EPI-001

Last updated
EPI-001
EPI-001.svg
Clinical data
Drug class Nonsteroidal antiandrogen
ATC code
  • None
Identifiers
  • 3-(4-[2-[4-(3-Chloro-2-hydroxypropoxy)phenyl]-2-propanyl]phenoxy)-1,2-propanediol
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C21H27ClO5
Molar mass 394.89 g·mol−1
3D model (JSmol)
  • ClCC(O)COc1ccc(cc1)C(c2ccc(OCC(O)CO)cc2)(C)C
  • 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).

Contents

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). [1] [2] 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. [1] 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. [1]

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. [3] 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. [4] 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. [5] Importantly, if the AR lacks an LBD, the receptor will be nuclear and constitutively-active. [5] Constitutively active splice variants of the AR that lack the C-terminal LBD are correlated to CRPC and poor survival. [6] [7] [8] [9] [10] [11] EPI-001 is an inhibitor of constitutively active splice variant of ARs that lack the C-terminal LBD. [2] 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, [4] [12] [13] whereas EPI-001 does not cause the AR to become nuclear. [2] 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. [2] Unlike antiandrogens such as bicalutamide, [12] [14] EPI-001 does not cause the AR to bind to androgen response elements on the DNA of target genes. [2]

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. [15] 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. [15]

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. [2] EPI-001 has specificity to the AR (aside from the PPARγ) and has excellent anti-tumor activity in vivo with xenografts of CRPC. [2]

See also

Related Research Articles

<span class="mw-page-title-main">Antiandrogen</span> Class of pharmaceutical drugs

Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production. They can be thought of as the functional opposites of AR agonists, for instance androgens and anabolic steroids (AAS) like testosterone, DHT, and nandrolone and selective androgen receptor modulators (SARMs) like enobosarm. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens.

<span class="mw-page-title-main">Peroxisome proliferator-activated receptor</span> Group of nuclear receptor proteins

In the field of molecular biology, the peroxisome proliferator–activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism, and tumorigenesis of higher organisms.

<span class="mw-page-title-main">Bicalutamide</span> Antiandrogen medication

Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer (mPC). To a lesser extent, it is used at high doses for locally advanced prostate cancer (LAPC) as a monotherapy without castration. Bicalutamide was also previously used as monotherapy to treat localized prostate cancer (LPC), but authorization for this use was withdrawn following unfavorable trial findings. Besides prostate cancer, bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women, as a puberty blocker and component of feminizing hormone therapy for transgender girls and women, to treat gonadotropin-independent early puberty in boys, and to prevent overly long-lasting erections in men. It is taken by mouth.

<span class="mw-page-title-main">Androgen receptor</span> Mammalian protein found in humans

The androgen receptor (AR), also known as NR3C4, is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in the cytoplasm and then translocating into the nucleus. The androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor.

<span class="mw-page-title-main">Enzalutamide</span> Antiandrogen medication used in treatment of prostate cancer

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 castration-resistant prostate cancer (mCRPC), nonmetastatic castration-resistant prostate cancer, and metastatic castration-sensitive prostate cancer (mCSPC). It is taken by mouth.

The first antiandrogen was discovered in the 1960s. Antiandrogens antagonise the androgen receptor (AR) and thereby block the biological effects of testosterone and dihydrotestosterone (DHT). Antiandrogens are important for men with hormonally responsive diseases like prostate cancer, benign prostatic hyperplasia (BHP), acne, seborrhea, hirsutism and androgen alopecia. Antiandrogens are mainly used for the treatment of prostate diseases. Research from 2010 suggests that ARs could be linked to the disease progression of triple-negative breast cancer and salivary duct carcinoma and that antiandrogens can potentially be used to treat it.

<span class="mw-page-title-main">Galeterone</span> Chemical compound

Galeterone is a steroidal antiandrogen which was under development by Tokai Pharmaceuticals for the treatment of prostate cancer. It possesses a unique triple mechanism of action, acting as an androgen receptor antagonist, androgen receptor down regulator, and CYP17A1 inhibitor, the latter of which prevents the biosynthesis of androgens. As a CYP17A1 inhibitor, galeterone shows selectivity for 17,20-lyase over 17α-hydroxylase.

