Review
Biochemistry & Molecular Biology
Regis Guieu, Clara Degioanni, Julien Fromonot, Lucille De Maria, Jean Ruf, Jean Claude Deharo, Michele Brignole
Summary: Adenosine plays a role in neuro-humoral syncope through its interaction with different receptor subtypes. The modulation of ion channels, calcium channels, and cAMP production are involved in adenosine's effects on the cardiovascular system. Adenosine receptor antagonists may be useful in the treatment of syncope.
Article
Biochemistry & Molecular Biology
Michal Zaluski, Tadeusz Karcz, Anna Drabczynska, Christin Vielmuth, Agnieszka Olejarz-Maciej, Monika Gluch-Lutwin, Barbara Mordyl, Agata Siwek, Grzegorz Satala, Christa E. Muller, Katarzyna Kiec-Kononowicz
Summary: Multitarget drugs designed with a hybrid dopamine-xanthine core have potential as drug candidates for neurodegenerative diseases. Further development of monoamine oxidase B (MAO-B) inhibitors with A(2A) adenosine receptor (A(2A)AR) antagonistic properties led to additional phosphodiesterase-4 and -10 (PDE4/10) inhibition and/or dopamine D-2 receptor (D2R) agonistic activity. The compounds showed MAO-B inhibition combined with A(2A)AR affinity, and some compounds exhibited enhanced PDE-inhibitory and D2R-agonistic activity through structural modifications. The multitarget drugs also demonstrated antioxidant properties in vitro and neuroprotective effects in a cellular model.
Review
Hematology
Ronan Lordan, Alexandros Tsoupras, Ioannis Zabetakis
Summary: Platelets play a crucial role in cardiovascular diseases by modulating inflammatory pathways that impact pro-inflammatory and coagulation processes. Current antiplatelet therapies, while effective, come with an increased risk of bleeding, prompting the need for further research into safer alternative treatments.
Article
Chemistry, Medicinal
Andrea Spinaci, Michela Buccioni, Daniela Catarzi, Chang Cui, Vittoria Colotta, Diego Dal Ben, Eleonora Cescon, Beatrice Francucci, Ilenia Grieco, Catia Lambertucci, Gabriella Marucci, Davide Bassani, Matteo Pavan, Flavia Varano, Stephanie Federico, Giampiero Spalluto, Stefano Moro, Rosaria Volpini
Summary: Through screening of a chemical library, a series of di- and tri-substituted adenine derivatives were synthesized and tested for their ability to inhibit the activity of CK1 delta and to bind ARs. The compound N-6-methyl-(2-benzimidazolyl)-2-dimethyamino-9-cyclopentyladenine (17) showed the best balance of A(2A)AR affinity and CK1 delta inhibitory activity. Computational studies were performed to simulate the protein-ligand interactions. Therefore, compound 17 could be considered a lead compound for the treatment of chronic neurodegenerative and cancer diseases with synergistic effects.
Article
Chemistry, Multidisciplinary
Jonas Gossen, Rui Pedro Ribeiro, Dirk Bier, Bernd Neumaier, Paolo Carloni, Alejandro Giorgetti, Giulia Rossetti
Summary: This study presents an approach that combines structural data with a random forest agonist/antagonist classifier and a signal-transduction kinetic model to identify novel chemotype ligands. As a test case, the approach is applied to identify novel antagonists of the human adenosine transmembrane receptor type 2A, a target against Parkinson's disease and cancer.
Article
Medicine, General & Internal
Eleni Vrigkou, Argirios Tsantes, Dimitrios Konstantonis, Evdoxia Rapti, Eirini Maratou, Athanasios Pappas, Panagiotis Halvatsiotis, Iraklis Tsangaris
Summary: This study evaluated platelet and coagulation function in patients with chronic thromboembolic pulmonary hypertension (CTEPH), and found abnormalities in platelet aggregation, fibrinolysis, thrombin generation, and other clot formation markers in these patients.
