Review
Pharmacology & Pharmacy
Xiuying Ren, Zhi Lin, Wensu Yuan
Summary: This review focuses on recent research progress in the structural and functional studies of the TNFRSF member, death receptor 6 (DR6), to gain a better understanding of DR6-mediated signaling and the treatment of DR6-related diseases.
FRONTIERS IN PHARMACOLOGY
(2022)
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
Oncology
Elizabeth Thomas, Retheesh S. Thankan, Puranik Purushottamachar, David J. Weber, Vincent C. O. Njar
Summary: In this study, the researchers demonstrate the potential role of VNPP433-3 beta as a molecular glue that brings Androgen Receptor and MDM2 E3 ligase physically close in prostate cancer cells. This interaction promotes the degradation of AR through ubiquitination and inhibits the growth of prostate cancer cells.
Article
Biotechnology & Applied Microbiology
Tomohiro Kagi, Rio Naganuma, Aya Inoue, Takuya Noguchi, Shuhei Hamano, Yuto Sekiguchi, Gi-Wook Hwang, Yusuke Hirata, Atsushi Matsuzawa
Summary: Polymyxin B (PMB) is a potent antibiotic against multidrug-resistant bacteria, but its clinical use is limited due to serious side effects like nephrotoxicity and neurotoxicity. This study found that PMB induces necrosis and inflammatory cytokine release in macrophages, potentially contributing to organ toxicity. This provides novel insights into the mechanisms of PMB-related adverse effects.
JOURNAL OF ANTIBIOTICS
(2022)
Article
Cell Biology
Mohamed A. Eldeeb, Wenbin Zhou, Mansoore Esmaili, Alaa M. Elgohary, Hai Wei, Richard P. Fahlman
Summary: Cellular signalling leads to apoptotic pathways and caspase activation, resulting in the generation of protein fragments with new functions. These proteolytically activated protein fragments can be degraded by the N-degron degradation pathways. The stability of the pro-apoptotic fragment of PKC-theta was investigated, revealing that it is unstable due to its N-terminal lysine targeting it for proteasomal degradation. Inhibition of N-degron degradation enhanced the apoptosis-inducing effect of staurosporine.
CELLULAR SIGNALLING
(2023)
Article
Endocrinology & Metabolism
Amani A. Mahbub, Akhmed Aslam, Mohamed E. Elzubier, Mohamed El-Boshy, Abdelghany H. Abdelghany, Jawwad Ahmad, Shakir Idris, Riyad Almaimani, Aiman Alsaegh, Mahmoud Zaki El-Readi, Mohammed A. Baghdadi, Bassem Refaat
Summary: The study found that the individual use of E2 and P4 can inhibit the development of colorectal cancer, showing good anti-tumor effects in male mice and cell experiments. The combination of the two shows a stronger anti-cancer effect.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Multidisciplinary Sciences
Wandayi Emmanuel Amlabu, Cynthia Mmalebna Amisigo, Christine Achiaa Antwi, Gordon Akanzuwine Awandare, Theresa Manful Gwira
Summary: Leishmaniasis, closely associated with poverty, is a disease that requires new chemotherapeutic approaches. This study evaluated the antileishmanial potency of eighteen compounds and found that some of them exhibited cytotoxic effects on the parasites, affecting their biology. Further in vivo studies are recommended to validate the findings.
Article
Biochemistry & Molecular Biology
Dhirodatta Senapati, Vikas Sharma, Santosh Kumar Rath, Uddipak Rai, Naresh Panigrahi
Summary: The article discusses the role of the androgen receptor in prostate cancer and the mechanisms of resistance. It highlights the plasticity of AR-DNA binding and emphasizes the importance of developing alternative strategies to antagonize AR activity.
