한빛사논문
Tae Hyun Bae1,2§, Ki Woon Sung1,2,3§, Tri Pham4§, Abdo J. Najy4, Alaleh Zamiri4, Hyejeong Jang5,6, Su Ran Mun1,2, Seongho Kim5,6, Ha Kyoung Kwon3, Yeon Sung Son2, Dongping Shi4, Steven Kregel7, Elisabeth I. Heath5, Michael L. Cher8, Yong Tae Kwon1,2,3*, Hyeong-Reh Choi Kim4,5*
1Cellular Degradation Biology Center, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea;
2Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea;
3AUTOTAC Bio Inc., 254, Changgyeonggung-ro, Jongno-gu, Seoul, 03077, Republic of Korea;
4Department of Pathology, Barbara Ann Karmanos Institute, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA;
5Department of Oncology, Barbara Ann Karmanos Institute, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA;
6Biostatistics and Bioinformatics Core, Barbara Ann Karmanos Institute, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA;
7Department of Cancer Biology, Loyola University, Maywood, IL 60153, USA;
8Department of Urology, Barbara Ann Karmanos Institute, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA
§These authors share the first authorship.
*Correspondence: Hyeong-Reh Choi Kim, Yong Tae Kwon
Abstract
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.
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