Article
Multidisciplinary Sciences
Yuanyuan Qiao, Jesse W. Wotring, Yang Zheng, Charles J. Zhang, Yuping Zhang, Xia Jiang, Carla D. Pretto, Sanjana Eyunni, Abhijit Parolia, Tongchen He, Caleb Cheng, Xuhong Cao, Rui Wang, Fengyun Su, Stephanie J. Ellison, Yini Wang, Jun Qin, Honghua Yan, Qianxiang Zhou, Liandong Ma, Jonathan Z. Sexton, Arul M. Chinnaiyan
Summary: Early in the COVID-19 pandemic, it was observed that males had a higher risk of severe disease and androgen deprivation therapy could provide protection. Proxalutamide, an androgen receptor antagonist, exhibited similar effects as enzalutamide in decreasing AR signaling and inhibiting SARS-CoV-2 infection. Proxalutamide also protected against lung inflammation and cell death.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Yue Gu, Mengxia Xue, Qizhi Wang, Xiaodan Hong, Xinyu Wang, Fang Zhou, Jianguo Sun, Guangji Wang, Ying Peng
Summary: This study evaluated the potential efficacy of proxalutamide as a novel therapy strategy for prostate cancer. Proxalutamide demonstrated superior inhibitory effects on proliferation and migration of PCa cells, induced apoptosis, reduced lipid accumulation, inhibited de novo lipogenesis, and decreased AR expression. By co-targeting the AR axis and endogenous adipogenesis, proxalutamide offers a promising approach to combat drug resistance and prolong the clinical service life of AR-targeted therapy for PCa.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(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
Oncology
Tie Zhou, Shengfei Qin, Weidong Xu, Shouyan Tang, Guanghua Chen, Song Li, Jianguo Hou, Xu Gao, Guowei Shi, Zhongquan Sun, Jie Jin, Lijun Chen, Weibing Sun, Ben Liu, Jingen Wang, Qinggui Meng, Dongwen Wang, Zhiquan Hu, Dalin He, Yong Yang, Xishuang Song, Cheng Fu, Yinhuai Wang, Dingwei Ye, Wei Zhang
Summary: This study assessed the safety and efficacy of proxalutamide, a novel androgen receptor antagonist, in men with metastatic castration-resistant prostate cancer (mCRPC). By evaluating various endpoints, it was found that the 200 mg dose group showed the best antitumor activity with manageable safety. Therefore, a daily dose of 200 mg proxalutamide is recommended for future phase 3 trials.
INTERNATIONAL JOURNAL OF CANCER
(2023)
Article
Medicine, General & Internal
John McCoy, Andy Goren, Flavio Adsuara Cadegiani, Sergio Vano-Galvan, Maja Kovacevic, Mirna Situm, Jerry Shapiro, Rodney Sinclair, Antonella Tosti, Andrija Stanimirovic, Daniel Fonseca, Edinete Dorner, Dirce Costa Onety, Ricardo Ariel Zimerman, Carlos Gustavo Wambier
Summary: The use of proxalutamide as an androgen receptor antagonist in men with COVID-19 has shown to significantly reduce the hospitalization rate, with a 91% reduction compared to usual care.
FRONTIERS IN MEDICINE
(2021)
Article
Oncology
Cristina Aguirre-Portoles, Riley Payne, Aspen Trautz, J. Kevin Foskett, Christopher A. Natale, John T. Seykora, Todd W. Ridky
Summary: Testosterone signaling through ZIP9 mediates some of the sex differences in melanoma, and drugs that target AR can be repurposed to block ZIP9 and inhibit melanoma in males.
Article
Biochemistry & Molecular Biology
Ao Wang, Yawan Wang, Xin Meng, Yushe Yang
Summary: Prostate cancer is the most common malignancy in men worldwide. In this study, novel thiohydantoin derivatives of enzalutamide were designed and synthesized, with compound 31c identified as a more potent AR antagonist than enzalutamide. The data suggest that 31c could be a promising lead compound for the treatment of prostate cancer.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
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
Takashi Matsuoka, Aiko Sugiyama, Yoshifumi Miyawaki, Yusuke Hidaka, Yukiko Okuno, Hiroaki Sakai, Hiroki Tanaka, Kiyotsugu Yoshikawa, Tomohiro Fukui, Kei Mizuno, Takayuki Sumiyoshi, Takayuki Goto, Takahiro Inoue, Shusuke Akamatsu, Takashi Kobayashi, Eijiro Nakamura
Summary: In this study, new CRPC cell lines AILNCaP14 and AILNCaP15 were established, which showed higher levels of AR and PSA expression and primary resistance to enzalutamide. Through GFP fluorescence-based screening, the broad-spectrum CDK inhibitor flavopiridol was identified as a potential drug for inhibiting the proliferation of CRPC cells. Flavopiridol also successfully suppressed tumor growth of CRPC in in vivo experiments. The data suggested that broad-spectrum CDK inhibitors might be effective candidate drugs for the treatment of CRPC.