Article
Chemistry, Medicinal
Giuseppe Faudone, Silvia Arifi, Daniel Merk
Summary: Caffeine is a widely consumed psychostimulant drug with multiple beneficial pharmacological activities, especially in neurodegenerative diseases. Despite being extensively studied, the mechanistic understanding of caffeine's pharmacological effects is incomplete, with continuously discovered new protein interactions providing potential for improved understanding and future medicinal chemistry. The diversity of caffeine's molecular activities on receptors and enzymes in the CNS indicates a complex interplay of mechanisms contributing to neuroprotective effects.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Weixia Li, Baichun Hu, Haihan Liu, Jiasi Luan, Lu Chen, Shizun Wang, Liye Fan, Jian Wang
Summary: Adenosine A(1) receptor and adenosine A(2A) receptor play different roles in regulating arteriolar pressure and urine flow as well as relieving neurodegenerative disorders. Understanding their selective inhibition mechanisms is crucial for the rational design of selective inhibitors.
NEW JOURNAL OF CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Monika Kubacka, Szczepan Mogilski, Marek Bednarski, Krzysztof Pociecha, Artur Swierczek, Noemi Nicosia, Jakub Schabikowski, Michal Zaluski, Grazyna Chlon-Rzepa, Joerg Hockemeyer, Christa E. Mueller, Katarzyna Kiec-Kononowicz, Magdalena Kotanska
Summary: The platelet aggregation inhibitory activity of selected xanthine-based adenosine A(2A) and A(2B) receptor antagonists was investigated, and the compounds were found to act as moderately potent non-selective inhibitors of phosphodiesterases (PDEs). The highest inhibitory activity against PDE3A was observed in TB-42, along with moderate activity against PDE2A and PDE5A. The antiplatelet activity of the compounds may be due to inhibition of PDEs, leading to increased cAMP and/or cGMP concentrations in platelets.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Hematology
Monica Sacco, Stefano Lancellotti, Alessio Branchini, Maira Tardugno, Maria Francesca Testa, Barbara Lunghi, Francesco Bernardi, Mirko Pinotti, Betti Giusti, Giancarlo Castaman, Raimondo De Cristofaro
Summary: This study investigates a case of low VWF phenotype in an Italian woman and characterizes it from a genetic and biochemical perspective. The study identifies a genetic mutation and a scavenger receptor-related gene variant that impact the clearance of VWF.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Cell Biology
Jing Yang, Claudio Mapelli, Zhaoqing Wang, Chi Shing Sum, Ji Hua, R. Michael Lawrence, Yan Ni, Dietmar A. Seiffert
Summary: Protease-activated receptor 4 (PAR4) is a promising drug target for improving the efficacy and safety of antiplatelet agents. However, the current PAR4 agonist peptides have limited utility in pharmacodynamic assays due to their high concentrations required to elicit an agonist response. This study developed a more potent PAR4 agonist peptide and a platelet aggregation assay for evaluating PAR4 antagonists, providing a valuable tool for the clinical development of PAR4 antagonists.
Article
Biochemical Research Methods
Mukuo Wang, Shujing Hou, Yu Wei, Dongmei Li, Jianping Lin
Summary: Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system. Dual adenosine A(1)/A(2A) receptor antagonists provide a possible effective therapy that can simultaneously solve motor symptoms and nonmotor symptoms in the medical treatment of PD. In this study, a multistage virtual screening approach involving deep learning, pharmacophore models, and molecular docking methods identified two 1,2,4-triazole derivatives as dual adenosine A(1) and A(2A) receptor antagonists. The results of molecular dynamics (MD) simulations showed strong binding interactions between the adenosine A(1)/A(2A) receptors and the compounds.
PLOS COMPUTATIONAL BIOLOGY
(2021)
Review
Chemistry, Medicinal
Ewelina Krolicka, Katarzyna Kiec-Kononowicz, Dorota Lazewska
Summary: With the increasing life expectancy, there is a significant rise in the number of people suffering from neurodegenerative diseases (ND). Parkinson's disease (PD), the second most common ND after Alzheimer's disease, is characterized by motor and non-motor symptoms that severely impact patients' lives. Current therapies can only alleviate symptoms and slow down disease progression, but cannot effectively cure it. Therefore, it is important to understand the mechanism and causes of PD and find potent treatment strategies. This review focuses on chalcones and related structures as potential therapeutics for PD, exploring their enzyme inhibitory properties, anti-neuroinflammatory activity, and receptor antagonism.
