Article
Biology
Lisa Goebel, Tonia Kirschner, Sandra Koska, Amrita Rai, Petra Janning, Stefano Maffini, Helge Vatheuer, Paul Czodrowski, Roger S. Goody, Matthias P. Mueller, Daniel Rauh
Summary: In this study, we developed nucleotide-based covalent inhibitors for the oncogenic mutant KRasG13C, which has been difficult to target in the past. These inhibitors showed promising properties and successfully locked KRasG13C in a crystal structure. Importantly, the modified KRasG13C protein with these inhibitors was unable to undergo nucleotide exchange and induce oncogenic signaling in cells, suggesting the potential use of nucleotide-based inhibitors for KRasG13C-driven cancer.
Review
Pharmacology & Pharmacy
Abhishek Guha, Saboora Waris, Louis B. Nabors, Natalia Filippova, Myriam Gorospe, Thaddaeus Kwan, Peter H. King
Summary: Glioblastoma (GBM) is a malignant brain tumor characterized by treatment resistance due to cellular and molecular heterogeneity. Targeting HuR, a regulator of posttranscriptional RNA regulation, represents a plausible therapeutic strategy for attacking GBM.
ADVANCED DRUG DELIVERY REVIEWS
(2022)
Article
Biochemistry & Molecular Biology
Benjamin Philipp Joseph, Verena Weber, Lisa Knuepfer, Alejandro Giorgetti, Mercedes Alfonso-Prieto, Sybille Krauss, Paolo Carloni, Giulia Rossetti
Summary: In this study, novel HuR inhibitors were identified using a combination of chemoinformatic methods, high-throughput virtual screening, and RNA-protein pulldown assays. The 4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoate ligand showed dose-dependent inhibition of HuR binding. This novel chemical scaffold provides a new avenue for the design of pharmaceutical agents targeting HuR.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Ying Wang, Feifei Huang, Ming Liu, Quan Zhao
Summary: UBE2C is frequently overexpressed in gastric cancer patients, primarily through high expression of UBE2C mRNA, which can inhibit gastric cancer colony formation by suppressing DNA biosynthesis. MicroRNA-300 and an RNA binding protein HuR also play a role in suppressing gastric cancer progression by reducing UBE2C mRNA abundance. Additionally, analysis of genes correlated with UBE2C expression in gastric cancer cell lines identified key genes regulated by UBE2C, contributing to its oncogenic activity.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Review
Oncology
Luca Pagliaro, Matteo Marchesini, Giovanni Roti
Summary: P-type ATPase inhibitors are widely used in modern pharmacology, but clinical translation of Ca2+ -ATPase modulators remains challenging. Recent evidence suggests that SERCA inhibitors can exert anti-leukemia effects by inhibiting Notch1 signaling.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2021)
Article
Multidisciplinary Sciences
Dali Wang, Qiwei Wang, Yuyan Wang, Peiru Chen, Xueguang Lu, Fei Jia, Yehui Sun, Tingyu Sun, Lei Zhang, Fangyuan Che, Jialu He, Liming Lian, Gemma Morano, Michael Shen, Mengqi Ren, Sijia S. Dong, Jean J. Zhao, Ke Zhang
Summary: The bottlebrush polyethylene glycol (PEG)-conjugated antisense oligonucleotides (ASOs) can effectively reduce KRAS and inhibit tumor growth, surpassing the performance of current ASO paradigms, and relaxing the requirement on ASO chemistry.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Martin A. Redhead, C. David Owen, Lennart Brewitz, Amelia H. Collette, Petra Lukacik, Claire Strain-Damerell, Sean W. Robinson, Patrick M. Collins, Philipp Schaefer, Mark Swindells, Chris J. Radoux, Iva Navratilova Hopkins, Daren Fearon, Alice Douangamath, Frank von Delft, Tika R. Malla, Laura Vangeel, Thomas Vercruysse, Jan Thibaut, Pieter Leyssen, Tu-Trinh Nguyen, Mitchell Hull, Anthony Tumber, David J. Hallett, Christopher J. Schofield, David I. Stuart, Andrew L. Hopkins, Martin A. Walsh
Summary: Effective agents to treat coronavirus infection are urgently needed to tackle COVID-19 and prepare for future outbreaks. Target identification, such as the main protease (M-pro) and papain-like protease (PLpro), is essential for protecting against future outbreaks. The discovery of non-antiviral therapeutic agents, including SDZ 224015 and Tarloxotinib, provides promising candidates for clinical evaluation in addressing COVID-19.
SCIENTIFIC REPORTS
(2021)
Review
Biochemistry & Molecular Biology
Fei Shao, Xiaonan Pang, Gyeong Hun Baeg
Summary: Breast cancer is the most common malignant tumor in women worldwide. Traditional treatments have side effects, but targeted therapies for breast cancer, focusing on the JAK/STAT signaling pathway, show promising potential. Inhibitors of JAK and STAT proteins have exhibited strong effects in inhibiting breast cancer and are being explored for clinical use.
