Review
Biochemistry & Molecular Biology
Navid Sobhani, Praveen Kumar Neeli, Alberto D'Angelo, Matteo Pittacolo, Marianna Sirico, Ilaria Camilla Galli, Giandomenico Roviello, Gabriella Nesi
Summary: Metastatic prostate cancer is the most common cancer in males with a poor prognosis, and many patients develop the AR-V7 variant. AR-V7 acts as a transcription factor in the nucleus, repressing crucial tumor suppressor genes. Anti-AR-V7 drugs show promise for this subset of patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Jian-Jia Liang, Hang Xie, Rui-Hua Yang, Ni Wang, Zi-Jun Zheng, Chen Zhou, Ya-Lei Wang, Zhi-Jia Wang, Hong-Min Liu, Li-Hong Shan, Yu Ke
Summary: In this study, novel PROTACs containing different linker phthalimide degrons were designed, synthesized, and evaluated for their AR degradation activity. Compound A16 showed the best AR binding affinity and degradation activity, while B10 exhibited effective internalization and visualization in LNCaP cells. Molecular docking of A16 with AR and the DDB1-CRBN E3 ubiquitin ligase complex provides guidance for designing new PROTAC degrons targeting AR in prostate cancer therapy. This research represents progress towards developing novel and improved AR PROTACs.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Oncology
Danyang Zhou, Mei Li, Mohamed Hussein Yasin, Qianyi Lu, Jia Fu, Kuikui Jiang, Ruoxi Hong, Shusen Wang, Fei Xu
Summary: This study aimed to investigate the prognostic value of AR in HER2+ nonmetastatic breast invasive ductal carcinoma (IDC) and its relationship with the immune microenvironment. The results showed that AR was closely correlated with overall survival (OS) and had a negative correlation with PD-L1/TILs in HER2+HR- nonmetastatic breast cancer patients.
Article
Oncology
Neele Wuestmann, Konstantin Seitzer, Verena Humberg, Julia Vieler, Norbert Grundmann, Julie Steinestel, Dorothee Tiedje, Stefan Duensing, Laura-Maria Krabbe, Martin Boegemann, Andres Jan Schrader, Christof Bernemann, Katrin Schlack
Summary: This study found that the level of AR-FL and the appearance and increase of AR-Vs are associated with elevated levels of AR pre-mRNA in prostate cancer cells. The levels of AR-FL and AR-Vs also increase during disease progression. In patients undergoing ARTA treatment, AR-FL shows prognostic value but not predictive value. Additionally, even AR-V positive patients show a significant clinical response to ARTA treatment. Therefore, AR-FL and AR-V may be considered as prognostic biomarkers in mCRPC patients, but not predictive biomarkers.
BIOMARKER RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Mengping Long, Chong You, Qianqian Song, Lina X. J. Hu, Zhaorong Guo, Qian Yao, Wei Hou, Wei Sun, Baosheng Liang, Xiaohua Zhou, Yiqiang Liu, Taobo Hu
Summary: This study analyzed the expression of androgen receptor (AR) in both estrogen receptor (ER)-positive and ER-negative breast cancer, and its association with clinicopathological and molecular features. The results showed that AR negativity was associated with different characteristics in ER-positive and ER-negative breast cancer. AR-positive breast cancer had better clinicopathological features, especially in the ER-negative subtype. These findings suggest a distinctive role of AR in ER-negative breast cancer compared to ER-positive breast cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Shengli Dong, Hassan Yousefi, Isabella Van Savage, Samuel C. Okpechi, Maryl K. Wright, Margarite D. Matossian, Bridgette M. Collins-Burow, Matthew E. Burow, Suresh K. Alahari
Summary: Combination therapy with ceritinib and enzalutamide inhibits the growth of AR(+) TNBC cells, while combination therapy with ceritinib and paclitaxel drastically inhibits tumor growth. These findings suggest that combination treatment with these FDA-approved drugs can improve the therapeutic response in both AR-positive and negative breast cancer.
