Abstract Androgen receptor (AR) and its downstream signaling play a critical role in the development and progression of both localized and metastatic prostate cancer. As a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC), previous strategies that successfully target AR signaling have focused on blocking androgen synthesis by drugs such as abiraterone and inhibition of AR function by AR antagonists such as enzalutamide and apalutamide (ARN-509). However, such agents become ineffective in advanced prostate cancer with AR gene amplification, mutation and alternate splicing. It is very clear however that in most patients with CRPC, the AR protein continues to be expressed and tumors are still dependent upon AR signaling. Here we describe our design, synthesis and evaluation of small-molecule AR degraders based on the proteolysis targeting chimera (PROTAC) concept and our investigation of their therapeutic potential and mechanism of action in vitro and in vivo. In vitro, our potent AR degraders effectively induce degradation of AR protein in AR+ LNCaP, VCaP and 22Rv1 prostate cancer cell lines with DC50 values as low as 1 nM. AR degraders are capable of reducing the AR protein level by >95% in these AR+ cancer cell lines and effectively reduces AR-regulated gene expression suppression. In vivo, our AR degrader showed potent AR degradation effects and anti-tumor activities in multiple murine xenograft models of prostate cancer at well-tolerated dosing schedules. Our data provides clear evidence that targeting AR for degradation by the PROTAC methodology is a novel and very exciting therapeutic approach for the treatment of mCRPC. Citation Format: Xin Han, Lijie Zhao, Weiguo Xiang, Chong Qin, Bukeyan Miao, Tianfeng Xu, Jianfeng Lu, Mi Wang, Shaomeng Wang. Targeted androgen receptor (AR) protein degradation for the treatment of metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1960.