Article
Chemistry, Medicinal
Andrea Spinaci, Michela Buccioni, Diego Dal Ben, Federica Maggi, Gabriella Marucci, Beatrice Francucci, Giorgio Santoni, Catia Lambertucci, Rosaria Volpini
Summary: The study identified a potential anti-tumor agent that exhibited significant cytostatic activity on prostate cancer cell lines, suggesting it could become a new approach in diagnosis and treatment.
Article
Chemistry, Organic
Ramakotaiah Mulamreddy, Xin Hou, Sylvain Chemtob, William D. Lubell
Summary: The synthesis of 6-hydroxymethyl indolizidin-2-one amino acids from L-serine involves 10 steps, including intramolecular ring opening and lactam formation. X-ray analyses showed ideal peptide geometry, and the analogue exhibited inhibitory activity on myometrial contractility within a prostaglandin-F-2 alpha receptor modulator.
Letter
Hematology
Sonia Esparza, Benyam Muluneh, Jonathan Galeotti, Melissa Matson, Daniel R. Richardson, Nathan D. Montgomery, Catherine C. Coombs, Katarzyna Jamieson, Matthew C. Foster, Joshua F. Zeidner
BRITISH JOURNAL OF HAEMATOLOGY
(2020)
Article
Oncology
Joshua F. Zeidner, Hanna A. Knaus, Amer M. Zeidan, Amanda L. Blackford, Raul Montiel-Esparza, Hubert Hackl, Gabrielle T. Prince, Lukasz P. Gondek, Gabriel Ghiaur, Margaret M. Showel, Amy E. DeZern, Keith W. Pratz, B. Douglas Smith, Mark J. Levis, Steven Gore, Catherine C. Coombs, Matthew C. Foster, Howard Streicher, Judith E. Karp, Leo Luznik, Ivana Gojo
Editorial Material
Oncology
Joshua F. Zeidner
CLINICAL CANCER RESEARCH
(2020)
Article
Oncology
Joshua F. Zeidner, Daniel J. Lee, Mark Frattini, Gil D. Fine, Judy Costas, Kathryn Kolibaba, Stephen P. Anthony, David Bearss, B. Douglas Smith
Summary: Alvocidib, when combined with 7+3 induction therapy, shows promising clinical activity in newly diagnosed acute myeloid leukemia patients, indicating the potential for further investigation of Alvocidib combinations in this population.
CLINICAL CANCER RESEARCH
(2021)
Letter
Oncology
Mikkael A. Sekeres, Justin Watts, Atanas Radinoff, Montserrat Arnan Sangerman, Marco Cerrano, Patricia Font Lopez, Joshua F. Zeidner, Maria Diez Campelo, Carlos Graux, Jane Liesveld, Dominik Selleslag, Nikolay Tzvetkov, Robert J. Fram, Dan Zhao, Jill Bell, Sharon Friedlander, Douglas V. Faller, Lionel Ades
Review
Oncology
Daniel R. Richardson, Steven D. Green, Matthew C. Foster, Joshua F. Zeidner
Summary: Secondary acute myeloid leukemia (s-AML) is a distinct subgroup of AML with poor outcomes despite recent advances in treatment. Patients with s-AML who have received prior hypomethylating agent (HMA) therapy have limited treatment options and are underrepresented in clinical trials. Novel therapeutic options for this population are critically needed.
CURRENT HEMATOLOGIC MALIGNANCY REPORTS
(2021)
Review
Pharmacology & Pharmacy
Davis F. Phillips, Joshua F. Zeidner
Summary: Patients with AML-MRC historically have poor outcomes with conventional chemotherapy regimens. Although CPX-351 has shown to significantly improve response rates and survival, there is still an unmet need for developing novel therapeutic strategies for this patient population. Emerging therapies such as immunotherapeutic strategies, small-molecule inhibitors, and targeted agents show promise in improving outcomes for AML-MRC patients, with a need for more clinical trials focused specifically on this population.
EXPERT OPINION ON EMERGING DRUGS
(2021)
Letter
Oncology
Lori A. Ramkissoon, Kaitlyn Buhlinger, Angela Nichols, Catherine C. Coombs, Matthew C. Foster, Jonathan Galeotti, Kathleen Kaiser-Rogers, Daniel R. Richardson, Nathan D. Montgomery, Joshua F. Zeidner
LEUKEMIA & LYMPHOMA
(2021)
Review
Hematology
Manuel Ricardo Espinoza-Gutarra, Steven D. Green, Joshua F. Zeidner, Heiko Konig
Summary: AML, a neoplastic transformation of hematopoietic stem cells, has seen therapeutic progress due to recent advances in genomic classification leading to new drug approvals. CD123 is a promising therapeutic target for improving AML patient outcomes, with ongoing clinical trials evaluating various targeted strategies.
