Enzalutamide

Last updated

Enzalutamide
Antiandrogen MDV3100.png
Clinical data
Trade names Xtandi
Other namesMDV-3100; ASP-9785
AHFS/Drugs.com Monograph
MedlinePlus a612033
License data
Pregnancy
category
  • AU:X (High risk) [1]
Routes of
administration 		By mouth [2] [3]
Drug class Nonsteroidal antiandrogen
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Rats: 89.7% [5]
Humans: unknown (but at least 84.6% based on recovery from excretion) [6] [3]
Protein binding Enzalutamide: 97–98% (primarily to albumin) [2]
NDME: 95% [2]
Metabolism Liver (primarily CYP2C8 and CYP3A4) [2]
Metabolites • NDME Tooltip N-Desmethylenzalutamide (active) [2] [3]
• Carboxylic acid derivative metabolite (inactive) [3]
Elimination half-life Enzalutamide: 5.8 days (range 2.8–10.2 days) [2]
NDME: 7.8–8.6 days [2]
Excretion Urine: 71.0% [3]
Bile: 13.6% [3]
Feces: 0.39% [3]
Identifiers
  • 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.231.722 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H16F4N4O2S
Molar mass 464.44 g·mol−1
3D model (JSmol)
  • CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1F
  • InChI=1S/C21H16F4N4O2S/c1-20(2)18(31)28(12-5-4-11(10-26)15(8-12)21(23,24)25)19(32)29(20)13-6-7-14(16(22)9-13)17(30)27-3/h4-9H,1-3H3,(H,27,30)
  • Key:WXCXUHSOUPDCQV-UHFFFAOYSA-N

Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. [2] [7] It is indicated for use in conjunction with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC), [2] nonmetastatic castration-resistant prostate cancer, [2] and metastatic castration-sensitive prostate cancer (mCSPC). [8] It is taken by mouth. [2]

Contents

Side effects of enzalutamide when added to castration include asthenia, back pain, diarrhea, arthralgia, and hot flashes. [2] Rarely, it can cause seizures. [2] It has a high potential for drug interactions. [2] Enzalutamide is an antiandrogen, and acts as an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone. [2] In doing so, it prevents the effects of these hormones in the prostate gland and elsewhere in the body. [2]

Enzalutamide was first described in 2006, and was introduced for the treatment of prostate cancer in 2012. [9] [10] [11] It was the first second-generation NSAA to be introduced. [12] It is on the World Health Organization's List of Essential Medicines. [13]

Medical uses

Enzalutamide is indicated for the treatment of people with castration-resistant prostate cancer; metastatic castration-sensitive prostate cancer; and non‑metastatic castration‑sensitive prostate cancer with biochemical recurrence at high risk for metastasis. [2]

Prostate cancer

There is good evidence that enzalutamide is an effective treatment for increasing overall survival among people with high-risk non-metastatic castration-resistant prostate cancer, particularly those with a PSA doubling time ≤ 6 months. [14]

Other uses

Enzalutamide can be used as an antiandrogen in feminizing hormone therapy for transgender women. [15] [16]

Available forms

Enzalutamide is provided as a capsule or tablet. [2]

Contraindications

Enzalutamide is contraindicated in women during pregnancy. [2] It may cause fetal harm. [2]

Side effects

Notable side effects of enzalutamide seen in clinical trials have included gynecomastia, breast pain/tenderness, fatigue, diarrhea, hot flashes, headache, sexual dysfunction, and, less commonly, seizures. [17] [18] [19] [20] Other "common" side effects reported in clinical trials have included neutropenia, visual hallucinations, anxiety, cognitive disorder, memory impairment, hypertension, dry skin, and pruritus (itching). [21] Enzalutamide monotherapy is regarded as having a moderate negative effect on sexual function and activity, significantly less than that of GnRH analogues but similar to that of other NSAAs such as bicalutamide. [22]

