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Carcinoma of the prostate is the most commonly diagnosed cancer in men. The current pharmacological treatment of choice for progressive androgen-dependent prostate cancer is the nonsteroidal antiandrogen, bicalutamide, either as monotherapy or with adjuvant castration or luteinizing hormone-releasing hormone superagonists to block the synthesis of endogenous testosterone. To date, no nonsteroidal or antagonist-bound androgen receptor (AR) structure is available. We solved the x-ray crystal structure of the mutant W741L AR ligand-binding domain bound to R-bicalutamide at 1.8-Å resolution. This mutation confers agonist activity to bicalutamide and is likely involved in bicalutamide withdrawal syndrome. The three-dimensional structure demonstrates that the B ring of R-bicalutamide in the W741L mutant is accommodated at the location of the indole ring of Trp-741 in the WT AR bound to dihydrotestosterone. Knowledge of the binding mechanism for R-bicalutamide will provide molecular rationale for the development of new antiandrogens and selective AR modulators.androgen receptor ͉ crystallography T he androgen receptor (AR) is a ligand-inducible hormone receptor of the nuclear receptor superfamily that plays a role in development and regulation of male secondary characteristics, spermatogenesis, bone and muscle mass, and androgenic tissue. Agents that block the actions (i.e., antiandrogens) of endogenous androgens (e.g., testosterone) are highly effective and routinely used for the treatment of prostate cancer. The first nonsteroidal antiandrogen, f lutamide (Eulexin) was approved for prostate cancer in 1989 (1) and the structurally related compounds, bicalutamide (Casodex) and nilutamide (Nilandron) (2), were later launched in 1995 and 1996, respectively. Nonsteroidal ligands are more favorable for clinical applications because of the lack of crossreactivity with other steroid receptors (e.g., progesterone receptor) and improved oral bioavailability. Of this structural class of antiandrogens, bicalutamide is the most potent (3) and best tolerated (4 -6). Emerging data from clinical studies further reinforce the idea that bicalutamide is a drug of choice for progressive androgen-dependent prostate cancers often in conjunction with leuprolide or other luteinizing hormone-releasing hormone superagonists as a component of total androgen blockade (7-12). Although antiandrogen treatment and androgen blockade usually exhibit favorable responses, prostate cancers often become refractory, as evidenced by increasing prostatespecific antigen levels (i.e., progression) and͞or regression upon cessation of antiandrogen therapy (i.e., antiandrogen withdrawal syndrome) (13). AR gene mutations in the ligandbinding domain (LBD) that alter ligand specificity and͞or functional activity exist and are thought to contribute to the ability of some antiandrogens to exhibit androgenic activity. The LNCaP prostate cancer cell line expresses AR with a T877A point mutation that causes proliferation in the presence of the antiandrogens hydroxyf lut...

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BackgroundCachexia, also known as muscle wasting, is a complex metabolic condition characterized by loss of skeletal muscle and a decline in physical function. Muscle wasting is associated with cancer, sarcopenia, chronic obstructive pulmonary disease, end-stage renal disease, and other chronic conditions and results in significant morbidity and mortality. GTx-024 (enobosarm) is a nonsteroidal selective androgen receptor modulator (SARM) that has tissue-selective anabolic effects in muscle and bone, while sparing other androgenic tissue related to hair growth in women and prostate effects in men. GTx-024 has demonstrated promising pharmacologic effects in preclinical studies and favorable safety and pharmacokinetic profiles in phase I investigation.MethodsA 12-week double-blind, placebo-controlled phase II clinical trial was conducted to evaluate GTx-024 in 120 healthy elderly men (>60 years of age) and postmenopausal women. The primary endpoint was total lean body mass assessed by dual energy X-ray absorptiometry, and secondary endpoints included physical function, body weight, insulin resistance, and safety.ResultsGTx-024 treatment resulted in dose-dependent increases in total lean body mass that were statistically significant (P < 0.001, 3 mg vs. placebo) and clinically meaningful. There were also significant improvements in physical function (P = 0.013, 3 mg vs. placebo) and insulin resistance (P = 0.013, 3 mg vs. placebo). The incidence of adverse events was similar between treatment groups.ConclusionGTx-024 showed a dose-dependent improvement in total lean body mass and physical function and was well tolerated. GTx-024 may be useful in the prevention and/or treatment of muscle wasting associated with cancer and other chronic diseases.