Selective androgen receptor modulators(SARMs)are a class of nonsteroidal drugs that are favored over anabolic androgenic steroids(AASs)for their tissue-selectivity and improved side-effect profile.These drugs have bee...Selective androgen receptor modulators(SARMs)are a class of nonsteroidal drugs that are favored over anabolic androgenic steroids(AASs)for their tissue-selectivity and improved side-effect profile.These drugs have been evaluated for treatment of various diseases including muscle-wasting disorders,osteoporosis,and breast cancer.Despite lacking approval for therapeutic use,SARMs are widely used recreationally as performance enhancing drugs by bodybuilders and athletes.In recent years,cases of drug-induced liver injury(DILI)secondary to SARMs have begun to emerge,but little is known regarding their hepatotoxicity.In this review,we provide current knowledge regarding DILI from SARMs.A literature search was conducted regarding SARMs and liver injury to evaluate relevant cases and information.SARMs have been associated with a cholestatic syndrome congruent with that of DILI from AASs,and it consists of a bland cholestasis in which there is minimal bile duct injury,inflammation,or necrosis.Patients present with an insidious onset of jaundice with marked hyperbilirubinemia and mild hepatic enzyme elevations.No clear treatment exists,although patients typically show improvement with cessation of the offending SARM.Given the novelty of these drugs,further study is necessary to understand diagnosis,management,and complications of SARM-related DILI.展开更多
Androgen receptor(AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding ...Androgen receptor(AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway.Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening(VS) on the basis of the crystal structure of the AR ligand binding domain(LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them(HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC50 values of HBP1-51 and HBP1-58 are 3.96 m M and 4.92 m M, respectively, which are even lower than that of enzalutamide(Enz, IC50= 13.87 m M), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics(MD) simulations and principal components analysis(PCA) were carried out to reveal the binding principle of the newlyidentified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary,the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.展开更多
文摘Selective androgen receptor modulators(SARMs)are a class of nonsteroidal drugs that are favored over anabolic androgenic steroids(AASs)for their tissue-selectivity and improved side-effect profile.These drugs have been evaluated for treatment of various diseases including muscle-wasting disorders,osteoporosis,and breast cancer.Despite lacking approval for therapeutic use,SARMs are widely used recreationally as performance enhancing drugs by bodybuilders and athletes.In recent years,cases of drug-induced liver injury(DILI)secondary to SARMs have begun to emerge,but little is known regarding their hepatotoxicity.In this review,we provide current knowledge regarding DILI from SARMs.A literature search was conducted regarding SARMs and liver injury to evaluate relevant cases and information.SARMs have been associated with a cholestatic syndrome congruent with that of DILI from AASs,and it consists of a bland cholestasis in which there is minimal bile duct injury,inflammation,or necrosis.Patients present with an insidious onset of jaundice with marked hyperbilirubinemia and mild hepatic enzyme elevations.No clear treatment exists,although patients typically show improvement with cessation of the offending SARM.Given the novelty of these drugs,further study is necessary to understand diagnosis,management,and complications of SARM-related DILI.
基金supported by the National Key R&D Program of China (Grant Nos.2016YFA0501701 and 2016YFA0202900)the National Natural Science Foundation of China (Grant Nos.21575128,81773632,and 81302679)
文摘Androgen receptor(AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway.Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening(VS) on the basis of the crystal structure of the AR ligand binding domain(LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them(HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC50 values of HBP1-51 and HBP1-58 are 3.96 m M and 4.92 m M, respectively, which are even lower than that of enzalutamide(Enz, IC50= 13.87 m M), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics(MD) simulations and principal components analysis(PCA) were carried out to reveal the binding principle of the newlyidentified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary,the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.
