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letterman新虫 (小有名气)
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Current drug target for Prostate Cancer
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[Content] In this series, each posting will include the current or emerging drug targets for one type of cancer. [Intended audience] Students and researchers who are interested in anticancer drug discovery. Topic 1: Current drug targets and emerging drug targets for prostate cancer Prostate cancer is critically depending on the signaling of androgen receptor (AR). Current major drug target for advanced prostate cancer is the AR. There are three domains in the AR: i) The N-terminal domain (NTD); ii) DNA-binding domain (DBD); and iii) Ligand-binding domain (LBD). When the hormone (DHT) binds with AR that the LBD, the AR signaling is activated. Thus, the current strategy to inhibit the AR signaling is to develop compounds to bind with AR at the LBD (to prevent the binding of DHT with AR). Such compounds are referred to as anti-androgen and a number of such compounds have been developed into drugs, including bicalutamide and enzalutamide. However, during the treatment of anti-androgen, despite of initial response, the patients almost always become resistance to the treatment and the AR signaling is reactivated (despite of the anti-androgen treatment). While there are many possible mechanisms have been proposed, there are two key mechanisms: First, the emergence of AR splice variants that do not have the LBD confer resistance to the LBD-targeting antiandrogens. It is important to note that all of the current clinically used antiandrogens are designed to target the AR LBD; Second, the mutation in the AR LBD could confer resistance to antiandrogens. Worse yet, some mutations at the LBD could lead to the AR mutants that are activated by antiandrogensuch as enzalutamide. How to develop potent and selective inhibitors of the AR splice variants is a burning issue in the field. One approach is to target the AR NTD, but this is very challenging. The major reason is that the AR NTD is intrinsically disorder. No crystal structure of the AR NTD is available. Nevertheless, the 3rd generation of antiandrogens could be the compounds that target the AR NTD. |
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