- MeSH
- léčivé přípravky normy MeSH
- přehodnocení terapeutických indikací léčivého přípravku MeSH
- schvalování léčiv * MeSH
- Geografické názvy
- Evropa MeSH
Non-small cell lung cancer (NSCLC) has been marked as the major cause of death in lung cancer patients. Due to tumor heterogeneity, mutation burden, and emerging resistance against the available therapies in NSCLC, it has been posing potential challenges in the therapy development. Hence, identification of cancer-driving mutations and their effective inhibition have been advocated as a potential approach in NSCLC treatment. Thereof, this study aims to employ the genomic and computational-aided integrative drug repositioning strategy to identify the potential mutations in the selected molecular targets and repurpose FDA-approved drugs against them. Accordingly, molecular targets and their mutations, i.e., EGFR (V843L, L858R, L861Q, and P1019L) and ROS1 (G1969E, F2046Y, Y2092C, and V2144I), were identified based on TCGA dataset analysis. Following, virtual screening and redocking analysis, Elbasvir, Ledipasvir, and Lomitapide drugs for EGFR mutants (>-10.8 kcal/mol) while Indinavir, Ledipasvir, Lomitapide, Monteleukast, and Isavuconazonium for ROS1 mutants (>-8.8 kcal/mol) were found as putative inhibitors. Furthermore, classical molecular dynamics simulation and endpoint binding energy calculation support the considerable stability of the selected docked complexes aided by substantial hydrogen bonding and hydrophobic interactions in comparison to the respective control complexes. Conclusively, the repositioned FDA-approved drugs might be beneficial alone or in synergy to overcome acquired resistance to EGFR and ROS1-positive lung cancers.
- MeSH
- antitumorózní látky * farmakologie terapeutické užití MeSH
- erbB receptory * genetika antagonisté a inhibitory MeSH
- genomika metody MeSH
- inhibitory proteinkinas farmakologie terapeutické užití MeSH
- lidé MeSH
- mutace * MeSH
- nádory plic * genetika farmakoterapie MeSH
- nemalobuněčný karcinom plic * farmakoterapie genetika MeSH
- přehodnocení terapeutických indikací léčivého přípravku * MeSH
- protoonkogenní proteiny * genetika MeSH
- simulace molekulového dockingu MeSH
- tyrosinkinasy * genetika antagonisté a inhibitory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- léčivé přípravky * MeSH
- lidé MeSH
- přehodnocení terapeutických indikací léčivého přípravku * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: In the two European Union (EU)-funded projects, PCM4EU (Personalized Cancer Medicine for all EU citizens) and PRIME-ROSE (Precision Cancer Medicine Repurposing System Using Pragmatic Clinical Trials), we aim to facilitate implementation of precision cancer medicine (PCM) in Europe by leveraging the experience from ongoing national initiatives that have already been particularly successful. PATIENTS AND METHODS: PCM4EU and PRIME-ROSE gather 17 and 24 partners, respectively, from 19 European countries. The projects are based on a network of Drug Rediscovery Protocol (DRUP)-like clinical trials that are currently ongoing or soon to start in 11 different countries, and with more trials expected to be established soon. The main aims of both the projects are to improve implementation pathways from molecular diagnostics to treatment, and reimbursement of diagnostics and tumour-tailored therapies to provide examples of best practices for PCM in Europe. RESULTS: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. CONCLUSION: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. CONCLUSION: European collaboration can facilitate the implementation of PCM and thereby provide affordable and equitable access to precision diagnostics and matched therapies for more patients.
- MeSH
- Evropská unie MeSH
- individualizovaná medicína * metody MeSH
- klinické zkoušky jako téma organizace a řízení MeSH
- lidé MeSH
- nádory * terapie MeSH
- přehodnocení terapeutických indikací léčivého přípravku MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa MeSH
As the world population ages, there will be an increasing need for effective therapies for aging-associated neurodegenerative disorders, which remain untreatable. Dementia due to Alzheimer's disease (AD) is one of the leading neurological diseases in the aging population. Current therapeutic approaches to treat this disorder are solely symptomatic, making the need for new molecular entities acting on the causes of the disease extremely urgent. One of the potential solutions is to use compounds that are already in the market. The structures have known pharmacokinetics, pharmacodynamics, toxicity profiles, and patient data available in several countries. Several drugs have been used successfully to treat diseases different from their original purposes, such as autoimmunity and peripheral inflammation. Herein, we divulge the repurposing of drugs in the area of neurodegenerative diseases, focusing on the therapeutic potential of antineoplastics to treat dementia due to AD and dementia. We briefly touch upon the shared pathological mechanism between AD and cancer and drug repurposing strategies, with a focus on artificial intelligence. Next, we bring out the current status of research on the development of drugs, provide supporting evidence from retrospective, clinical, and preclinical studies on antineoplastic use, and bring in new areas, such as repurposing drugs for the prion-like spreading of pathologies in treating AD.
- MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- antitumorózní látky * farmakologie terapeutické užití chemie MeSH
- demence * farmakoterapie MeSH
- lidé MeSH
- pozorovací studie jako téma MeSH
- přehodnocení terapeutických indikací léčivého přípravku * MeSH
- preklinické hodnocení léčiv MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The global shortage of corneal endothelial graft tissue necessitates the exploration of alternative therapeutic strategies. Rho-associated protein kinase inhibitors (ROCKi), recognized for their regenerative potential in cardiology, oncology, and neurology, have shown promise in corneal endothelial regeneration. This study investigates the repurposing potential of additional ROCKi compounds. Through screening a self-assembled library of ROCKi on B4G12 corneal endothelial cells, we evaluated their dose-dependent effects on proliferation, migration, and toxicity using live-cell imaging. Nine ROCKi candidates significantly enhanced B4G12 proliferation compared to the basal growth rate. These candidates were further assessed for their potential to accelerate wound closure as another indicator for tissue regeneration capacity, with most demonstrating notable efficacy. To assess the potential impact of candidate ROCKi on key corneal endothelial cell markers related to cell proliferation, leaky tight junctions and ion efflux capacity, we analyzed the protein expression of cyclin E1, CDK2, p16, ZO-1 and Na+/K+-ATPase, respectively. Immunocytochemistry and western blot analysis confirmed the preservation of corneal endothelial markers post-treatment with ROCKi hits. However, notable cytoplasm enlargement and nuclear fragmentation were detected after the treatment with SR-3677 and Thiazovivin, indicating possible cellular stress. In compared parameters, Chroman-1 at a concentration of 10 nM outperformed other ROCKi, requiring significantly 1000-fold lower effective concentration than established ROCKi Y-27632 and Fasudil. Altogether, this study underscores the potential of repurposing ROCKi for treating corneal endothelial dysfunctions, offering a viable alternative to conventional grafting methods, and highlights Chroman-1 as a promising candidate structure for hit-to-lead development.
- MeSH
- buněčné linie MeSH
- endoteliální buňky účinky léků MeSH
- inhibitory proteinkinas * farmakologie MeSH
- kinázy asociované s rho * antagonisté a inhibitory metabolismus MeSH
- lidé MeSH
- pohyb buněk účinky léků MeSH
- přehodnocení terapeutických indikací léčivého přípravku MeSH
- proliferace buněk * účinky léků MeSH
- regenerace * účinky léků MeSH
- rohovkový endotel * účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
