar and 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 Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that surr ...

(CRPC). EPI-001 is an

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

of the

androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in th ...

(AR) that acts by binding covalently to the

N-terminal domain The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

(NTD) of the AR and blocking protein-protein interactions required for transcriptional activity of the AR and its

splice variant Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be in ...

s ( IC₅₀ for inhibition of AR NTD transactivation ≈ 6 μM). This is different from all currently-used antiandrogens, which, conversely, bind to the

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

ligand-binding domain In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...

(LBD) of the AR and competitively block binding and activation of the receptor by

androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This inc ...

s. Due to its unique

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...

, EPI-001 type compounds may prove to be effective in the treatment of advanced prostate cancer resistant to conventional antiandrogens such as

enzalutamide Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castrat ...

. EPI-001's successor,

ralaniten acetate Ralaniten acetate (developmental code name EPI-506) is a first-in-class antiandrogen that targets the ''N''-terminal domain (NTD) of the androgen receptor (AR) developed by ESSA Pharmaceuticals and was under investigation for the treatment of p ...

(EPI-506), a

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

ralaniten Ralaniten (developmental code name EPI-002) is an N-terminal domain antiandrogen which was never marketed. It is a derivative (chemistry), derivative of bisphenol A and one of the four stereoisomers of EPI-001. A prodrug of ralaniten, ralaniten ac ...

(EPI-002), one of the four

stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...

s of EPI-001, was under clinical investigation in a phase I study. 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.

Pharmacology

Pharmacodynamics

EPI-001 is a mixture of four

s. 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. 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 Cyclic adenosine monophosphate Response Element Binding protein Binding Protein (CREB-binding protein), also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the ''CREBBP'' gene in humans, located on chromosome 16p13.3. CBP has intrin ...

RAP74 General transcription factor IIF subunit 1 is a protein that in humans is encoded by the ''GTF2F1'' gene. Interactions GTF2F1 has been shown to interact with: * CTDP1, * GTF2H4, * HNRPU, * MED21, * POLR2A, * Serum response factor * TAF1 ...

, 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 element Response elements are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes. Under conditions of stress, a transcription activator protein binds ...

s on the DNA of target genes. EPI-001 at extremely high concentrations of 50 to 200 uM has also been found to act as a

selective PPARγ modulator A selective PPAR modulator (SPPARM) is a selective receptor modulator of the peroxisome proliferator-activated receptor (PPAR). Examples include SPPARMs of the PPARγ, BADGE, EPI-001, INT-131, MK-0533, and S26948. See also * PPAR agonist PPAR ...

(SPPARM), with both agonistic and antagonistic actions on the

PPARγ Peroxisome proliferator- activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone reverse insulin resistance receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor functioning as a tran ...

. 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. 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

xenograft Xenotransplantation (''xenos-'' from the Greek meaning "foreign" or strange), or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenograft ...

s of CRPC.

References

{{PPAR modulators Abandoned drugs Alkylating agents 2,2-Bis(4-hydroxyphenyl)propanes Halohydrins Nonsteroidal antiandrogens Organochlorides PPAR agonists Triols Glycerols