Scientists from the Department of Experimental Biology at the UP Faculty of Science, in collaboration with Prof Herman Sintim’s research group at Purdue University in the USA, will focus their attention on chemical compounds that could play an important role in the future treatment of acute myeloid leukaemia and some other types of cancers.
The joint Czech-American project, entitled “Pyrazoloquinoline Kinase Inhibitors and their Characterization in Relation to Cancer” received the support of the Ministry of Education, Youth and Sports from the INTER-EXCELLENCE II programme, which focuses on research, development and innovation.
Researchers will investigate inhibitors of cyclin-dependent kinases (CDKs) and FLT3 kinases over the next five years. Abnormal function of the FLT3 receptor kinase, which is often subject to oncogenic hyperactivation, is associated with the development of acute myeloid leukemia. “However, CDKs have also become a relevant target in the potential therapy of acute myeloid leukaemia because of their irreplaceable role in the direct regulation of the cell cycle as well as transcription. Simultaneous inhibition of two distinct cellular targets has been a trend in the development of new anti-cancer therapeutics in recent years, and blocking FLT3 and CDKs has already been tested in some models of acute myeloid leukaemia,” said project investigator Radek Jorda from the Department of Experimental Biology.
Preliminary results confirmed that by modifying the pyrazoloquinoline skeleton at different positions, the activity of the prepared compounds towards FLT3 and CDKs kinases can be modulated. “A series of new analogues of these compounds will be prepared during this project. In order to maximise their potential, they must be studied as best as possible in biochemical and cellular models. We also need to confirm their mechanism of action and structure-activity relationships so that new, more effective compounds can be designed. A closer characterisation of the new inhibitors in a variety of in vitro cell models will contribute to further understanding of these derivatives and their potential therapeutic use for the treatment of oncological diseases,” described Jorda.
While FLT3 kinase targeting has proven effective in the treatment of acute myeloid leukaemia, inhibition of selected CDKs by itself offers the potential to treat specific subtypes of solid tumours. “CDK2 kinase inhibition has been confirmed in several studies to be relevant in breast and ovarian cancer models with enhanced CCNE gene expression. Blocking the transcriptional kinase CDK12, in turn, led to increased sensitivity to drugs affecting DNA repair enzymes or DNA itself,” explained Jorda.