Chemistry and structural biology of androgen receptor.
This review focuses on well-characterized AR ligands that bind to the AR with high affinity and integrates discussion regarding the biology, metabolism, and structure-activity relationships for therapeutic and emerging classes of AR ligand.
FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma.
FTY720 treatment resulted in significant prolonged survival in a xenograft severe combined immunodeficiency mouse model of disseminated B-cell lymphoma/leukemia, providing the first evidence for the potential use of FTY720 as a therapeutic agent in a variety of B- cell malignancies, including CLL.
Structural basis for antagonism and resistance of bicalutamide in prostate cancer
- Casey E. Bohl, Wenqing Gao, Duane D. Miller, C. Bell, J. Dalton
- Biology, MedicineProceedings of the National Academy of Sciences…
- 15 April 2005
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.
Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia.
Flavopiridol administered using this novel schedule has significant clinical activity in refractory CLL and other diseases, and patients with bulky disease and high-risk genetic features have achieved durable responses, thereby justifying further study of flavopirIDol.
The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind,…
- J. Dalton, K. G. Barnette, M. Steiner
- MedicineJournal of Cachexia, Sarcopenia and Muscle
- 2 August 2011
GTx-024 showed a dose-dependent improvement in total lean body mass and physical function and was well tolerated and may be useful in the prevention and/or treatment of muscle wasting associated with cancer and other chronic diseases.
Drug Insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging
Meta-analyses indicate that testosterone supplementation increases fat-free mass and muscle strength in HIV-positive men with weight loss, glucocorticoid-treated men, and older men with low or low-normal testosterone levels, and selective androgen-receptor modulators that are preferentially anabolic hold promise as anabolic therapies.
Structural Basis for Accommodation of Nonsteroidal Ligands in the Androgen Receptor*
- Casey E. Bohl, Duane D. Miller, Jiyun Chen, C. Bell, J. Dalton
- Biology, ChemistryJournal of Biological Chemistry
- 11 November 2005
These studies provide the first crystallographic evidence of the mechanism by which nonsteroid ligands interact with the wild type AR and provide critical new insight for receptor-based drug design of nonsteroidal AR agonists and antagonists.
Pharmacodynamics of Selective Androgen Receptor Modulators
- D. Yin, Wenqing Gao, J. Dalton
- Biology, MedicineJournal of Pharmacology and Experimental…
- 1 March 2003
Compounds S-1 and S-4 were identified as SARMs with potent and tissue-selective in vivo pharmacological activity, and represent the first members of a new class of SAR Ms with selective anabolic effects.
FTY720 Shows Promising In vitro and In vivo Preclinical Activity by Downmodulating Cyclin D1 and Phospho-Akt in Mantle Cell Lymphoma
These results provide the first evidence for a potential use of FTY720 in targeting key pathways that are operable in the pathogenesis of MCL and warrant further investigation of F TY720 in clinical trials to treat patients with MCL.
Discovery of nonsteroidal androgens.
- J. Dalton, A. Mukherjee, Z. Zhu, L. Kirkovsky, D. Miller
- BiologyBiochemical and Biophysical Research…
- 6 March 1998
These ligands represent the first members of a novel class of androgens with potential therapeutic applications in male fertility and hormone replacement therapy and demonstrate that nonsteroidal ligands can be structurally modified to produce agonist activity.