scispace - formally typeset
Search or ask a question
Author

Samedy Ouk

Bio: Samedy Ouk is an academic researcher from University of California. The author has contributed to research in topics: Prostate cancer & Androgen receptor. The author has an hindex of 10, co-authored 24 publications receiving 2865 citations. Previous affiliations of Samedy Ouk include University of California, Los Angeles & Cornell University.

Papers
More filters
Journal ArticleDOI
08 May 2009-Science
TL;DR: The diarylthiohydantoins RD162 and MDV3100 are characterized, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression that appear to be promising candidates for treatment of advanced prostate cancer.
Abstract: Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.

2,046 citations

Journal ArticleDOI
TL;DR: ARS-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists, and offers preclinical proof of principle for ARN-509 as a promising therapeutic in bothCastration-sensitive and castration-resistant forms of prostate cancer.
Abstract: Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR-pathway targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor this is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/day of ARN-509, whereas the same response required 100 mg/kg/day of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.

603 citations

Journal ArticleDOI
TL;DR: A structure-activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.
Abstract: A structure-activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.

269 citations

Patent
27 Mar 2007
TL;DR: A hydantoin compound is a compound useful for the prevention or treatment of hyperproliferative diseases or disorders as mentioned in this paper, but it is not suitable for the treatment of cancer.
Abstract: A hydantoin compound useful for the prevention or treatment of hyperproliferative diseases or disorders.

72 citations

Journal ArticleDOI
TL;DR: This work developed a novel strategy to ameliorate GVHD while preserving graft-versus-tumor activity by small molecule-based inhibition of the NF-κB family member c-Rel, validating c-rel as a promising target for immunomodulatory therapy and demonstrating the feasibility and efficacy of pharmaceutical inhibition of c- Rel activity.
Abstract: Preventing unfavorable GVHD without inducing broad suppression of the immune system presents a major challenge of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We developed a novel strategy to ameliorate GVHD while preserving graft-versus-tumor (GVT) activity by small molecule-based inhibition of the NF-κB family member c-Rel. Underlying mechanisms included reduced alloactivation, defective gut homing, and impaired negative feedback on interleukin (IL)-2 production, resulting in optimal IL-2 levels, which, in the absence of competition by effector T cells, translated into expansion of regulatory T cells. c-Rel activity was dispensable for antigen-specific T-cell receptor (TCR) activation, allowing c-Rel-deficient T cells to display normal GVT activity. In addition, inhibition of c-Rel activity reduced alloactivation without compromising antigen-specific cytotoxicity of human T cells. Finally, we were able to demonstrate the feasibility and efficacy of systemic c-Rel inhibitor administration. Our findings validate c-Rel as a promising target for immunomodulatory therapy and demonstrate the feasibility and efficacy of pharmaceutical inhibition of c-Rel activity.

51 citations


Cited by
More filters
Journal ArticleDOI
TL;DR: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy, and was shown with respect to all secondary end points.
Abstract: Background Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor–signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. Methods In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival. Results The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for de...

3,866 citations

Journal ArticleDOI
TL;DR: Analysis of genomic and clinical outcome data from 218 prostate cancer tumors revealed that copy-number alterations robustly define clusters of low- and high-risk disease beyond that achieved by Gleason score.

3,310 citations

Journal ArticleDOI
TL;DR: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer.
Abstract: BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).

2,426 citations

Journal ArticleDOI
TL;DR: In this article, the androgen-receptor splice variant 7 (AR-V7) was found to be associated with resistance to enzalutamide and abiraterone.
Abstract: Background The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. Methods We used a quantitative reverse-transcriptase–polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression–free survival), clinical or radiographic progression–free survival, and overall survival. Resul...

2,221 citations

Journal ArticleDOI
TL;DR: In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates.
Abstract: The concept of isosterism between relatively simple chemical entities was originally contemplated by James Moir in 1909, a notion further refined by H. G. Grimm’s hydride displacement law and captured more effectively in the ideas advanced by Irving Langmuir based on experimental observations. Langmuir coined the term “isostere” and, 18 years in advance of its actual isolation and characterization, predicted that the physical properties of the then unknown ketene would resemble those of diazomethane. The emergence of bioisosteres as structurally distinct compounds recognized similarly by biological systems has its origins in a series of studies published byHans Erlenmeyer in the 1930s, who extended earlier work conducted by Karl Landsteiner. Erlenmeyer showed that antibodies were unable to discriminate between phenyl and thienyl rings or O, NH, and CH2 in the context of artificial antigens derived by reacting diazonium ions with proteins, a process that derivatized the ortho position of tyrosine, as summarized in Figure 1 The term “bioisostere” was introduced by Harris Friedman in 1950 who defined it as compounds eliciting a similar biological effect while recognizing that compounds may be isosteric but not necessarily bioisosteric. This notion anticipates that the application of bioisosterism will depend on context, relying much less on physicochemical properties as the underlying principle for biochemical mimicry. Bioisosteres are typically less than exact structural mimetics and are often more alike in biological rather than physical properties. Thus, an effective bioisostere for one biochemical application may not translate to another setting, necessitating the careful selection and tailoring of an isostere for a specific circumstance. Consequently, the design of bioisosteres frequently introduces structural changes that can be beneficial or deleterious depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering physical properties, reducing or redirecting metabolism, eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examined are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chemistry setting has been adopted by this community.

2,049 citations