Article
Chemistry, Medicinal
Weiguo Xiang, Lijie Zhao, Xin Han, Tianfeng Xu, Steven Kregel, Mi Wang, Bukeyan Miao, Chong Qin, Mingliang Wang, Donna McEachern, Jianfeng Lu, Longchuan Bai, Chao-Yie Yang, Paul D. Kirchhoff, John Takyi-Williams, Lu Wang, Bo Wen, Duxin Sun, Mark Ator, Robert Mckean, Arul M. Chinnaiyan, Shaomeng Wang
Summary: In this study, the highly potent and orally efficacious PROTAC degrader of the androgen receptor (AR), ARD-1676, was discovered and extensively characterized. ARD-1676 effectively induces degradation of clinically relevant AR mutants and inhibits tumor growth in mouse models. It shows great potential as a development candidate for the treatment of AR-positive human prostate cancer.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Oncology
Zhengfang Liu, Cheng Liu, Keqiang Yan, Jikai Liu, Zhiqing Fang, Yidong Fan
Summary: The huaier extract demonstrated potent antiproliferative effects in both hormone sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC) cells by downregulating AR-FL and AR-V7 mRNA levels via targeting the SMYD3 signaling pathway, and enhancing proteasome-mediated protein degradation of AR-FL and AR-V7 by downregulating USP14. Additionally, the extract inhibited AR transcriptional activity and their nuclear translocation, and could re-sensitize enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vitro and in vivo models.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Hanfang Jiang, Quchang Ouyang, Yongmei Yin, Zhongshen Tong, Kunwei Shen, Zhongyu Yuan, Cuizhi Geng, Yaxin Liu, Guohong Song, Ran Ran, Wei Li, Qing Qu, Meiyu Wang, Luping Meng, Youzhi Tong, Huiping Li
Summary: The study evaluated the efficacy and safety of a novel non-steroidal androgen receptor antagonist, Proxalutamide, in patients with AR-positive metastatic breast cancer. The results showed promising anti-tumor activity and tolerability of Proxalutamide, supporting further investigation of this drug.
EUROPEAN JOURNAL OF CANCER
(2022)
Article
Biochemistry & Molecular Biology
Xu Li, Shu Zhuo, Yong Suk Cho, Yuchen Liu, Yingzi Yang, Jian Zhu, Jin Jiang
Summary: Hippo signaling inhibits the oncogenic potential of YAP/TAZ-TEAD transcriptional complex, restricting tumor growth. In AR-positive prostate cancer, YAP acts as a tumor suppressor by counteracting TEAD-mediated AR signaling. YAP competes with AR for TEAD binding, disrupting AR-TEAD interaction and preventing TEAD from promoting AR signaling. Targeting the Hippo signaling pathway may provide a therapeutic opportunity to treat therapy resistant AR variants-driven prostate cancer.
Article
Oncology
Angeleke Saridakis, Elizabeth R. Berger, Malini Harigopal, Tristen Park, Nina Horowitz, Justin Le Blanc, Gregory Zanieski, Anees Chagpar, Rachel Greenup, Mehra Golshan, Donald R. Lannin
Summary: Invasive apocrine carcinomas have more aggressive features than non-apocrine carcinomas but the breast cancer-specific survival is the same. Half of these apocrine tumors are triple negative but these have more favorable features and much better survival than non-apocrine triple-negative cancers. The characteristics of apocrine carcinomas vary dramatically by molecular type, with triple-negative apocrine patients having better survival outcomes compared to non-apocrine triple-negative patients, while luminal apocrine patients have worse survival outcomes compared to non-apocrine luminal patients.
