Doctoral defence: Tanel Sõrmus “Development of stimuli-responsive and covalent bisubstrate inhibitors of protein kinases”

On 14 December at 14:15 Tanel Sõrmus will defend his doctoral thesis “Development of stimuli-responsive and covalent bisubstrate inhibitors of protein kinases” for obtaining the degree of Doctor of Philosophy (in Chemistry).

Supervisor:
Associate Professor Kaido Viht, University of Tartu

Opponent:
Associate Professor Matthias Gehringer, Eberhard Karls Universität Tübingen (Germany)

Summary
Protein kinases are enzymes, which catalyse protein phosphorylation. Protein phosphorylation affects almost all cell functions via a myriad of mechanisms. Dysregulation of protein kinases may lead to excess protein kinase activity, which is related to different kinds of diseases, including cancer. Inhibitors, which bind protein kinases and deactivate them, are developed. During the past twenty years around 100 protein kinase inhibitors have been approved as drugs.

ARC-inhibitors are bisubstrate protein kinase inhibitors, which have been developed in the University of Tartu for the past 30 years. Bisubstrate inhibitors bind two protein kinase binding sites simultaneously and thus prevent the substrates from binding. Therefore, ARC inhibitors have a very strong binding affinity and good selectivity towards their protein kinase targets. However, the structures of bisubstrate inhibitors are usually larger and more complicated.

It was demonstrated that special features can be added to ARC-inhibitors by incorporating optimized structural modifications. Namely, high affinity stimuli-responsive bisubstrate protein kinase inhibitors were constructed, which could be activated or deactivated on command using different stimuli (e.g., by illuminating with LED light or producing a reductive environment). For example, the ability to remotely regulate protein kinase inhibitors could lead to light-sensitive cancer drugs, which could be locally activated. Further, covalent ARC-inhibitors were developed, which form an irreversible covalent bond to their target protein kinase. The inhibitors which function via a covalent mechanism can be more selective towards their target.

Previously measured crystal structures of protein-inhibitor complexes were an important element in the design of new inhibitors. This work illustrates the flexibility of bisubstrate protein kinase inhibitor structures for integrating new features.

Defence can be also followed in Teams.