What is the mechanism of Enzalutamide?

Enzalutamide is a nonsteroidal antiandrogen medication used primarily in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Its mechanism of action is intricate, targeting multiple stages of the androgen receptor (AR) signaling pathway, which is crucial for the growth and survival of prostate cancer cells.

The AR signaling pathway begins when androgens, such as testosterone and dihydrotestosterone (DHT), bind to the androgen receptor within the cytoplasm of prostate cancer cells. Once bound, the AR undergoes a conformational change that allows it to translocate into the nucleus, where it binds to specific DNA sequences known as androgen response elements (AREs). This binding initiates the transcription of androgen-responsive genes that promote tumor growth and proliferation.

Enzalutamide disrupts this process in several ways. Firstly, it binds to the androgen receptor with greater affinity than natural androgens. This competitive inhibition prevents androgens from activating the receptor. Secondly, Enzalutamide impedes AR nuclear translocation. Even if the AR were to become activated in the cytoplasm, Enzalutamide prevents it from moving into the nucleus, effectively halting the transcriptional activity necessary for tumor growth.

Additionally, Enzalutamide interferes with the DNA binding capability of the androgen receptor. Should any AR manage to translocate to the nucleus, Enzalutamide reduces its ability to bind to AREs, thus impairing the transcriptional activation of genes that facilitate cancer cell growth. Furthermore, Enzalutamide also disrupts the recruitment of co-activators needed for the transcriptional complex, adding another layer of inhibition to the pathway.

By targeting these multiple stages, Enzalutamide effectively reduces the androgen receptor signaling that drives prostate cancer cell proliferation. This multi-faceted mechanism of action makes it particularly effective in treating prostate cancer that has become resistant to other forms of hormone deprivation therapy.

In summary, Enzalutamide exerts its effects by competitively inhibiting androgen binding, impeding AR nuclear translocation, blocking DNA binding, and disrupting co-activator recruitment. These actions collectively suppress the androgen receptor signaling pathway, providing a robust therapeutic approach for managing metastatic castration-resistant prostate cancer.