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
Pathogen-induced senescence as the initiation trigger for the onset of Alzheimer’s disease
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Dasa Bohaciakova, PhD (MUNI), Katerina Sheardova MD (FNUSA), Marie Vajrychova, PhD
Abstract:
Alzheimer´s disease (AD) is a progressive neurodegenerative disorder in the elderly population worldwide, underlaid by two pathological features in the AD brain: 1) extracellular beta-amyloid plaques (Aß) and 2) intraneuronal Tau-containing neurofibrillary tangles (P-Tau). However, clinical trials aiming to prevent P-Tau and/or Aß deposition failed to demonstrate the effectiveness of disease-modifying treatments. This implies that protein aggregation is perhaps not a cause but rather a consequence of unknown mechanism(s) that eventually lead to the AD pathology. Interestingly, it has been proposed that Aß peptides can also function as antimicrobial peptides as a part of innate immunity. And although they are normally protective, their accumulation can lead to the induction of senescence and senescence activated secretory phenotype (SASP) eventually leading to chronic inflammation, and degenerative pathologies. Such systemic SASP could be potentially detected from patients’ CSF or plasma samples and could be thus a relevant biomarker of early events that eventually lead to the development of AD. Therefore, here we aim to uncover novel biomarkers of AD by studying the molecular triggers leading to the onset of Alzheimer’s disease phenotype. We hypothesize that infection of the brain with pathogens is one of the initial triggers leading to the accumulation of Aß oligomers. This is then followed by induction of cellular senescence in neurons and/or glia that subsequently, via the production of SASP, leads to inflammation, neuronal loss, and dementia. By combining samples from clinically and biomarker well-defined patients, highly-sensitive analytical tools, the unique stem-cell-based model of cerebral organoids, and strong expertise in neurodifferentiation, senescence, and SASP, we will be able to identify novel factors that contribute specifically to the initiation of AD and translate this knowledge to discovering relevant AD biomarkers directly from CSF and/or blood.
Project duration:
1st May 2021–31st December 2024
Quantification of intra-amniotic inflammation in late preterm prelabour rupture of membranes associated with the response of amniotic fluid proteome
Junior
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Marie Vajrychova, PhD
Abstract:
Preterm prelabour rupture of membranes is associated with the risk of intra-amniotic inflammation even beyond 34 weeks of gestation (late PPROM). Currently, the determination of interleukin-6
(IL-6) in amniotic fluid is frequently used to confirm or reject the presence of intra-amniotic inflammation (IAI) in PPROM. However, there is a lack of information about the level of IL-6 associated with the global change of amniotic fluid proteome as a response to IAI. Hence, we employed a Tandem Mass Tag-based approach to uncover amniotic fluid proteome response to the presence of IAI in late PPROM. We believe that the correlation of IL-6 with the level of other proteins in amniotic fluid will better define the cut off value for IAI confirmation based on the level of IL-6 associated with the global change of amniotic fluid proteome and help to reveal women with the highest risk of excessive inflammatory response in late PPROM.
Project duration:
1st May 2021–31st December 2024
From hit-to-lead candidate – development of novel agents to combat tuberculosis
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Jan Korabecny, Jaroslav Roh
Abstract:
Tuberculosis (TB) remains a widespread infectious disease and one of the top 10 causes of death worldwide. Screening of our in-house library of small molecules identified new anti-TB lead candidate K1297 that acted in low micromolar range against M. tuberculosis. Hence, this project aims to develop new clinical candidates related to K1297 with respect to antimycobacterial activity in cellular and animal models. Given the structural simplicity of K1297 and the possibility of several feasible structural modifications, there is a high potential for the improvement of the biological properties of K1297. In particular, we will focus on in vitro biological properties of prepared compounds, mainly their anti-TB properties with stress on clinically isolated M. tuberculosis strains including multi- and extensively- drug-resistant strains; their mechanism of action, selectivity profile, cytotoxicity, genotoxicity risk, physicochemical characteristics, and in vivo profile of selected drug candidates including acute toxicity, pharmacokinetic and pharmacodynamic properties in a murine model of TB.
Project duration:
1-May-2021–31-December 2024