CURRENT MEDICINAL CHEMISTRY
(2021)
Article
Oncology
Sung Jin Kim, Eun Gene Sun, Jeong A. Bae, Sehoon Park, Chang-Soo Hong, Zee-Yong Park, Hangun Kim, Kyung Keun Kim
Summary: This study reveals that KITENIN forms a homo-oligomeric complex and the intracellular C-terminal domain is crucial for this oligomerization process.
CLINICAL AND TRANSLATIONAL MEDICINE
(2022)
Article
Chemistry, Multidisciplinary
Aishwarya Vetrivel, Santhi Natchimuthu, Vidyalakshmi Subramanian, Rajeswari Murugesan
Summary: Pseudomonas aeruginosa, an opportunistic pathogen, utilizes quorum sensing to promote biofilm formation and virulent gene expression. In this study, high-throughput virtual screening identified three potential LasR inhibitors as promising candidates for treating P. aeruginosa infections. Molecular dynamics simulation confirmed the stable interaction between these compounds and the target protein LasR, validating their potential as quorum sensing inhibitors.
Review
Cell Biology
Elena G. Pasyukova, Alexander Symonenko, Olga Y. Rybina, Alexander M. Vaiserman
Summary: Developing interventions to improve healthspan is a priority for academic and public health authorities. Geroscience focuses on targeting aging as an effective way to combat age-related disorders. Epigenome-targeted interventions in geroscience research show promise in preventing and treating various aging-related conditions.
AGEING RESEARCH REVIEWS
(2021)
Article
Chemistry, Multidisciplinary
Somaye Karimian, Mohsen Shekouhy, Somayeh Pirhadi, Aida Iraji, Mahshid Attarroshan, Najmeh Edraki, Mehdi Khoshneviszadeh
Summary: In this study, a series of benzimidazole/1,3,5-triazine-2,4-diamine hybrid derivatives were designed and synthesized for the treatment of Alzheimer's disease. The compounds showed inhibitory activity against AChE, BuChE, and BACE1, and interacted with the active sites of AChE and BuChE. In silico analysis of the compounds' ADMET profiles indicated drug-like properties.
NEW JOURNAL OF CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Mariia Radaeva, Fuqiang Ban, Fan Zhang, Eric LeBlanc, Nada Lallous, Paul S. Rennie, Martin E. Gleave, Artem Cherkasov
Summary: The research focused on further developing small molecule inhibitors of AR DBD dimerization and demonstrated their improved biological activity in various assays, including mammalian two-hybrid analysis, inhibition of AR-V7 transcriptional activity, and enhanced microsomal stability. These findings provide a foundation for the development of AR inhibitors with entirely novel mechanisms of action.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Natasha Christabella Sutopo, Ji Hye Kim, Jae Youl Cho
Summary: This review discusses the biological and clinical relevance of histone methylation-modifying enzymes in skin cancer, specifically examining the roles of histone lysine methyltransferases, histone arginine methyltransferase, lysine-specific demethylases, and JmjC demethylases. Additionally, the efficacy of epigenetic inhibitors targeting histone methylation-modifying enzymes in cutaneous cancers such as basal cell carcinoma, squamous cell carcinoma, and melanoma is summarized. The authors propose these enzymes as novel targets for next-generation pharmaceuticals in the treatment of skin cancers and provide a rationale for developing epigenetic drugs specifically targeting histone methylases/demethylases in cutaneous tumors.
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
(2023)
Review
Cell Biology
Muhammed Kocak, Saba Ezazi Erdi, Guillem Jorba, Ines Maestro, Judith Farres, Vladimir Kirkin, Ana Martinez, Ole Pless
Summary: Autophagy is a conserved pathway responsible for clearing cellular debris and dysfunctional components, with implications in various human diseases. Research on autophagy modulation for therapeutic purposes is ongoing, but is hindered by the lack of selective pharmacological agents and biomarkers.
Article
Neurosciences
Rajeshwari Chellappan, Abhishek Guha, Ying Si, Thaddaeus Kwan, Louis B. Nabors, Natalia Filippova, Xiuhua Yang, Anish S. Myneni, Shriya Meesala, Ashley S. Harms, Peter H. King
Summary: Glial activation with the production of pro-inflammatory mediators is driven by HuR, an RNA regulator that plays a critical role in regulating inflammatory cytokine production in glia. The development of a small molecule inhibitor, SRI-42127, which blocks HuR's translocation, has shown promising effects in suppressing the production of pro-inflammatory mediators and microglial activation, indicating the potential for treating neurological diseases driven by this activation.