Central adverse effects

Seizures have occurred in approximately 1% of patients treated with enzalutamide in clinical trials. [17] [19] This is thought to be due to enzalutamide crossing the blood–brain barrier [23] [24] and exerting off-target binding to and inhibition of the GABAA receptor in the central nervous system (it has been found to inhibit the GABAA receptor in vitro (IC50 Tooltip half-maximal inhibitory concentration = 3.6 μM) [24] [25] [26] and induces convulsions in animals at high doses). [17] [19] In addition to seizures, other potentially GABAA receptor-related side effects observed with enzalutamide treatment in clinical trials have included anxiety, insomnia, vertigo, paresthesia, and headache. [27] Due to its ability to lower the seizure threshold, patients with known seizure disorders or brain injury should be closely monitored during enzalutamide treatment. [28] NSAA-induced seizures are responsive to benzodiazepine treatment, and it has been suggested that GABAA receptor inhibition by enzalutamide could be treated with these drugs. [25] In dose-ranging studies, severe fatigue was observed with enzalutamide at doses of 240 mg/day and above. [29] [30]

Rare adverse reactions

There is a single case report of posterior reversible encephalopathy syndrome (PRES) with enzalutamide treatment. [31] The mechanism of action of the side effect is unknown, but it was proposed to a consequence of inhibition of the GABAA receptor by enzalutamide. [31]

Overdose

Enzalutamide may cause seizures in overdose. [2]

Interactions

Enzalutamide is a moderate to strong inducer of multiple cytochrome P450 enzymes including CYP3A4, CYP2C9, and CYP2C19 and hence has a high potential for clinically relevant drug interactions. [2] Circulating concentrations of enzalutamide may be altered by inhibitors and inducers of CYP2C8 and CYP3A4, and should be avoided if possible. [32]

In a clinical study of enzalutamide for ER Tooltip estrogen receptor-positive breast cancer in women, enzalutamide was found to decrease serum concentrations of the aromatase inhibitors anastrozole and exemestane by 90% and 50%, respectively, which could reduce their effectiveness. [33]

Pharmacology

Pharmacodynamics

Enzalutamide acts as a selective silent antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). Unlike the first-generation NSAA bicalutamide, enzalutamide does not promote translocation of AR to the cell nucleus and in addition prevents binding of AR to deoxyribonucleic acid (DNA) and AR to coactivator proteins. [34] As such, it has been described as an AR signaling inhibitor in addition to antagonist. [17] The drug is described as a "second-generation" NSAA because it has greatly increased efficacy as an antiandrogen relative to so-called "first-generation" NSAAs like flutamide and bicalutamide. The drug has only 2-fold lower affinity for the AR than DHT, the endogenous ligand of the AR in the prostate gland. [35]

When LNCaP cells (a prostate cancer cell line) engineered to express elevated levels of AR (as found in patients with advanced prostate cancer) were treated with enzalutamide, the expression of androgen-dependent genes PSA and TMPRSS2 was down regulated in contrast to bicalutamide where the expression was upregulated. [34] In VCaP cells which over-express the AR, enzalutamide induced apoptosis whereas bicalutamide did not. [34] Furthermore, enzalutamide behaves as an antagonist of the W741C mutant AR in contrast to bicalutamide which behaves as a pure agonist when bound to the W741C mutant. [34]

Dose-ranging studies of enzalutamide in men with prostate cancer have been performed. [30]

Changes in hormone levels

Enzalutamide monotherapy at a dosage of 160 mg/day has been found to increase circulating levels of testosterone by 114.3%, dihydrotestosterone (DHT) by 51.7%, estradiol by 71.7%, sex hormone-binding globulin (SHBG) by 100.6%, dehydroepiandrosterone (DHEA) by 9.6%, androstenedione by 51.1%, luteinizing hormone (LH) by 184.7%, follicle-stimulating hormone (FSH) by 47.0%, and prolactin by 16.8%. [22] [36] These changes in hormone levels are similar to those with high-dose bicalutamide monotherapy. [22] [36] The median maximum decrease in levels of prostate-specific antigen (PSA) levels was 99.6%. [22]