ANNALS OF SURGICAL ONCOLOGY
(2021)
Article
Oncology
Maryam Labaf, Muqing Li, Lily Ting, Breelyn Karno, Songqi Zhang, Shuai Gao, Susan Patalano, Jill A. A. Macoska, Kourosh Zarringhalam, Dong Han, Changmeng Cai
Summary: This study examines the acute effects of overexpressed androgen receptor (AR) on its cistrome and transcriptome in a prostate cancer (PCa) model. The results show that overexpression of AR leads to redistribution of AR chromatin binding and activation of a distinct transcription program, including DNA damage repair pathways. The study also predicts the involvement of EZH2 in this AR reprogramming and identifies a subset of AR/EZH2 co-targeting genes that are overexpressed in castration-resistant PCa and associated with worse patient outcomes.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
Ho Tsoi, Johann Lok, Ellen P. S. Man, Cheuk-Nam Cheng, Man-Hong Leung, Chan-Ping You, Sum-Yin Chan, Wing-Lok Chan, Ui-Soon Khoo
Summary: This study revealed that overexpression of a novel splice variant BQ323636.1 is associated with resistance to the non-steroidal aromatase inhibitor anastrozole in ER+ post-menopausal breast cancer. Mechanistic studies showed that BQ overexpression enhances androgen receptor (AR) activity, leading to hyper-activation of AR signaling and increased cell proliferation. Targeting AR can overcome anastrozole resistance in breast cancer with BQ overexpression. Clinical study also demonstrated that high nuclear expression of both BQ and AR is significantly associated with poor survival in non-steroidal aromatase inhibitor-treated ER+ breast cancer patients.
JOURNAL OF PATHOLOGY
(2023)
Review
Chemistry, Medicinal
Teesha Downton, Fiona Zhou, Davendra Segara, Rinath Jeselsohn, Elgene Lim
Summary: The translated article discusses the limitations of current endocrine therapies for ER-positive breast cancer and the mechanisms of drug resistance, focusing on ESR1 mutations. It also provides an overview of the development and research progress of oral SERDs in improving treatment outcomes.
DRUG DESIGN DEVELOPMENT AND THERAPY
(2022)
Review
Chemistry, Multidisciplinary
Chaoguo Cao, Ming He, Liguo Wang, Yuna He, Yu Rao
Summary: Proteolysis targeting chimeras (PROTACs) technology utilizes small molecules to induce ubiquitin-dependent degradation of proteins, offering a promising therapeutic strategy. However, the design and optimization of PROTACs face challenges, with a trial-and-error approach based on experience being the current general strategy. This review summarizes the principles and strategies for PROTACs design and optimization from the perspective of chemical structure design, and proposes potential future pathways for development.
CHEMICAL SOCIETY REVIEWS
(2022)
Article
Chemistry, Multidisciplinary
Xin Han, Hai-Bing Zhou, Chune Dong
Article
Chemistry, Medicinal
Xin Han, Ningyuan Sun, Haoming Wu, Deyin Guo, Po Tien, Chune Dong, Shuwen Wu, Hai-Bing Zhou
JOURNAL OF MEDICINAL CHEMISTRY
(2016)
Article
Chemistry, Medicinal
Yangbing Li, Jiuling Yang, Angelo Aguilar, Donna McEachern, Sally Przybranowski, Liu Liu, Chao-Yie Yang, Mi Wang, Xin Han, Shaomeng Wang
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Xin Han, Chao Wang, Chong Qin, Weiguo Xiang, Ester Fernandez-Salas, Chao-Yie Yang, Mi Wang, Lijie Zhao, Tianfeng Xu, Krishnapriya Chinnaswamy, James Delproposto, Jeanne Stuckey, Shaomeng Wang
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Xin-Yu Liao, Yang Lei, Song-Feng Chen, Jing Cheng, Dan Zhao, Zhi-Feng Zhang, Xin Han, Ya Zhang, Hua-Bao Liao, Yang Zhuang, Juan Chen, Hai-Bing Zhou, Qi Wan, Ying-Ying Zou
DRUG DESIGN DEVELOPMENT AND THERAPY
(2019)
Article
Chemistry, Medicinal