<span class="mw-page-title-main">Apalutamide</span> Chemical compound

Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication used for the treatment of prostate cancer. It is an androgen receptor inhibitor. It is taken by mouth.

<span class="mw-page-title-main">Ralaniten acetate</span> Chemical compound

Ralaniten acetate 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 prostate cancer. This mechanism of action is believed to allow the drug to block signaling from the AR and its splice variants. EPI-506 is a derivative of bisphenol A and a prodrug of ralaniten (EPI-002), one of the four stereoisomers of EPI-001, and was developed as a successor of EPI-001. The drug reached phase I/II prior to the discontinuation of its development. It showed signs of efficacy in the form of prostatic specific antigen (PSA) decreases (4–29%) predominantly at higher doses (≥1,280 mg) in some patients but also caused side effects and was discontinued by its developer in favor of next-generation AR NTD inhibitors with improved potency and tolerability.

A hormone-sensitive cancer, or hormone-dependent cancer, is a type of cancer that is dependent on a hormone for growth and/or survival. Examples include breast cancer, which is dependent on estrogens like estradiol, and prostate cancer, which is dependent on androgens like testosterone.

<span class="mw-page-title-main">Proxalutamide</span> Chemical compound

Proxalutamide is a nonsteroidal antiandrogen (NSAA) – specifically, a selective high-affinity silent antagonist of the androgen receptor (AR) – which is under development by Suzhou Kintor Pharmaceuticals, inc., a subsidiary of Kintor Pharmaceutical Limited, for the potential treatment of COVID-19, prostate cancer, and breast cancer. It was approved in Paraguay for the treatment of COVID-19 in July 2021, but has not been approved at this time in other countries.

Ketodarolutamide is a nonsteroidal antiandrogen (NSAA) and the major active metabolite of darolutamide, an NSAA which is used in the treatment of prostate cancer in men. Similarly to its parent compound, ketodarolutamide acts as a highly selective, high-affinity, competitive silent antagonist of the androgen receptor (AR). Both agents show much higher affinity and more potent inhibition of the AR relative to the other NSAAs enzalutamide and apalutamide, although they also possess much shorter and comparatively less favorable elimination half-lives. They have also been found not to activate certain mutant AR variants that enzalutamide and apalutamide do activate. Both darolutamide and ketodarolutamide show limited central nervous system distribution, indicating peripheral selectivity, and little or no inhibition or induction of cytochrome P450 enzymes such as CYP3A4, unlike enzalutamide and apalutamide.

Ralaniten is an N-terminal domain antiandrogen which was never marketed. It is a derivative of bisphenol A and one of the four stereoisomers of EPI-001. A prodrug of ralaniten, ralaniten acetate (EPI-506), was under development for the treatment of prostate cancer.

5<i>N</i>-Bicalutamide Chemical compound

5N-Bicalutamide, or 5-azabicalutamide, is a highly potent nonsteroidal antiandrogen (NSAA) which was discovered in 2016. It is a structural modification of bicalutamide differing it from it only by the replacement of a carbon atom with a nitrogen atom in one of its phenyl rings. Similarly to bicalutamide, the drug acts as a selective antagonist of the androgen receptor (AR). However, unlike bicalutamide, it is a reversible covalent antagonist and stays bound to the receptor for a far longer amount of time. As a result of this difference, 5N-bicalutamide has markedly improved potency relative to bicalutamide, with approximately 150-fold higher affinity for the AR (Ki = 0.15 nM versus 22.3 nM) and about 20-fold greater functional inhibition (IC50Tooltip Half-maximal inhibitory concentration = 15 nM versus 310 nM) of the AR. Future studies of 5N-bicalutamide in normal and mutated prostate cancer cells are planned or underway and it is anticipated that N-bicalutamide may be able to overcome resistance. to current antiandrogens that are used in the treatment of prostate cancer.

The medical uses of bicalutamide, a nonsteroidal antiandrogen (NSAA), include the treatment of androgen-dependent conditions and hormone therapy to block the effects of androgens. Indications for bicalutamide include the treatment of prostate cancer in men, skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women, high testosterone levels in women, hormone therapy in transgender women, as a puberty blocker to prevent puberty in transgender girls and to treat early puberty in boys, and the treatment of long-lasting erections in men. It may also have some value in the treatment of paraphilias and hypersexuality in men.