Comparison with other antiandrogens

Enzalutamide has approximately 8-fold higher binding affinity for the androgen receptor (AR) compared to bicalutamide. [34] [37] One study found an IC50 Tooltip half-maximal inhibitory concentration of 21 nM for enzalutamide and 160 nM for bicalutamide at the AR in the LNCaP cell line (7.6-fold difference), [38] while another found respective IC50 values of 36 nM and 159 nM (4.4-fold difference). [39] In accordance, clinical findings suggest that enzalutamide is a significantly more potent and effective antiandrogen in comparison to first-generation NSAAs such as bicalutamide, flutamide, and nilutamide. [22] [36] Also, unlike with the first-generation NSAAs, there has been no evidence of hepatotoxicity or elevated liver enzymes in association with enzalutamide treatment in clinical trials. [40] [41]

Resistance mechanisms in prostate cancer

Enzalutamide is only effective for a certain period of time, after that the growth of the cancer is not inhibited by this antiandrogen. The mechanisms of resistance to Enzalutamide are being intensively studied. [42] Currently, several mechanisms have been found:

Cytochrome P450 modulation

Enzalutamide is reported to be a strong inducer of the enzyme CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19, and can affect the circulating concentrations of drugs that are metabolized by these enzymes. [52] [32]

Pharmacokinetics

The bioavailability of enzalutamide in humans is unknown, but is at least 84.6% based on the amount recovered from urine and bile in excretion studies. [6] [3] Similarly, the bioavailability of enzalutamide in rats is 89.7%. [5] Steady-state concentrations of enzalutamide are achieved within 28 days of treatment initiation. [38] The plasma protein binding of enzalutamide is 97 to 98%, while that of N-desmethylenzalutamide (NDME), its major metabolite, is 95%. [2] Enzalutamide is primarily bound to albumin. [2] The medication is metabolized in the liver, mainly by the cytochrome P450 enzymes CYP2C8 and CYP3A4. [2] CYP2C8 is primarily responsible for the formation of NDME. [32] Enzalutamide has a long elimination half-life of 5.8 days on average, with a range of 2.8 to 10.2 days. [2] The elimination half-life of NDME is even longer, at about 7.8 to 8.6 days. [2] Enzalutamide is eliminated 71.0% in urine, 13.6% in bile, and 0.39% in feces. [3]

Chemistry

Enzalutamide is a synthetic diaryl thiohydantoin derivative and is structurally related to the earlier first-generation NSAAs such as flutamide, nilutamide, and bicalutamide as well as to newer second-generation NSAAs like apalutamide and proxalutamide. [53]

History

Enzalutamide was discovered by Charles Sawyers and Michael Jung at the University of California, Los Angeles. [54] [55] [56] They and their colleagues synthesized and evaluated nearly 200 thiohydantoin derivatives of RU-59063, an analogue of nilutamide, for AR antagonism in human prostate cancer cells, and identified enzalutamide and RD-162 as lead compounds. [34] [56] These compounds were patented in 2006 and described in 2007. [9] Enzalutamide was developed and marketed by Medivation for the treatment of prostate cancer. [57] It was approved by the US Food and Drug Administration (FDA) for the treatment of mCRPC in the United States in August 2012, and for the treatment of nonmetastatic castration-resistant prostate cancer in July 2018. [17] [58] Enzalutamide was the first new AR antagonist to be approved for the treatment of prostate cancer in over 15 years, following the introduction of the first-generation NSAA bicalutamide in 1995. [59] It was the first second-generation NSAA to be introduced. [12]

In July 2018, the FDA approved enzalutamide for the treatment of people with castration-resistant prostate cancer. [60] The approval broadens the indication to include people with both non-metastatic castration-resistant prostate cancer and metastatic castration-resistant prostate cancer. [60] Enzalutamide was previously approved for the treatment of people with metastatic castration-resistant prostate cancer. [60]

In December 2019, the FDA approved enzalutamide for the treatment of people with metastatic castration-sensitive prostate cancer (mCSPC). [8] Enzalutamide was previously approved for the treatment of people with castration-resistant prostate cancer. [8]

