Genetic alterations play a pivotal role in various human diseases, particularly cancer. The androgen receptor (AR) is a crucial transcription factor driving prostate cancer (PCa) progression across all stages. Current AR-targeting therapies utilize competitive AR antagonists or pathway suppressors. However, therapy resistance often emerges due to AR mutations and AR splice variants, such as AR-v7. To overcome this, we developed ATC-324, an AR degrader using the innovative protein degradation technology platform AUTOphagy-TArgeting Chimera (AUTOTAC). ATC-324 was designed to comprise enzalutamide, an AR inhibitor, as a target-binding ligand and YT 6-2, a ligand of the autophagy receptor p62/SQSTM1, as an autophagy-targeting ligand. ATC-324 induces the formation of the AR/p62 complex, leading to autophagy-lysosomal degradation of AR. Importantly, ATC-324 effectively degrades AR mutants frequently detected in PCa and co-degrades AR-v7 as a heterodimer with full-length AR. ATC-324 reduces nuclear AR levels and downregulates the target gene expression of AR and AR-v7, leading to cytotoxicity in AR-positive PCa cells. We also provide evidence of the therapeutic potential of ATC-324 in vivo as well as ex vivo bone organ culture. Moreover, ATC-324 remains potent in enzalutamide-resistant PCa cells. These results demonstrate the potential of the AUTOTAC platform to target previously considered undruggable proteins and overcome certain drug resistance mechanisms.
Cancer research. 2024 Nov 12 [Epub ahead of print]
Tae Hyun Bae, Ki Woon Sung, Tri M Pham, Abdo J Najy, Alaleh Zamiri, Hyejeong Jang, Su Ran Mun, Seongho Kim, Ha Kyoung Kwon, Yeon Sung Son, Dongping Shi, Steven Kregel, Elisabeth I Heath, Michael L Cher, Yong Tae Kwon, Hyeong-Reh C Kim
Seoul National University, Seoul, Korea (South), Republic of., Wayne State University School of Medicine, Detroit, MI, United States., Karmanos Cancer Institute, Detroit, MI, United States., Wayne State University, Detroit, MI, United States., AUTOTAC Bio Inc., Seoul, Korea (South), Republic of., Wayne State University School of Medicine, Detroit, United States., Loyola University Chicago, Maywood, IL, United States., Karmanos Cancer Center, Detroit, MI, United States., College of Medicine, Seoul National University, Seoul, Korea (South), Republic of.