Xin Han, Lijie Zhao, Weiguo Xiang, Chong Qin, Bukeyan Miao, Tianfeng Xu, Mi Wang, Chao-Yie Yang, Krishnapriya Chinnaswamy, Jeanne Stuckey, Shaomeng Wang
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Oncology
Steven Kregel, Chao Wang, Xin Han, Lanbo Xiao, Ester Fernandez-Salas, Pushpinder Bawa, Brooke L. McCollum, Kari Wilder-Romans, Ingrid J. Apel, Xuhong Cao, Corey Speers, Shaomeng Wang, Arul M. Chinnaiyan
Article
Chemistry, Medicinal
Weiguo Xiang, Lijie Zhao, Xin Han, Chong Qin, Bukeyan Miao, Donna McEachern, Yu Wang, Hoda Metwally, Paul D. Kirchhoff, Lu Wang, Aleksas Matvekas, Miao He, Bo Wen, Duxin Sun, Shaomeng Wang
Summary: This study identifies a promising AR degrader for the treatment of advanced prostate cancer, which demonstrates potent inhibition in cell lines with AR gene amplification or mutations and shows good oral bioavailability in mice.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Xin Han, Lijie Zhao, Weiguo Xiang, Chong Qin, Bukeyan Miao, Donna McEachern, Yu Wang, Hoda Metwally, Lu Wang, Aleksas Matvekas, Bo Wen, Duxin Sun, Shaomeng Wang
Summary: This study outlines strategies for discovering highly potent PROTAC degraders of androgen receptor (AR) with excellent oral pharmacokinetics, successfully identifying compound ARD-2128 as the most effective in inhibiting tumor growth in mice with good oral bioavailability.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Medicine, Research & Experimental
Xiaojuan Jia, Xin Han
Summary: Inhibition of androgen receptor (AR) has been extensively studied for treating prostate cancer, but resistance mechanisms limit its efficacy. Small-molecule PROTAC AR degraders have emerged as a new therapeutic strategy to overcome resistance mechanisms. In the last two decades, potent PROTAC AR degraders have shown promising results in preclinical and clinical trials, with ARV-110 demonstrating good clinical effects in patients with mCRPC. This highlights the high clinical value of PROTAC strategy in treating human diseases. This review summarizes the recent advances in the development of potential clinical-stage PROTAC AR degraders.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Chemistry, Medicinal
Xin Han, Lijie Zhao, Weiguo Xiang, Bukeyan Miao, Chong Qin, Mi Wang, Tianfeng Xu, Donna McEachern, Jianfeng Lu, Yu Wang, Hoda Metwally, Chao-Yie Yang, Paul D. D. Kirchhoff, Lu Wang, Aleksas Matvekas, John Takyi-Williams, Bo Wen, Duxin Sun, Mark Ator, Robert Mckean, Shaomeng Wang
Summary: We report the discovery of ARD-2051, a highly potent and orally efficacious androgen receptor (AR) proteolysis-targeting chimera degrader. ARD-2051 demonstrates strong AR protein degradation activity and effectively suppresses AR-regulated genes in prostate cancer cell lines. It shows good oral bioavailability and pharmacokinetic profile in animal models. In addition, ARD-2051 inhibits tumor growth and exhibits no signs of toxicity in mice, making it a promising therapeutic option for AR+ human cancers.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Multidisciplinary
Xin Han, Yi Sun
Summary: This review focuses on the discovery and development of orally available anti-cancer PROTAC degraders, summarizing the strategies applied to this end, which may provide a reference for the future discovery of new oral-available PROTAC degraders for the treatment of various human diseases.
CELL REPORTS PHYSICAL SCIENCE
(2022)
Article
Pharmacology & Pharmacy
Zhi-Feng Zhang, Juan Chen, Xin Han, Ya Zhang, Hua-Bao Liao, Rui-Xue Lei, Yang Zhuang, Ze-Fen Wang, Zhiqiang Li, Jin-Cao Chen, Wei-Jing Liao, Hai-Bing Zhou, Fang Liu, Qi Wan
BRITISH JOURNAL OF PHARMACOLOGY
(2017)