Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer
نویسندگان
چکیده
Clinical resistance to the second-generation antiandrogen enzalutamide in castration-resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights an unmet medical need for next-generation antagonists. We have identified and characterized tetra-aryl cyclobutanes (CBs) as a new class of competitive AR antagonists that exhibit a unique mechanism of action. These CBs are structurally distinct from current antiandrogens (hydroxyflutamide, bicalutamide, and enzalutamide) and inhibit AR-mediated gene expression, cell proliferation, and tumor growth in several models of CRPC. Conformational profiling revealed that CBs stabilize an AR conformation resembling an unliganded receptor. Using a variety of techniques, it was determined that the AR-CB complex was not recruited to AR-regulated promoters and, like apo AR, remains sequestered in the cytoplasm, bound to heat shock proteins. Thus, we have identified third-generation AR antagonists whose unique mechanism of action suggests that they may have therapeutic potential in CRPC.
منابع مشابه
Inhibitor of p52 NF-κB subunit and androgen receptor (AR) interaction reduces growth of human prostate cancer cells by abrogating nuclear translocation of p52 and phosphorylated ARser81
Accumulating evidence shows that androgen receptor (AR) activation and signaling plays a key role in growth and progression in all stages of prostate cancer, even under low androgen levels or in the absence of androgen in the castration-resistant prostate cancer. Sustained activation of AR under androgen-deprived conditions may be due to its interaction with co-activators, such as p52 NF-κB sub...
متن کاملCH5137291, an androgen receptor nuclear translocation-inhibiting compound, inhibits the growth of castration-resistant prostate cancer cells.
Resistance of prostate cancer to castration is currently an unavoidable problem. The major mechanisms underlying such resistance are androgen receptor (AR) overexpression, androgen-independent activation of AR, and AR mutation. To address this problem, we developed an AR pure antagonist, CH5137291, with AR nuclear translocation-inhibiting activity, and compared its activity and characteristics ...
متن کاملThe Iranian Society of Nuclear Medicine practical guideline on radioligand therapy in metastatic castration-resistant prostate cancer using 177Lu-PSMA
Prostate-specific membrane antigen (PSMA) is a type II transmembrane protein, which is anchored in the cell membrane of prostate epithelial cells. It is highly expressed on prostate epithelial cells and strongly up-regulated in prostate cancer. Although, 177Lu-PSMA has been recently introduced for radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC) with co...
متن کاملSingle Orbital Metastasis in Castration-Resistant Prostate Cancer
Introduction: Orbital metastasis of prostate cancer (PC) is very rare and even more unique in castration-resistant PC (CRPC). In this scenario, choline positron emission tomography/computed tomography (choline PET/CT) is the gold-standard restaging method of choice available in our setting, and new anti-androgens treatments show improvement in overall survival. Case presentation: We report the...
متن کاملSingle Orbital Metastasis in Castration-Resistant Prostate Cancer
Introduction: Orbital metastasis of prostate cancer (PC) is very rare and even more unique in castration-resistant PC (CRPC). In this scenario, choline positron emission tomography/computed tomography (choline PET/CT) is the gold-standard restaging method of choice available in our setting, and new anti-androgens treatments show improvement in overall survival. Case presentation: We report the...
متن کامل