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 (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, ri ...

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 ...

(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 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 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 in ...

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 targ ...

, EPI-001 type compounds may prove to be effective in the treatment of advanced prostate cancer resistant to conventional antiandrogens such as enzalutamide. EPI-001's successor, ralaniten acetate (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 dru ...

of ralaniten (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 intri ...

, 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 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 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 xenograf ...

s of CRPC.

References

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

Pharmacology

Pharmacodynamics

See also

References