Article
Oncology
Huiping Li, Guohong Song, Qiaoxia Zhou, Ran Ran, Hanfang Jiang, Ruyan Zhang, Yaxin Liu, Jiayang Zhang, Luping Meng, Liandong Ma, Ye Sun, Meiyu Wang, Qingqing Zhou, Honghua Yan, Qianxiang Zhou, Xunwei Dong, Youzhi Tong
Summary: GT0918 effectively suppresses AR-positive breast cancer tumor growth in animal models and shows good tolerability and pharmacokinetic profile in clinical studies at an appropriate dose level.
BREAST CANCER RESEARCH AND TREATMENT
(2021)
Article
Chemistry, Medicinal
Jan Vietor, Christian Gege, Tanja Stiller, Romy Busch, Espen Schallmayer, Hella Kohlhof, Georg Hoefner, Joerg Pabel, Julian A. Marschner, Daniel Merk
Summary: Nuclear receptor related 1 (Nurr1) is a neuro-protective transcription factor with potential therapeutic implications for neuro-degenerative diseases. We discovered that the clinically studied dihydroorotate dehydrogenase (DHODH) inhibitor vidofludimus calcium can activate Nurr1 effectively and optimized this scaffold to develop a superior Nurr1 agonist. This optimized compound showed strong activation efficacy, nanomolar potency, and selectivity for Nurr1 over Nur77 and NOR1, making it a valuable tool for studying Nurr1 activation in vitro and in vivo.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Endocrinology & Metabolism
Jia-Ming Wang, Zhen-Fang Li, Wan-Xi Yang
Summary: The androgen receptor signaling pathway is crucial for spermatogenesis in the testes. Sertoli cells, the only somatic cell type in seminiferous tubules, are regulated by this pathway, which affects both Sertoli and germ cells. The pathway plays roles in Sertoli cell proliferation and maturation, as well as the integrity of the blood-testis barrier. Meiotic and post-meiotic processes are also regulated by this pathway, ensuring the development and release of mature sperm.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Engineering, Environmental
Yi Zhao, Xue-Nan Li, Hao Zhang, Jia-Gen Cui, Jia-Xin Wang, Ming-Shan Chen, Jin-Long Li
Summary: Male infertility is a significant concern due to the decline in sperm quality worldwide. Phthalates, particularly DEHP or its metabolite MEHP, have negative effects on male reproductive development and function, leading to reduced fertility. Lycopene, a natural antioxidant, has the potential to be used as a therapeutic option for male infertility. This research demonstrates that DEHP reduces testosterone production in Leydig cells and impairs secretory function in Sertoli cells, resulting in impaired spermatogenesis. Additionally, MEHP causes mitochondrial and oxidative damage, posing a serious threat to spermatogenesis. However, LYC supplementation reverses these changes. Mechanistically, DEHP disrupts the T/AR signaling pathway, contributing to male infertility. Overall, this study highlights the critical role of the T/AR signal transduction in male fertility and provides promising insights into the protective role of LYC in phthalate-induced male reproductive disorders.
JOURNAL OF HAZARDOUS MATERIALS
(2022)
Article
Chemistry, Multidisciplinary
Tian-bang Wu, Qiu-ping Xiang, Chao Wang, Chun Wu, Cheng Zhang, Mao-feng Zhang, Zhao-xuan Liu, Yan Zhang, Lin-jiu Xiao, Yong Xu
Summary: In this study, a novel selective BET inhibitor, 6-(3,5-dimethylisoxazol-4-yl)benzo[cd]indol-2(1H)-one derivative, was designed, synthesized, and demonstrated to have potent inhibitory effects on prostate cancer cells with high selectivity. This molecule, represented by compound 19 (Y06014), showed promising potential as a small molecule probe for further validation of BET as a molecular target for PC drug development.
ACTA PHARMACOLOGICA SINICA
(2021)
Letter
Immunology
Angela Londero, Marta Fusi, Marika Cinausero, Carlo Tascini, Cristina Gervasoni, Dario Cattaneo
Summary: Enzalutamide, an androgen receptor inhibitor used for prostate cancer treatment, may interact with some antiretrovirals. However, this case report found no significant pharmacokinetic differences in the main antiretrovirals, dolutegravir and tenofovir, after the introduction of enzalutamide, even at higher doses.