Review
Pharmacology & Pharmacy
Abhishek Guha, Saboora Waris, Louis B. Nabors, Natalia Filippova, Myriam Gorospe, Thaddaeus Kwan, Peter H. King
Summary: Glioblastoma (GBM) is a malignant brain tumor characterized by treatment resistance due to cellular and molecular heterogeneity. Targeting HuR, a regulator of posttranscriptional RNA regulation, represents a plausible therapeutic strategy for attacking GBM.
ADVANCED DRUG DELIVERY REVIEWS
(2022)
Review
Geriatrics & Gerontology
Caesar M. Hernandez, Abigail R. Hernandez, Jessica M. Hoffman, Peter H. King, Lori L. McMahon, Thomas W. Buford, Christy Carter, Jennifer L. Bizon, Sara N. Burke
Summary: The article discusses the history of neuroscience research on the neurobiology of aging and introduces gerontologists to the methodological approaches used by neuroscientists. The goal is to enhance collaboration between neuroscientists and gerontologists in order to strengthen the field of cognitive aging.
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Michael A. Lopez, Ying Si, Xianzhen Hu, Valentyna Williams, Fuad Qushair, Jackson Carlyle, Lyndsy Alesce, Michael Conklin, Shawn Gilbert, Marcas M. Bamman, Matthew S. Alexander, Peter H. King
Summary: Duchenne muscular dystrophy (DMD) is characterized by muscle instability, wasting, and fibrosis. This study found an aberrant upregulation of a signaling pathway and a decrease in specific microRNAs in DMD patient muscle cells. Inhibition of this pathway promoted muscle cell differentiation and suppressed inflammation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Clinical Neurology
Robert E. Sorge, Ying Si, Lyse A. Norian, Abhishek Guha, Grace E. Moore, L. Burt Nabors, Natalia Filippova, Xiuhua Yang, Reed Smith, Rajeshwari Chellappan, Peter H. King
Summary: Microglial activation and the production of pro-inflammatory mediators play a significant role in neuropathic pain following peripheral nerve injury. This study demonstrates that inhibiting HuR, a RNA binding protein, attenuates the production of these inflammatory mediators and reduces mechanical allodynia in mice. The systemic administration of SRI-42127, a novel HuR inhibitor, suppresses neuroinflammatory responses and shows promise as a new direction for the treatment of neuropathic pain.
Editorial Material
Oncology
Burt Nabors
Review
Neurosciences
Abhishek Guha, Mohammed Amir Husain, Ying Si, L. Burt Nabors, Natalia Filippova, Grace Promer, Reed Smith, Peter H. King
Summary: Neuroinflammation is characterized by the activation of microglia and astrocytes, leading to the production of inflammatory mediators. The regulation of mRNA stability and translational efficiency plays a crucial role in the expression of these mediators. The adenine- and uridine-rich element (ARE) present in the mRNA's untranslated region (UTR) is a key factor in this regulation. This review discusses the impact of ARE-mediated RNA regulation on glial-driven neuroinflammatory diseases.
Article
Biochemistry & Molecular Biology
Han-Cheon Kim, Yan Zhang, Peter H. H. King, Liang Lu
Summary: ALS is a fatal neurodegenerative disease characterized by motor neuron damage and TDP-43 proteinopathy. This study shows that miR-183-5p is aberrantly upregulated in ALS patients and regulates TDP-43 protein levels through the SQSTM1/p62 pathway. It provides a novel mechanism linking abnormal RNA processing and protein degradation in ALS pathogenesis.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Cell Biology
Dimitrios Tsitsipatis, Krystyna Mazan-Mamczarz, Ying Si, Allison B. Herman, Jen-Hao Yang, Abhishek Guha, Yulan Piao, Jinshui Fan, Jennifer L. Martindale, Rachel Munk, Xiaoling Yang, Supriyo De, Brijesh K. Singh, Ritchie Ho, Myriam Gorospe, Peter H. King
Summary: This study identified differentially abundant circRNAs in ALS-relevant tissues, such as muscle and spinal cord, and revealed the expression patterns of these circRNAs in different stages of the disease. These findings help understand the neuromuscular molecular programs in ALS and could potentially guide the development of therapies.
Article
Oncology
Natalia Filippova, Jeffrey M. Grimes, Jianmei W. Leavenworth, David Namkoong, Xiuhua Yang, Peter H. King, Michael Crowley, David K. Grossman, L. Burt Nabors
Summary: The study demonstrates that the TREM1(+)-myeloid-derived microenvironment plays an important role in glioblastoma heterogeneity and can serve as a therapeutic target. By inhibiting HuR dimerization, the TREM1(+)-myeloid-derived microenvironment in glioblastoma can be effectively suppressed.
NEURO-ONCOLOGY ADVANCES
(2022)