Targeting androgen receptor and the variants by an orally bioavailable Proteolysis Targeting Chimeras compound in castration resistant prostate cancerResearch in context
Chiu-Lien Hung,
Hao-Hsuan Liu,
Chih-Wei Fu,
Hsun-Hao Yeh,
Tsan-Lin Hu,
Zong-Keng Kuo,
Yu-Chin Lin,
Mei-Ru Jhang,
Chrong-Shiong Hwang,
Hung-Chih Hsu,
Hsing-Jien Kung,
Ling-Yu Wang
Affiliations
Chiu-Lien Hung
Department of Preclinical Drug Discovery Technology, Biomedical Technology and Devices Research Labs, Industrial Technology Research Institute, Hsinchu 31040, Taiwan
Hao-Hsuan Liu
Department of Preclinical Drug Discovery Technology, Biomedical Technology and Devices Research Labs, Industrial Technology Research Institute, Hsinchu 31040, Taiwan
Chih-Wei Fu
Department of Preclinical Drug Discovery Technology, Biomedical Technology and Devices Research Labs, Industrial Technology Research Institute, Hsinchu 31040, Taiwan
Hsun-Hao Yeh
Department of Biochemistry and Molecular Biology, Chang Gung University, Taoyuan 33302, Taiwan
Tsan-Lin Hu
Department of Preclinical Drug Discovery Technology, Biomedical Technology and Devices Research Labs, Industrial Technology Research Institute, Hsinchu 31040, Taiwan
Zong-Keng Kuo
Department of Preclinical Drug Discovery Technology, Biomedical Technology and Devices Research Labs, Industrial Technology Research Institute, Hsinchu 31040, Taiwan
Yu-Chin Lin
Department of Preclinical Drug Discovery Technology, Biomedical Technology and Devices Research Labs, Industrial Technology Research Institute, Hsinchu 31040, Taiwan
Mei-Ru Jhang
Department of Preclinical Drug Discovery Technology, Biomedical Technology and Devices Research Labs, Industrial Technology Research Institute, Hsinchu 31040, Taiwan
Chrong-Shiong Hwang
Department of Preclinical Drug Discovery Technology, Biomedical Technology and Devices Research Labs, Industrial Technology Research Institute, Hsinchu 31040, Taiwan
Hung-Chih Hsu
Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan; College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
Hsing-Jien Kung
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan; Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan; Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
Ling-Yu Wang
Department of Biochemistry and Molecular Biology, Chang Gung University, Taoyuan 33302, Taiwan; Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan; Corresponding author. Department of Biochemistry and Molecular Biology, Chang Gung University, No.259, Wenhua 1st Rd., Guishan District, Taoyuan City 33302, Taiwan.
Summary: Background: Despite the advent of improved therapeutic options for advanced prostate cancer, the durability of clinical benefits is limited due to inevitable development of resistance. By constitutively sustaining androgen receptor (AR) signaling, expression of ligand-binding domain truncated AR variants (AR-V(ΔLBD)) accounts for the major mechanism underlying the resistance to anti-androgen drugs. Strategies to target AR and its LBD truncated variants are needed to prevent the emergence or overcome drug resistance. Methods: We utilize Proteolysis Targeting Chimeras (PROTAC) technology to achieve induced degradation of both full-length AR (AR-FL) and AR-V(ΔLBD) proteins. In the ITRI-PROTAC design, an AR N-terminal domain (NTD) binding moiety is appended to von-Hippel-Lindau (VHL) or Cereblon (CRBN) E3 ligase binding ligand with linker. Findings: In vitro studies demonstrate that ITRI-PROTAC compounds mechanistically degrade AR-FL and AR-V(ΔLBD) proteins via ubiquitin-proteasome system, leading to impaired AR transactivation on target gene expression, and inhibited cell proliferation accompanied by apoptosis activation. The compounds also significantly inhibit enzalutamide-resistant growth of castration resistant prostate cancer (CRPC) cells. In castration-, enzalutamide-resistant CWR22Rv1 xenograft model without hormone ablation, ITRI-90 displays a pharmacokinetic profile with decent oral bioavailability and strong antitumor efficacy. Interpretation: AR NTD that governs the transcriptional activities of all active variants has been considered attractive therapeutic target to block AR signaling in prostate cancer cells. We demonstrated that utilizing PROTAC for induced AR protein degradation via NTD represents an efficient alternative therapeutic strategy for CRPC to overcome anti-androgen resistance. Funding: The funding detail can be found in the Acknowledgements section.
