GTx-758 (tentative brand name Capesaris) is a synthetic

nonsteroidal estrogen A nonsteroidal estrogen is an estrogen with a nonsteroidal chemical structure. The most well-known example is the stilbestrol estrogen diethylstilbestrol (DES). Although nonsteroidal estrogens formerly had an important place in medicine, they hav ...

which was under development by GTx, Inc. for the treatment of advanced

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...

. As of 2016, it had completed two phase II

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

Pharmacology

Pharmacodynamics

GTx-758 acts as a selective

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the

estrogen receptor Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen ( 17β-estradiol). Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the ...

(ER), with a more than 10-fold preference for activation of

ERα Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the sex ...

relative to

ERβ Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by ...

( EC₅₀ = 2.1 and 27 nM, respectively). The selectivity of GTx-758 for ERα over ERβ may confer reduced hypercoagulability and thrombophilia, as

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of f ...

directly produces these effects in

platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...

s via activation of ERβ, which is the predominant isoform of the ER expressed in platelets. It has been said that suppression of free testosterone levels by ERα activation-induced increase in

hepatic The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...

sex hormone-binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it has also been called androgen ...

(SHBG) production is the primary

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 targe ...

of GTx-758 in the treatment of prostate cancer.

Chemistry

GTx-758 is a di

phenyl In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...

benzamide Benzamide is a organic compound with the chemical formula of C6H5C(O)NH2. It is the simplest amide derivative of benzoic acid Benzoic acid is a white (or colorless) solid organic compound with the formula , whose structure consists of a benz ...

and has a similar

structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...

stilbestrol Stilbestrol, or stilboestrol, also known as 4,4'-dihydroxystilbene or 4,4'-stilbenediol, is a stilbenoid nonsteroidal estrogen and the parent compound of a group of more potent nonsteroidal estrogen derivatives that includes, most notably, dieth ...

derivatives like diethylstilbestrol and

triphenylethylene Triphenylethylene (TPE) is a simple aromatic hydrocarbon that possesses weak estrogenic activity. Its estrogenic effects were discovered in 1937. TPE was derived from structural modification of the more potent estrogen diethylstilbestrol, which is ...

derivatives like

chlorotrianisene Chlorotrianisene (CTA), also known as tri-''p''-anisylchloroethylene (TACE) and sold under the brand name Tace among others, is a nonsteroidal estrogen related to diethylstilbestrol (DES) which was previously used in the treatment of menopausal ...

Research

Preclinical studies

In animal studies, GTx-758 reversibly suppresses

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...

concentrations to castrate levels, reduces

prostate The prostate is both an Male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, ...

size and levels of

prostate-specific antigen Prostate-specific antigen (PSA), also known as gamma-seminoprotein or kallikrein-3 (KLK3), P-30 antigen, is a glycoprotein enzyme encoded in humans by the ''KLK3'' gene. PSA is a member of the kallikrein-related peptidase family and is secreted b ...

(PSA), but does not induce typical

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s associated with

hyperestrogenism Hyperestrogenism, hyperestrogenic state, or estrogen excess, is a medical condition characterized by an excessive amount of estrogenic activity in the body. Signs and symptoms Signs of hyperestrogenism may include heightened levels of one or mo ...

(or

hypoestrogenism Hypoestrogenism, or estrogen deficiency, refers to a lower than normal level of estrogen. It is an umbrella term used to describe estrogen deficiency in various conditions. Estrogen deficiency is also associated with an increased risk of cardiova ...

) including

hot flash Hot flashes (also known as hot flushes) are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and ...

es,

bone loss Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...

, thrombophilia, hypercoagulation, or increased

body fat Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular en ...

. Unlike

diethylstilbestrol Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a ...

, GTx-758 also does not induce

gynecomastia Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse (1 ...

in male monkeys, despite similarly suppressing testosterone levels to the castrate range (≤50 ng/dL) and markedly reducing PSA levels.

Clinical studies

In a phase II clinical trial of 1000 mg/day and 2000 mg/day GTx-758 versus

leuprorelin Leuprorelin, also known as leuprolide, is a manufactured version of a hormone used to treat prostate cancer, breast cancer, endometriosis, uterine fibroids, as part of transgender hormone therapy, for early puberty, or to perform chemical castra ...

for the treatment of

, GTx-758 suppressed total testosterone levels to a lower extent than leuprorelin but decreased free testosterone and PSA levels to a greater extent, suggesting superior effectiveness. GTx-758 increased median SHBG levels by 495% (at 1000 mg/day) and 583% (at 2000 mg/day), which was considered to account for the greater relative decrease in levels of free testosterone. There was a significantly lesser incidence of

estrogen deficiency Hypoestrogenism, or estrogen deficiency, refers to a lower than normal level of estrogen. It is an umbrella term used to describe estrogen deficiency in various conditions. Estrogen deficiency is also associated with an increased risk of cardiov ...

-associated

s in the GTx-758 group. For instance, there was a more than 4-fold lower incidence of hot flashes for GTx-758,

C-terminal telopeptide The C-terminal telopeptide (CTX), also known as carboxy-terminal collagen crosslinks, is the C-terminal telopeptide of fibrillar collagens such as collagen type I and type II. It is used as a biomarker in the serum to measure the rate of bone ...

(CTX) and bone specific alkaline phosphatase (BSAP) levels (markers of bone turnover) increased in the leuprorelin group but decreased in the GTx-758 group (indicating a beneficial bone-sparing effect for GTx-758), and

insulin-like growth factor-1 Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in tertiary structure, molecular structure to insulin which plays an important role in childhood growth, and has Anabolism, anabolic effects in adults. IGF-1 ...

levels (which are positively associated with

insulin resistance Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...

and

metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndrome ...

as well as progression of prostate cancer) increased in the leuprorelin group but decreased in the GTx-758 group. Incidence of gynecomastia was not reported with GTx-758. However, a higher incidence of

venous thromboembolism Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...

(VTE) was observed with GTx-78 (4.1%) relative to leuprorelin (0.0%), and this led to early termination of the clinical trial. The drug was said to be well tolerated aside from VTE. Studies are underway with lower doses of GTx-758 as secondary hormonal therapy in prostate cancer to see if such doses minimize the incidence of VTE. In a subsequent phase II clinical trial of 150 mg/day and 250 mg/day GTx-758 in castration-resistant prostate cancer, GTx-758 increased median SHBG levels by 301% (with 250 mg/day), decreased free testosterone levels by median 44%, and decreased PSA levels.http://meeting.ascopubs.org/cgi/content/abstract/34/2_suppl/185 Similarly to the prior phase II clinical trial, GTx-758 was regarded as well tolerated, and improved bone parameters, but there were still two possibly drug-related severe adverse effects (VTE and

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...

References

External links

GTx-758 - AdisInsight

Pipeline - GTx
{{Estrogen receptor modulators Phenols Benzamides Hormonal antineoplastic drugs Fluoroarenes Synthetic estrogens