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Targets, Volume 3, Issue 2 (June 2025) – 2 articles

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15 pages, 2964 KiB  
Article
Semisynthetic Flavonoids as GSK-3β Inhibitors: Computational Methods and Enzymatic Assay
by Heberth de Paula, Fernanda Souza, Lara Ferreira, Jéssica A. B. Silva, Rayssa Ribeiro, Juliana Vilachã, Flávio S. Emery, Valdemar Lacerda, Jr. and Pedro A. B. Morais
Targets 2025, 3(2), 13; https://doi.org/10.3390/targets3020013 - 15 Apr 2025
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Abstract
Glycogen synthase kinase-3 beta (GSK-3β) plays a crucial role in multiple cellular processes and is implicated in different types of cancers and neurological disorders, including Alzheimer’s disease. Despite extensive efforts to develop novel GSK-3β inhibitors, the discovery of potent and selective lead compounds [...] Read more.
Glycogen synthase kinase-3 beta (GSK-3β) plays a crucial role in multiple cellular processes and is implicated in different types of cancers and neurological disorders, including Alzheimer’s disease. Despite extensive efforts to develop novel GSK-3β inhibitors, the discovery of potent and selective lead compounds remains a challenge. In this study, we evaluated the GSK-3β inhibitory potential of semisynthetic flavonoid derivatives, which exhibited sub-micromolar activity. To gain further insights, we employed molecular docking, molecular dynamics simulations, and pharmacokinetic profile predictions. The docking studies revealed that the most potent inhibitor, compound 10, establishes key interactions with the ATP-binding site. Molecular dynamics simulations further confirmed that compound 10 maintains stable interactions with GSK-3β throughout the simulation. Additionally, pharmacokinetic predictions identified compound 3 as a promising candidate for Alzheimer’s disease therapy due to its ability to cross the blood–brain barrier. These findings suggest that, within the studied flavonoid derivatives, these compounds (particularly 10 and 3) hold potential as lead compounds for GSK-3β inhibition. The combination of strong enzymatic inhibition, stable binding interactions, and favorable pharmacokinetic properties highlights their promise for further development in cancer and neurodegenerative disease research. Full article
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Case Report
Rapid Response with Daratumumab for Pure Red Cell Aplasia in a Case of Aplastic Anemia with Mixed Chimerism After ABO-Mismatched Stem Cell Transplant
by Martina Canichella, Luca Cupelli, Mariagiovanna Cefalo, Cinzia Sparapani, Antonella Matteocci, Giuseppe Ausoni, Paola Zambardi, Flavia Cantoni, Vanessa Velotta, Giovanna Suppo and Paolo de Fabritiis
Targets 2025, 3(2), 12; https://doi.org/10.3390/targets3020012 - 3 Apr 2025
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Abstract
Pure red cell aplasia (PRCA) following major ABO-mismatched allogeneic hematopoietic stem cell transplantation (HSCT) is a challenging complication, affecting 7–10% of patients and significantly impacts quality of life. Despite half of patients showing a resolution within three–six months after HSCT, PRCA might require [...] Read more.
Pure red cell aplasia (PRCA) following major ABO-mismatched allogeneic hematopoietic stem cell transplantation (HSCT) is a challenging complication, affecting 7–10% of patients and significantly impacts quality of life. Despite half of patients showing a resolution within three–six months after HSCT, PRCA might require treatment. Various therapeutic approaches have been investigated, including erythropoietin, plasmapheresis or immunomodulatory therapies (rituximab, bortezomib, corticosteroids, donor lymphocyte infusion (DLI), or the early tapering of immunosuppressive drugs), and TPO-mimetic agents, though responses have generally remained suboptimal. Recently, daratumumab has emerged as a promising, safe, and effective treatment for PRCA, documented by numerous case reports and series. We present a case of PRCA arising in a patient with mixed chimerism following a sibling HSCT for aplastic anemia (AA). In line with the literature, our findings highlight the effectiveness of daratumumab in PRCA from the first dose, although daratumumab administrations were delayed by the onset of infectious complications. Our case supports the earlier introduction of daratumumab in the treatment strategy of PRCA to avoid patient exposure to ineffective therapies that carry risks of increased immunosuppression and infections. Indeed, in our specific case, the early introduction of daratumumab may interrupt the immune hematologic mechanism underlying PRCA, which, in the context of mixed chimerism, could increase the risk of graft failure. Full article
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