Prostate cancer is a common malignant tumor in men. The development of effective therapies for prostate cancer has been the main focus of scientific research. Prostate is an androgen dependent organ, and prostate cancer is an androgen dependent disease. Androgen action is mediated by androgen receptor (AR), which is a hormone activated transcription factor. AR belongs to steroid receptor in nuclear receptor superfamily. AR and its downstream signal transduction play a key role in the development and progression of local and metastatic prostate cancer.
Androgen receptor (AR) structure [1]
The main treatment for metastatic prostate cancer is androgen deprivation therapy (ADT). Many AR targeted drugs have been developed to treat advanced prostate cancer, including Abiraterone, which blocks androgen synthesis, and AR antagonists Enzalutamide, Apalutamide, and Darolutamide, which combine with AR. However, resistance to these drugs usually occurs within 2 years after treatment. In most tumors resistant to AR antagonists, AR signals continue to play a role and drive tumor growth and progression. Castration resistant prostate cancer (CRPC) depends on AR. AR gene amplification, point mutation and alternative splicing have been identified as some of the main mechanisms of resistance to these AR targeted drugs. In addition, changes in steroid metabolism, cell signaling and co regulatory proteins are also important factors for AR reactivation in CRPC. Most AR targeted therapies target hormone binding domains. The discovery that constitutive active AR splicing variants lacking hormone binding domains are often expressed in CRPC underscores the need to develop therapies targeting other parts of AR. Therefore, it is urgent to develop new therapeutic strategies for AR treatment of prostate cancer, especially for metastatic castration resistant prostate cancer (mCRPC). MCRPC is still incurable and fatal.
Targeted degradation of androgen receptor (AR)
The induced degradation of AR protein may be more effective than traditional AR antagonists in targeting AR signal transduction. Selective androgen receptor degrading agent (SARD) binds to the ligand binding domain in AR and destroys the interaction between AR and auxiliary regulators, leading to proteasome dependent AR degradation. Another new strategy to induce AR degradation is based on the proteolytic targeting chimeric (PROTAC) technology platform. PROTAC based AR degrading agent is a bifunctional small molecule, which is composed of AR ligand that binds to AR protein and ligand that binds to E3 ligase complex and is linked together through Linker. PROTAC small molecule degradant has become a promising new therapeutic agent, but it is a major challenge to design a PROTAC degradant with excellent oral pharmacokinetics. In some studies, researchers designed and synthesized highly effective PROTAC AR degradants with high oral bioavailability according to new strategies.
PROTAC AR degrading agent ARD-2128
In the following, researchers used Thalidomide to collect Cereblon/cullin 4A E3 ligase and solidified it through Linker, and found a highly effective AR degrading agent ARD-2128 with good oral pharmacokinetics in mice.