Chemistry:EPI-001

Short description: Chemical compound

EPI-001

Clinical data
Drug class	Nonsteroidal antiandrogen
ATC code	None
Identifiers
IUPAC name 3-(4-[2-[4-(3-Chloro-2-hydroxypropoxy)phenyl]-2-propanyl]phenoxy)-1,2-propanediol
CAS Number	227947-06-0 Y
PubChem CID	4166922
ChemSpider	3378517
Chemical and physical data
Formula	C21H27ClO5
Molar mass	394.89 g·mol−1
3D 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,11-14H2,1-2H3 Key:HDTYUHNZRYZEEB-UHFFFAOYSA-N

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 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.

See also

• EPI-002
• EPI-7386

References

{{Navbox

| name = Androgens and antiandrogens
| title = Androgens and antiandrogens
| state = collapsed
| listclass = hlist
| groupstyle = text-align:center;

| group1 = Androgens
(incl. AAS)

| list1 =

AR agonists

Testosterone derivatives: Androstenediol dipropionate Boldenone undecylenate Clostebol Clostebol acetate Clostebol caproate Clostebol propionate Cloxotestosterone acetate Prasterone (dehydroepiandrosterone, DHEA) Prasterone enanthate (DHEA enanthate) Prasterone sulfate (DHEA sulfate) Quinbolone Testosterone# Testosterone esters (e.g., testosterone cypionate, testosterone enanthate]], testosterone propionate]], testosterone undecanoate]], testosterone ester mixture]]s (Deposterona, Omnadren, Sustanon, Testoviron Depot)) Dihydrotestosterone derivatives: Androstanolone (stanolone, dihydrotestosterone, DHT) Androstanolone esters Bolazine capronate Drostanolone propionate (dromostanolone propionate) Epitiostanol Mepitiostane Mesterolone Metenolone acetate (methenolone acetate) Metenolone enanthate (methenolone enanthate) Stenbolone acetate 19-Nortestosterone derivatives: Bolandiol dipropionate Nandrolone esters (e.g., nandrolone decanoate, nandrolone phenylpropionate) Norclostebol Norclostebol acetate Oxabolone cipionate (oxabolone cypionate) Trenbolone acetate Trenbolone hexahydrobenzylcarbonate (trenbolone cyclohexylmethylcarbonate) 17α-Alkylated testosterone derivatives: Bolasterone Calusterone Chlorodehydromethyltestosterone (CDMT) Fluoxymesterone Formebolone Metandienone (methandienone, methandrostenolone) Methandriol (methylandrostenediol) Methandriol bisenanthoyl acetate Methandriol dipropionate Methandriol propionate Methyltestosterone Methyltestosterone 3-hexyl ether Oxymesterone Penmesterol Tiomesterone (thiomesterone) 17α-Alkylated dihydrotestosterone derivatives: Androisoxazole Furazabol Mebolazine (dimethazine) Mestanolone Oxandrolone Oxymetholone Stanozolol 17α-Alkylated 19-nortestosterone derivatives: Ethylestrenol Mibolerone Norethandrolone Normethandrone (methylestrenolone, normethisterone) Propetandrol (propethandrol) 17α-Vinyltestosterone derivatives: Norvinisterone (vinylnortestosterone) 17α-Ethynyltestosterone derivatives: Danazol Gestrinone Progestins (e.g., ethisterone (ethynyltestosterone), levonorgestrel, norgestrel, norethisterone (norethindrone), [[Chemistry:Lynestrlynestrenol, Norgestrienone|norgestrienone]]) Tibolone Progesterone derivatives: Medroxyprogesterone acetate

Progonadotropins

Antiestrogens (e.g., tamoxifen, Chemistry:Clomifene

| group2 = Antiandrogens
| list2 = {{Navbox|child
| groupstyle = text-align:center;
| groupwidth = 9em;

  | group1 = AR antagonists
  | list1 =

• Steroidal: Abiraterone acetate
• Canrenone
• Chlormadinone acetate
• Cyproterone acetate
• Delmadinone acetate
• Dienogest
• Drospirenone
• Medrogestone
• Megestrol acetate
• Nomegestrol acetate
• Osaterone acetate
• Oxendolone
• Potassium canrenoate
• Spironolactone

• Nonsteroidal: Apalutamide
• Bicalutamide
• Cimetidine
• Darolutamide
• Enzalutamide
• Flutamide
• Ketoconazole
• Nilutamide
• Seviteronel^†
• Topilutamide (fluridil)

  | group2 = Steroidogenesis
inhibitors

| list2 =

5α-Reductase	Alfatradiol Dutasteride Epristeride Finasteride Saw palmetto extract
Others	Abiraterone acetate Aminoglutethimide Bifluranol Cyproterone acetate Flutamide Ketoconazole Nilutamide Seviteronel† Spironolactone

  | group3 = Antigonadotropins
  | list3 =

• D₂ receptor antagonists (prolactin releasers) (e.g., domperidone, metoclopramide, risperidone, haloperidol, chlorpromazine, sulpiride)
• Estrogens (e.g., bifluranol, [[diethylstilbestrol, estradiol, estradiol esters, ethinylestradiol, ethinylestradiol sulfonate, paroxypropione)
• GnRH agonists (e.g., leuprorelin)
• GnRH antagonists (e.g., cetrorelix)
• Progestogens (incl., chlormadinone acetate, [[cyproterone acetate, hydroxyprogesterone caproate, gestonorone caproate, [[Chemistry:Medroxyprogesterone medroxyprogesterone acetate, Chemistry:Megestrol acetate|megestrol acetate]])

  | group4 = Others
  | list4 =

• Androstenedione immunogens: Androvax (androstenedione albumin)
• Ovandrotone albumin (Fecundin)

}}

| liststyle = background:#DDDDFF;

| list3 =

• ^#WHO-EM
• ^‡Withdrawn from market
• Clinical trials:
  • ^†Phase III
  • ^§Never to phase III

See also

Androgen receptor modulators

Estrogens and antiestrogens

Progestogens and antiprogestogens

List of androgens/anabolic steroids

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