Structure−Activity Relationship for Thiohydantoin Androgen Receptor Antagonists for Castration-Resistant Prostate Cancer (CRPC)
Michael E. Jung,Samedy Ouk,Dongwon Yoo,Charles L. Sawyers,Charlie Chen,Chris Tran,John Wongvipat +6 more
TLDR
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.read more
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Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy
Howard I. Scher,Karim Fizazi,Fred Saad,Mary-Ellen Taplin,Cora N. Sternberg,Kurt Miller,Ronald de Wit,Peter F.A. Mulders,Kim N. Chi,Neal D. Shore,Andrew J. Armstrong,Thomas W. Flaig,Aude Flechon,Paul N. Mainwaring,Mark D. Fleming,John D. Hainsworth,Mohammad Hirmand,Bryan Selby,Lynn Seely,Johann S. de Bono,B Ch +20 more
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.
Journal ArticleDOI
Synopsis of some recent tactical application of bioisosteres in drug design.
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.
Journal ArticleDOI
Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas
Yu Zhou,Jiang Wang,Zhanni Gu,Shuni Wang,Wei Zhu,José Luis Aceña,Vadim A. Soloshonok,Kunisuke Izawa,Hong Liu +8 more
TL;DR: Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas is presented.
Journal ArticleDOI
Overcoming mutation-based resistance to antiandrogens with rational drug design
Minna D. Balbas,Michael J. Evans,David J. Hosfield,John Wongvipat,Vivek K. Arora,Philip A. Watson,Yu Chen,Geoffrey L. Greene,Yang Shen,Charles L. Sawyers +9 more
TL;DR: A reporter-based mutagenesis screen and molecular dynamics simulations suggested a mechanism by which the F876L substitution alleviates antagonism through repositioning of the coactivator recruiting helix 12, which provided the rationale for a focused chemical screen which identified three novel compounds that effectively antagonized AR F 876L to suppress the growth of prostate cancer cells resistant to enzalutamide.
Journal ArticleDOI
New and unusual scaffolds in medicinal chemistry
TL;DR: This critical review surveys a necessarily limited selection of currently atypical scaffolds that have found application in medicinal chemistry, some being present in agents with therapeutic potential while others are found in agents already in clinical use.
References
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Journal ArticleDOI
The development of androgen-independent prostate cancer
Brian J. Feldman,David Feldman +1 more
TL;DR: It is predicted that understanding the pathways that lead to the development of androgen-independent prostate cancer will pave the way to effective therapies for these, at present, untreatable cancers.
Journal ArticleDOI
Molecular determinants of resistance to antiandrogen therapy
Charlie D. Chen,Derek S. Welsbie,Chris Tran,Sung Hee Baek,Randy Chen,Robert L. Vessella,Michael G. Rosenfeld,Charles L. Sawyers +7 more
TL;DR: Using microarray-based profiling of isogenic prostate cancer xenograft models, it is found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy.
Journal ArticleDOI
Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer
Chris Tran,Samedy Ouk,Nicola J. Clegg,Yu Chen,Philip A. Watson,Vivek K. Arora,John Wongvipat,Peter Smith-Jones,Dongwon Yoo,Andrew Kwon,Teresa Wasielewska,Derek S. Welsbie,Charlie D. Chen,Celestia S. Higano,Tomasz M. Beer,David T. Hung,Howard I. Scher,Michael E. Jung,Charles L. Sawyers +18 more
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.
Journal ArticleDOI
Molecular Biology of the Androgen Receptor
TL;DR: Funding for further understanding of AR action and new strategies to interfere with AR signaling hold promise for improving prostate cancer therapy.
Journal ArticleDOI
Structural Evidence for Ligand Specificity in the Binding Domain of the Human Androgen Receptor IMPLICATIONS FOR PATHOGENIC GENE MUTATIONS
Pedro M. Matias,Peter Donner,Ricardo Coelho,M. A. A. Thomaz,Cristina Peixoto,S. Macedo,Norbert Otto,Simone Joschko,Peter Scholz,Anja Wegg,Siegfried Bäsler,Martina Schäfer,Ursula Egner,Maria Arménia Carrondo +13 more
TL;DR: The crystal structures of the human androgen receptor (hAR) and human progesterone receptor ligand-binding domains in complex with the same ligand metribolone (R1881) have been determined and the change of two residues in the ligands-binding pocket between the hAR and hAR is most likely the source for the specificity of R1881.
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