Inhibition of cell response to DNA damage for the treatment of glioblastoma multiforme
Provider:
The Ministry of Health
Investigator:
Lukas Gorecki (University hospital Hradec Kralove)
Abstract:
Glioblastoma multiforme (GBM) is the most aggressive type of cancer localized in the brain. Treatment involves surgery supported with chemo and radiotherapy. Although, the current strategies are able to postpone tumor progression and extends patients’ survival, these tumors universally recur and unrelentingly result in patient death within one year. Temozolomide (TMZ), the fist line medication, or ionizing radiation generates DNA damage including single or double strand breaks that are repaired by several cellular mechanisms orchestrated by DNA damage response kinases. There are three key cellular orchestrators for DNA damage: ATR, ATM, and DNA PK. Whereas ATR is the principal responder of replication stress caused by e.g., alkylating agents like TMZ, ATM and DNA PK are the major regulators of serious double strand breaks repair caused by e.g., radiotherapy. All three kinases were frequently found overexpressed in GBM patients which is in accordance with poor patients’ prognosis, and chemo and radiotherapy resistance. Targeting these three kinases showed to be highly perspective in terms of personalized medicine which already led to several clinical trials phases I-III to be opened. This project aims to investigate therapeutic approach based on inhibition of one of the three apical DNA damage response kinases (ATR, ATM, and DNA-PK) that make GBM cells more vulnerable to TMZ, and/or ionizing radiation. Due to GBM heterogeneity we will evaluate these clinical candidates, including also in-house designed and prepared promising compounds, against variety of patient derived GBM cells that will be also clinically and immunohistochemically characterized. Whether those drug candidates are able to potentiate TMZ/radiation efficacies in various patients’ derived GBM samples will be concluded to validate their clinical significance. Besides, our lead candidate will be also inspected for antitumor activity using GBM mice xenografts.
Project duration:
1st May 2024–31st December 2027
Sensitizing Gram-negative bacteria to antibiotic treatment using efflux pump inhibitors
Provider:
The Ministry of Health
Investigator:
Jan Korabecny (University hospital Hradec Kralove), Jaroslav Roh (Faculty of Pharmacy Hradec Kralove, Charles University)
Abstract:
Antimicrobial resistance represents one of the most urgent healthcare issues of the 21st century. In 2017, the World Health Organization released a list of the 12 bacterial pathogens, including gram-negative Acinetobacter baumannii and Pseudomonas aeruginosa, and bacteria from the Enterobacteriaceae family. Efflux pumps are an important integral component of the cell membranes of these bacteria. They are often associated with the onset of antibiotic resistance in almost all types of marketed antibiotics, and more strikingly, they are also responsible for the resistance in drugs under clinical evaluation. The steep increase in antimicrobial resistance to current antibiotic therapy demands new approaches in the treatment of multidrug-resistant infections. One such startegy is to influence these efflux pump systems to sensitize resistant bacteria to antibiotic treatment. The importance of efflux pumps is exacerbated by the fact that they are involved in the formation of highly resistant biofilms that can pose another health risk with respect to medical devices and nosocomial infections. As a part of preliminary data, our research teams have discovered novel structural motifs of efflux pump inhibitors that, when combined with selected antibiotics, restore their efficacy against therapeutically resistant gram-negative strains, particularly clinically isolated Escherichia coli and Salmonella enteritidis. By optimizing these pilot molecules, we will search for new preclinical drug candidates using a comprehensive development process. This will include chemical synthesis, in vitro testing of antibiotic efficacy boosting, effect on biofilm growth inhibition, determination of safety profile, and validation of the whole concept under in vivo conditions in an animal model infected with Salmonella enterica. The results of this project will help address the socio-economic challenge of combating antimicrobial resistance in gram-negative bacteria using novel efflux pump inhibitor.
