Discovery of novel selective modulators of selected
therapeutically relevant biological targets
Abstract
My doctoral research mainly consists of two medicinal chemistry projects focused on
development of new biologically active small organic molecules. These small organic
molecules might find utilization as probes for chemical genetics, molecular/chemical biology
or as leads for development of compounds for clinical testing.
In the first project we report the identification of the furo[3,2-b]pyridine (FP) core as a novel
scaffold for potent and highly selective inhibitors of cdc-like kinases (CLKs) and efficient
modulators of the Hedgehog signalling pathway. Initially, a diverse target compound set was
prepared by synthetic sequences based on chemoselective metal-mediated couplings.
Optimization of the subseries containing 3,5-disubstituted furo[3,2-b]pyridines afforded
potent, cell-active and highly selective inhibitors of CLKs. It has been published that CLKs
could be promising targets for treatment of neurodegenerative diseases (Alzheimer,
Parkinson) or breast cancer. Profiling of the kinase-inactive subset of 3, 5, 7-trisubstituted
furo[3,2-b]pyridines revealed sub-micromolar non-toxic modulators of the Hedgehog
pathway. Inappropriate activation of Hedgehog signalling has been found in various cancers.
Second project is focused on the synthesis and biological evaluation of inhibitors of Casein
kinase 1 (CK1). In collaboration with colleagues from the Department of Experimental Biology
we have identified a new central pharmacophore, explored the structure-activity relationship
(SAR) and thereby discovered highly selective and potent CK1 inhibitors. Some inhibitors
exhibit also high activities in cells and promising in vivo profile. We are mostly focused on
utilization of these compounds in the treatment of chronic lymphocytic leukemia (CLL), but
CK1 inhibition is promising also for treatment of additional malignancies and other diseases
such as insomnia or obesity.