前立腺がん治療薬としての経口バイオアベイラブルアンドロゲン受容体分解剤AZD9750の発見

Androgen Receptor (AR) signaling plays a pivotal role in the development and progression of prostate cancer. Herein, we describe the discovery and optimization of a novel series of AR PROTACs capable of degrading AR and important resistance mutations such as L702H AR. A novel AR-binding cyanoindole motif was identified from a directed screen of the AstraZeneca collection. This was optimized and elaborated to identify a suitable exit vector from which to form an initial PROTAC capable of degrading AR. The series was further optimized in terms of potency and rodent oral bioavailability with an isomeric switch of the piperidine substitution, removing an in vitro mitotoxicity signal to give 3n. This compound inhibited AR signaling in vitro and was able to inhibit tumor growth in vivo in a mouse prostate cancer xenograft model. Extensive profiling in terms of drug-like properties allowed this to be progressed into development as AZD9750.