Project duration:
1st May 2024–31st December 2027
Novel agents inhibiting FLT3-tyrosine kinase for the treatment of leukemia
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Jan Korabecny (University hospital Hradec Kralove), Martina Ceckova (Faculty of Pharmacy Hradec Kralove, Charles University)
Abstract:
Acute myeloid leukemia (AML) represents an aggressive malignant disease with very low curability and one of the worst treatment response rates. Besides conventional therapy, the treatment options comprise recently introduced targeted drugs based on the cytogenetic characteristics of the patients` AML cells. Constitutive activation of FMS-like tyrosine kinase 3 (FLT3) receptor as the result of mutations (mostly internal tandem duplications) in the FLT3 gene can be found in approximately one-third of newly diagnosed AML patients. Several FLT3 inhibitors have been thereby developed and tested for clinical use, such as midostaurin (approved in 2017), or gilteritinib (2018). Both drugs have shown clinical benefit in AML, nevertheless, the existence of primary and secondary resistance is limiting their use and represents the main driving effort of medicinal chemists, aiming for the invention of new small-molecule FLT3 inhibiting compounds, that would target distinct FLT3 binding sites being less susceptible for point mutations compared to clinically approved drugs. Moreover, new FLT3 inhibitors might ideally show also beneficial offtarget
kinase activity further helping prevent and/or overcome resistance arising from FLT3 inhibition. Within this project, we will introduce and further develop new FLT3 clinical candidates derived from our lead compound K1872. This fact is corroborated by several preliminary data obtained for K1872, specifically from the in silico experiments and cellbased studies showing preferential ntiproliferative and proapoptotic activity in FLT3-mutated AML cells. The project is expected to have an emerging clinical impact in terms of developing new clinical candidate(s) based on FLT3 inhibition with improved pharmacodynamic profile compared to approved or currently investigated clinical candidates. Thereby, the project will broaden the current portfolio of marketed FLT3 inhibitors.
Project duration:
1st May 2023–31st December 2026
Hit-to-lead development of small molecules for enhanced medical radiation
protection
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Ales Tichy (FVZ UO), Jan Marek (UHHK), Martina Rezacova (1.LF UK)
Abstract:
In the last decade, the radiation exposure of the population related to radiodiagnostics and radiotherapy has increased significantly. So far, only a single radioprotective substance, amifostine, has successfully passed clinical trials, but it has a number of adverse effects. Our team recently prepared and tested a series of substances that showed a considerable radioprotective potential. The results of a pilot study of the most promising substance in experimental animals revealed that the administration before whole-body irradiation significantly increased their survival. The proposed project is focused on the hit-to-lead development of new substances derived from this parent structure with radioprotective effects and their application to irradiated cells and animals (in vitro and in vivo). Furthermore, the substances will be evaluated in terms of protection against ionizing radiation directly on human blood (ex vivo). Based on the comparison of the effectiveness of radioprotection with existing radioprotectants, new substances will be selected for further pre-clinical testing. As the parent structure interacts with Bcl-2 protein family (an excellent therapeutic target involved in many pathophysiological processes), several other potential applications can be anticipated. The radioprotective substances developed by this project can be used not only as a new tool of radiation protection in medicine but also in case of radiation accidents or terrorism and in all areas where radiation exposure can be expected (space research, industry, army, etc.).
Project duration:
1st May 2023–31st December 2026
Development of broad-spectrum disinfectants with enhanced virucidal activity
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Jan Marek (FVZ UO), Ondrej Soukup (UHHK)
Abstract:
The recent coronavirus pandemic (SARS-CoV-2) is not the only rapidly spreading viral disease. Recently, diseases that we considered eradicated (measles, whooping cough) or diseases that we know more from tropical areas (eg monkeypox) have been increasing in the European population. Such epidemiological phenomena are often associated with climate change or greater population migration (refugee crises, war in Ukraine, etc.). Thus, many easily spreading diseases, not only of viral origin, are still maintained in the population, which cause serious health complications in children and adults. However, appropriate preventive countermeasures (focused primarily on good hygiene) can maintain the frequency of these symptoms at a reasonable level (i.e. outside the epidemic or pandemic frequency). Quaternary ammonium salts are safe and long-term substances used as disinfectants and antiseptics. These compounds are known for their strong antimicrobial properties, but the virucidal effect is often not declared. In previous projects, a promising group of compounds was discovered that showed a strong virucidal effect while maintaining bactericidal and levurocidal effects. This project is focused on mapping the virucidal effect of quaternary ammonium salts, design and development of substances with a wide range of activity on all groups of microorganisms (bacteria, fungi, viruses) with the emphasis on enhanced virucidal effect. Selected substances will be evaluated for safety (cytotoxicity and skin irritation test) and by standard methods according to European legislation valid for possible registration as disinfectants or antiseptics. In addition, the emergence of resistance will be monitored. This project meets the priorities of the challenge: Search for active molecules with a strong disinfectant effect to stop the spread of infectious diseases not only of viral origin.
Project duration:
1st May 2023–31st December 2026