Comparison of the nonsteroidal antiandrogen (NSAA) bicalutamide with other antiandrogens reveals differences between the medications in terms of efficacy, tolerability, safety, and other parameters. Relative to the other first-generation NSAAs, flutamide and nilutamide, bicalutamide shows improved potency, efficacy, tolerability, and safety, and has largely replaced these medications in clinical practice. Compared to the second-generation NSAAs, enzalutamide and apalutamide, bicalutamide has inferior potency and efficacy but similar tolerability and safety and a lower propensity for drug interactions.

<span class="mw-page-title-main">Pharmacology of bicalutamide</span> Pharmaceutical compound

The pharmacology of bicalutamide is the study of the pharmacodynamic and pharmacokinetic properties of the nonsteroidal antiandrogen (NSAA) bicalutamide. In terms of pharmacodynamics, bicalutamide acts as a selective antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has no capacity to activate the AR. It does not decrease androgen levels and has no other important hormonal activity. The medication has progonadotropic effects due to its AR antagonist activity and can increase androgen, estrogen, and neurosteroid production and levels. This results in a variety of differences of bicalutamide monotherapy compared to surgical and medical castration, such as indirect estrogenic effects and associated benefits like preservation of sexual function and drawbacks like gynecomastia. Bicalutamide can paradoxically stimulate late-stage prostate cancer due to accumulated mutations in the cancer. When used as a monotherapy, bicalutamide can induce breast development in males due to its estrogenic effects. Unlike other kinds of antiandrogens, it may have less adverse effect on the testes and fertility.

<span class="mw-page-title-main">RU-59063</span> Chemical compound

RU-59063 is a nonsteroidal androgen or selective androgen receptor modulator (SARM) which was first described in 1994 and was never marketed. It was originally thought to be a potent antiandrogen, but subsequent research found that it actually possesses dose-dependent androgenic activity, albeit with lower efficacy than dihydrotestosterone (DHT). The drug is an N-substituted arylthiohydantoin and was derived from the first-generation nonsteroidal antiandrogen (NSAA) nilutamide. The second-generation NSAAs enzalutamide, RD-162, and apalutamide were derived from RU-59063.

<span class="mw-page-title-main">BMS-641988</span> Chemical compound

BMS-641988 is a nonsteroidal antiandrogen which was developed by Bristol-Myers Squibb for the treatment of prostate cancer but was never marketed. It acts as a potent competitive antagonist of the androgen receptor (AR) (Ki = 10 nM; IC50Tooltip half-maximal inhibitory concentration = 56 nM). The drug was found to have 20-fold higher affinity for the AR than bicalutamide in MDA-MB-453 cells, and showed 3- to 7-fold the antiandrogenic activity of bicalutamide in vitro. It may have some weak partial agonist activity at the androgen receptor. BMS-641988 is transformed by CYP3A4 into BMS-570511, and this metabolite is then reduced to BMS-501949 by cytosolic reductases. All three compounds show similar antiandrogenic activity. In addition to its antiandrogenic activity, BMS-641988 shows activity as a negative allosteric modulator of the GABAA receptor, and can produce seizures in animals at sufficiently high doses. It also shows some drug-induced QT prolongation. BMS-641988 reached phase I clinical trials prior to the discontinuation of its development. The clinical development of BMS-641988 was terminated due to the occurrence of a seizure in a patient during a phase I study.

Masofaniten, also known by its developmental code name EPI-7386, is an N-terminal domain antiandrogen, or antagonist of the N-terminal domain (NTD) of the androgen receptor (AR), which is under development for the treatment of prostate cancer. The compound was developed as a successor of previous drugs in the EPI series such as EPI-001, ralaniten (EPI-002), and ralaniten acetate (EPI-506). Masofaniten shows 20-fold higher antiandrogenic potency than ralaniten in vitro (IC50Tooltip Half-maximal inhibitory concentration = 535 nM vs. 9,580 nM, respectively), as well as greater stability in human hepatocytes. It was planned to enter phase I clinical trials in 2020. Preliminary results of a phase I/II clinical trial were published in 2023.

