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
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
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
Multidisciplinary Sciences
Wooi F. Lim, Mitra Forouhan, Thomas C. Roberts, Jesse Dabney, Ruth Ellerington, Alfina A. Speciale, Raquel Manzano, Maria Lieto, Gavinda Sangha, Subhashis Banerjee, Mariana Conceicao, Lara Cravo, Annabelle Biscans, Loic Roux, Naemeh Pourshafie, Christopher Grunseich, Stephanie Duguez, Anastasia Khvorova, Maria Pennuto, Constanza J. Cortes, Albert R. La Spada, Kenneth H. Fischbeck, Matthew J. A. Wood, Carlo Rinaldi
Summary: SBMA is a neuromuscular disease caused by a polyQ expansion in AR protein, with recent studies highlighting the importance of mutant AR-altered transcriptional activity. Targeting AR isoform 2 can ameliorate the disease phenotype in SBMA mice by restoring dysregulated transcriptional activity of polyQ AR protein.
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)
Article
Biochemistry & Molecular Biology
Zhihui Qin, Siyu Ou, Liping Xu, Kathleen Sorensen, Yingxue Zhang, Dan-Ping Hu, Zhe Yang, Wen-Yang Hu, Fei Chen, Gail S. Prins
Summary: The study designed a novel hybrid AR antagonist and combined it with a GSH synthesis inhibitor to efficiently treat CRPC. The drug combination induced ferroptosis, increased intracellular free iron ions, weakened cellular defense mechanisms, and cooperatively downregulated AR to enhance efficacy against CRPC.
CHEMICAL BIOLOGY & DRUG DESIGN
(2021)
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
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
Medicine, Research & Experimental
Neetu Saxena, Eliana Beraldi, Ladan Fazli, Syam Prakash Somasekharan, Hans Adomat, Fan Zhang, Chidi Molokwu, Anna Gleave, Lucia Nappi, Kimberly Nguyen, Pavn Brar, Nicholas Nikesitch, Yuzhuo Wang, Colin Collins, Poul H. Sorensen, Martin Gleave
Summary: This study reveals that after AR pathway inhibition, acute adaptive responses support the reactivation of AR and the development of PCa by regulating SDH activity and Hsp27 protein. Co-targeting AR and Hsp27 can enhance the sensitivity of PCa cells to ARPI treatments.
EMBO MOLECULAR MEDICINE
(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.
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
Chemistry, Medicinal
Qian Li, Tao Zhang, Peiran Song, Linjiang Tong, Fang Feng, Jing Guo, Yang Zhou, Hua Xie, Xiaoyun Lu
Summary: A series of novel selective ACK1 inhibitors were developed, and compound 10zi showed potent anti-tumor effect in NSCLC cells and synergistic activity in combination with ASK120067.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
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
Chemistry, Organic
Sara Meninno, Alessandra Lattanzi
Summary: A one-pot multicomponent reaction, involving Knoevenagel reaction, asymmetric epoxidation, and domino ring-opening cyclization, has been developed for the synthesis of 3-aryl/alkyl piperazin-2-ones and morpholin-2-ones. The reaction proceeds in good yields (38-90%) and high enantioselectivity (up to 99% ee), with two out of three steps being catalyzed by a quinine derived urea. The method has also been applied to the enantioselective synthesis of a key intermediate for the antiemetic drug Aprepitant.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Xiujin Chang, Di Zhang, Fangui Qu, Youquan Xie, Tian Chen, Yuqing Zhang, Qianming Du, Jinlei Bian, Zhiyu Li, Jubo Wang, Xi Xu
Summary: Prostate cancer (PC) is a common cancer in men, and androgen receptor (AR) is a validated drug target for PC treatment. However, PC often becomes resistant to AR antagonists, so there is a need for novel drugs. A new AR antagonist, molecule 26h, was discovered with improved antagonistic activity and potent degradation of AR. It also blocks AR nuclear translocation and inhibits AR/AR-V7 heterodimerization, leading to inhibition of gene transcription. In xenograft models, 26h showed potent efficacy against PC.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)