EXPERT REVIEW OF HEMATOLOGY
(2021)
Correction
Oncology
Mikkael A. Sekeres, Justin Watts, Atanas Radinoff, Montserrat Arnan Sangerman, Marco Cerrano, Patricia Font Lopez, Joshua F. Zeidner, Maria Diez Campelo, Carlos Graux, Jane Liesveld, Dominik Selleslag, Nikolay Tzvetkov, Robert J. Fram, Dan Zhao, Jill Bell, Sharon Friedlander, Douglas V. Faller, Lionel Ades
Letter
Oncology
Joshua F. Zeidner, Tara L. Lin, Carlos E. Vigil, Gil Fine, M. Yair Levy, Aziz Nazha, Jordi Esteve, Daniel J. Lee, Karen Yee, Andrew Dalovisio, Eunice S. Wang, Juan M. Bergua Burgues, Jeffrey Schriber, Mark R. Litzow, Olga Frankfurt, Teresa Bernal Del Castillo, Vijaya Raj Bhatt, Bhavana Bhatnagar, Priyanka Mehta, Richard Dillon, Maria Vidriales Vicente, Stephen Anthony, David Bearss, Pau Montesinos, B. Douglas Smith
BLOOD CANCER JOURNAL
(2021)
Article
Hematology
Nathan D. Montgomery, Jonathan Galeotti, Steven M. Johnson, Leah Commander, Eric T. Weimer, Pranil K. Chandra, Tariq Nazir, Thomas B. Alexander, Joshua F. Zeidner, Matthew C. Foster
Summary: A rare case of bilineal hematologic malignancy in a woman with B-lymphoblastic leukemia demonstrated evidence of both myeloid and lymphoid differentiation, suggesting a common precursor mutation in the U2AF1 gene. Targeted sequencing revealed distinct mutations in B-lymphoblasts and myeloid cells, indicating a process of divergent evolution and bilineal differentiation. This highlights the potential utility of fractionated sequencing in characterizing acute leukemia.
Editorial Material
Oncology
Steven D. Green, Joshua F. Zeidner
Summary: Azacitidine and venetoclax are commonly used as first-line treatment for newly diagnosed unfit acute myeloid leukemia (AML) patients. However, in patients with TP53 mutations and poor-risk cytogenetics, the addition of venetoclax to azacitidine does not provide significant benefits. It is important to consider alternative treatment regimens for these patients.
CLINICAL CANCER RESEARCH
(2022)
Review
Hematology
Anson Snow, Joshua F. Zeidner
Summary: Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder with limited treatment options. Pevonedistat, a novel inhibitor of NEDD8 activating enzyme, has shown promising potential in improving clinical outcomes by inhibiting the cell cycle and inducing apoptosis.
THERAPEUTIC ADVANCES IN HEMATOLOGY
(2022)
Article
Oncology
Joshua F. Zeidner, Benjamin G. Vincent, Anastasia Ivanova, Dominic Moore, Karen P. McKinnon, Alec D. Wilkinson, Rupkatha Mukhopadhyay, Francesco Mazziotta, Hanna A. Knaus, Matthew C. Foster, Catherine C. Coombs, Katarzyna Jamieson, Hendrik Van Deventer, Jonathan A. Webster, Gabrielle T. Prince, Amy E. DeZern, B. Douglas Smith, Mark J. Levis, Nathan D. Montgomery, Leo Luznik, Jonathan S. Serody, Ivana Gojo
Summary: The study demonstrated that pembrolizumab following high-dose cytarabine in relapsed/refractory AML patients was well-tolerated and feasible, showing promising clinical activity, especially in refractory AML and those receiving treatment as first salvage regimen. Further exploration of pembrolizumab and other immune-checkpoint blockade strategies post cytotoxic chemotherapy is recommended in AML.
BLOOD CANCER DISCOVERY
(2021)