In June 2023, the FDA approved talazoparib, in combination with enzalutamide, for the treatment of people with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). [61]

In November 2023, the FDA approved enzalutamide for the treatment of people with non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis (high-risk BCR). [62] Efficacy was evaluated in EMBARK (NCT02319837), a randomized, controlled clinical trial of 1068 patients with nmCSPC with high-risk BCR. [62] All patients had prior definitive therapy with radical prostatectomy and/or radiotherapy with curative intent, had PSA doubling time ≤ 9 months, and were not candidates for salvage radiotherapy at enrollment. [62] Patients were randomized 1:1:1 to receive blinded enzalutamide 160 mg once daily plus leuprolide, open-label single- agent enzalutamide 160 mg once daily, or blinded placebo once daily plus leuprolide. [62] The application was granted priority review and fast track designations. [62]

Research

Breast cancer

Research suggests that enzalutamide may be effective in the treatment of certain types of breast cancer in women. [63] [64] It has been tested for the treatment of triple-negative, AR-positive breast cancer in a phase II clinical trial. [65] [66]

Hirsutism

Enzalutamide has been suggested as a potential treatment for hirsutism and hyperandrogenism in women with polycystic ovary syndrome. [67] [68]

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">Bicalutamide</span> Prostate cancer treatment

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">Flutamide</span> Chemical compound

Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growth, and high androgen levels in women. It is taken by mouth, usually three times per day.

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

Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer. It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women. It is taken by mouth.

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

Cabazitaxel, sold under the brand name Jevtana, is a semi-synthetic derivative of a natural taxoid. It is a microtubule inhibitor, and the fourth taxane to be approved as a cancer therapy.

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.

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". EPI-001 and its stereoisomers and analogues were discovered by Marianne Sadar and Raymond Andersen, who co-founded the pharmaceutical company ESSA Pharma Inc for the clinical development of anitens for the treatment of castration-resistant prostate cancer (CRPC).

<span class="mw-page-title-main">Nonsteroidal antiandrogen</span> Antiandrogen with a nonsteroidal chemical structure

A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like testosterone and dihydrotestosterone (DHT). NSAAs are used in the treatment of androgen-dependent conditions in men and women. They are the converse of steroidal antiandrogens (SAAs), which are antiandrogens that are steroids and are structurally related to testosterone.

Darolutamide, sold under the brand name Nubeqa, is an antiandrogen medication which is used in the treatment of non-metastatic castration-resistant prostate cancer in men. It is specifically approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration. The medication is taken by mouth twice per day with food.

<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 which is used in the treatment of prostate cancer. It is specifically indicated for use in conjunction with castration in the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC). 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.

<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.

<i>N</i>-Desmethylenzalutamide Chemical compound

N-Desmethylenzalutamide is a nonsteroidal antiandrogen (NSAA) and the major metabolite of enzalutamide, an NSAA which is used as a hormonal antineoplastic agent in the treatment of metastatic prostate cancer. It has similar activity to that of enzalutamide and, with enzalutamide therapy, circulates at similar concentrations to those of enzalutamide at steady state. N-Desmethylenzalutamide is formed from enzalutamide in the liver by the cytochrome P450 enzymes CYP2C8 and CYP3A4. It has a longer terminal half-life than enzalutamide.

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>

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">RD-162</span> Chemical compound

RD-162 is a second-generation nonsteroidal antiandrogen (NSAA) which was developed for the treatment of prostate cancer but was never marketed. It acts as a potent and selective silent antagonist of the androgen receptor (AR). The drug is a diarylthiohydantoin derivative. It is closely related to enzalutamide and apalutamide. Both RD-162 and enzalutamide show 5- to 8-fold higher affinity for the AR than the first-generation NSAA bicalutamide, and only 2- to 3-fold lower affinity than dihydrotestosterone (DHT), the major endogenous ligand of the receptor in the prostate gland.

<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.

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). EPI-7386 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

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