Article
Chemistry, Multidisciplinary
Frances P. Rodriguez-Rivera, Samuel M. Levi
Summary: Small molecule degraders have the potential to catalytically destroy target proteins at substoichiometric concentrations, lowering administered doses and extending pharmacological effects. However, a holistic framework that evaluates different degradation modes from a catalytic perspective is currently lacking.
ACS CENTRAL SCIENCE
(2021)
Article
Biology
Lei Yuan, Peiyao Li, Huiru Jing, Qian Zheng, Hui Xiao
Summary: This study reveals a unique mechanism for maintaining appropriate levels of the phagocytic receptor CED-1, which is responsible for apoptotic cell clearance. The E3 ubiquitin ligase TRIM-21, along with other proteins, catalyzes the poly-ubiquitination of CED-1, leading to its degradation and maintaining its proper levels for effective cell corpse clearance.
Article
Chemistry, Medicinal
Hongxi Wu, Jie Ren, Lulu Zhao, Zhiyu Li, Wanli Ye, Yong Yang, Jubo Wang, Jinlei Bian
Summary: Prostate cancer is a common malignancy in men worldwide, and treatment targeting androgen receptor has been a focus for decades. The approved AR antagonists have similar chemical structures and mechanisms, leading to resistance issues. Novel chemical structures of AR antagonists are being explored to overcome resistance and develop new treatments.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Yingying Li, Xiyou Du, Xinru Kong, Yuelin Fang, Zhijing He, Dongzhu Liu, Hang Wu, Jianbo Ji, Xiaoye Yang, Lei Ye, Guangxi Zhai
Summary: This study proposes a novel nanoplatform based on the autophagy cascade to overcome the obstacles in chemo-immunotherapy. The platform combines chemotherapy and starvation therapy to initiate pro-death autophagy and enhance antigen presentation, while also remodeling the immunosuppressive tumor microenvironment. Furthermore, the study discovers a new therapeutic direction for the respiration inhibitor 3-bromopyruvic acid (3BP) in cancer treatment. Overall, this study offers an opportunity to improve antitumor efficacy and boost immune responses.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Biochemistry & Molecular Biology
Zhen Li, Yajing Duan, Wenhui Mao, Cheng Chen, Wensu Yuan, Xinghua Jin, Shuo Shi, Xun-Cheng Su, Carlos F. Ibanez, Zhi Lin
Summary: The p75 neurotrophin receptor contains a death domain (DD) that plays a crucial role in apoptotic and inflammatory signaling. Conflicting findings and controversy exist regarding the oligomeric states of the p75NTR-DD. However, new evidence from biophysical and biochemical studies demonstrates the coexistence of symmetric and asymmetric dimers of the p75NTR-DD, which can equilibrate with the monomeric form in solution. This reversible behavior may be important for the intracellular signaling function of the p75NTR-DD.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Multidisciplinary Sciences
Julianna R. Cresti, Abramo J. Manfredonia, Christopher E. Braganca, Joseph A. Boscia, Christina M. Hurley, Mary D. Cundiff, Daniel A. Kraut
Summary: The 26S proteasome, responsible for protein degradation in eukaryotic cells, transitions between substrate-accepting and substrate-processing conformations, with important intramolecular interactions stabilizing these conformations. A new conformationally sensitive assay revealed that interactions involving Rpn5 and Rpn2 are crucial for stabilizing substrate-processing conformations, impacting the proteasome's ability to successfully unfold and degrade difficult substrates.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Oncology
Kimberley Katleba, Alan P. Lombard, Maria-Malvina Tsamouri, Han Bit Baek, Kristine S. Nishida, Stephen J. Libertini, Alexander J. Platero, Ai-Hong Ma, Chong-xian Pan, Paramita M. Ghosh, Maria Mudryj
Summary: Bladder cancer cells express low molecular weight AR isoforms, including a novel AR-LMW variant AR-v19, which play a role in promoting cell survival and transcriptional activation in the nucleus. Targeting AR or its downstream effectors may be a potential therapeutic strategy for treating this malignancy.