References

  1. 1 2 3 Agarwal N, Di Lorenzo G, Sonpavde G, Bellmunt J (September 2014). "New agents for prostate cancer". Annals of Oncology. 25 (9): 1700–1709. doi: 10.1093/annonc/mdu038 . PMID   24658665.
  2. 1 2 3 4 5 6 7 Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, Myung JK, et al. (June 2010). "Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor". Cancer Cell. 17 (6): 535–546. doi: 10.1016/j.ccr.2010.04.027 . PMID   20541699.
  3. ↑ "Safety and Anti-Tumor Study of Oral EPI-506 for Patients With Metastatic Castration-Resistant Prostate Cancer - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-02-27.
  4. 1 2 Sadar MD (February 2011). "Small molecule inhibitors targeting the "achilles' heel" of androgen receptor activity". Cancer Research. 71 (4): 1208–1213. doi:10.1158/0008-5472.CAN_10-3398. PMC   3132148 . PMID   21285252.
  5. 1 2 Jenster G, van der Korput HA, van Vroonhoven C, van der Kwast TH, Trapman J, Brinkmann AO (October 1991). "Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization". Molecular Endocrinology. 5 (10): 1396–1404. doi: 10.1210/mend-5-10-1396 . PMID   1775129.
  6. ↑ Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, et al. (March 2009). "A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth". Cancer Research. 69 (6): 2305–2313. doi:10.1158/0008-5472.can-08-3795. PMC   2672822 . PMID   19244107.
  7. ↑ Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, et al. (January 2009). "Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer". Cancer Research. 69 (1): 16–22. doi:10.1158/0008-5472.can-08-2764. PMC   2614301 . PMID   19117982.
  8. ↑ Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, et al. (August 2010). "Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant". The Journal of Clinical Investigation. 120 (8): 2715–2730. doi:10.1172/jci41824. PMC   2912187 . PMID   20644256.
  9. ↑ Haile S, Sadar MD (December 2011). "Androgen receptor and its splice variants in prostate cancer". Cellular and Molecular Life Sciences. 68 (24): 3971–3981. doi:10.1007/s00018-011-0766-7. PMC   3729216 . PMID   21748469.
  10. ↑ Hörnberg E, Ylitalo EB, Crnalic S, Antti H, Stattin P, Widmark A, et al. (April 2011). "Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival". PLOS ONE. 6 (4): e19059. Bibcode:2011PLoSO...619059H. doi: 10.1371/journal.pone.0019059 . PMC   3084247 . PMID   21552559.
  11. ↑ Zhang X, Morrissey C, Sun S, Ketchandji M, Nelson PS, True LD, et al. (2011). "Androgen receptor variants occur frequently in castration resistant prostate cancer metastases". PLOS ONE. 6 (11): e27970. Bibcode:2011PLoSO...627970Z. doi: 10.1371/journal.pone.0027970 . PMC   3219707 . PMID   22114732.
  12. 1 2 Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, et al. (March 2012). "ARN-509: a novel antiandrogen for prostate cancer treatment". Cancer Research. 72 (6): 1494–1503. doi:10.1158/0008-5472.CAN-11-3948. PMC   3306502 . PMID   22266222.
  13. ↑ Sadar MD (June 2012). "Advances in small molecule inhibitors of androgen receptor for the treatment of advanced prostate cancer". World Journal of Urology. 30 (3): 311–318. doi:10.1007/s00345-011-0745-5. PMID   21833557. S2CID   11956563.
  14. ↑ Masiello D, Cheng S, Bubley GJ, Lu ML, Balk SP (July 2002). "Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor". The Journal of Biological Chemistry. 277 (29): 26321–26326. doi: 10.1074/jbc.M203310200 . PMID   12015321.
  15. 1 2 Brand LJ, Olson ME, Ravindranathan P, Guo H, Kempema AM, Andrews TE, et al. (February 2015). "EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer". Oncotarget. 6 (6): 3811–3824. doi:10.18632/oncotarget.2924. PMC   4414155 . PMID   25669987.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.