epi-001 epi-001 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-001clinical datadrug classnonsteroidal antiandrogenatc codenoneidentifiers iupac name 3-(4--2-propanyl]phenoxy)-1,2-propanediol cas number227947-06-0 ypubchem cid4166922chemspider3378517comptox dashboard (epa)dtxsid30400170 chemical and physical dataformulac21h27clo5molar mass394.89 g·mol−13d model (jsmol)interactive image smiles clcc(o)coc1ccc(cc1)c(c2ccc(occ(o)co)cc2)(c)c inchi inchi=1s/c21h27clo5/c1-21(2,15-3-7-19(8-4-15)26-13-17(24)11-22)16-5-9-20(10-6-16)27-14-18(25)12-23/h3-10,17-18,23-25h,11-14h2,1-2h3key:hdtyuhnzryzeeb-uhfffaoysa-n 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 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 of ralaniten (epi-002), one of the four stereoisomers 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 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. 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 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. 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 xenografts of crpc.