The design and synthesis of selective small molecule inhibitors of protein kinases to modulate their activity is of great interest for chemical biologists. However, most of the small molecule inhibitors are ATP-competitive, which can limit selectivity because the ATP binding sites of kinases show significant similarity.
In this thesis, I present the biological properties of a novel class of protein kinase inhibitors. Inspired from staurosporine, this approach involves introducing a metal center to an otherwise organic scaffold allowing one to explore unique chemical spaces. We envisioned that by using this approach, it should be possible to induce high selectivity and potency towards the targeted kinases.
The majority of this work focuses on the studies that were conducted on GSK-3, a model kinase. Initially, structure-activity relationships were carried out on a complex with pseudotetrahedral geometry around the metal center. These studies yielded a highly selective inhibitor for GSK-3 with picomolar affinity whose remarkable activity has been confirmed in tissue culture and zebrafish embryos. In addition, this class of compounds has also shown promising anti-cancer properties.
In the second half of the thesis, the binding mode of these pseudotetrahedral complexes for GSK-3 has been investigated using X-ray crystallography. The focus of these studies is to understand the nature of the potency and selectivity of this scaffold, which includes an inhibitor with a K i ≤ 5 pM, one of the tightest binding inhibitors of protein kinases. In the last part of this thesis, two new scaffolds with octahedral geometry for GSK-3 and DAPK-1 have been investigated. These X-ray crystallographic studies have helped us to understand the interactions that promote potent binding and good selectivity and have led to new ideas for developing superior scaffolds.
Overall, this thesis provides a proof of principle that ruthenium-based organometallic compounds can be used as superior scaffolds to design potent and selective protein kinase inhibitors. In addition, these complexes represent a great candidate as tools for chemical biology to unravel biological questions because they are stable in cellular environment and show cellular activities at very low concentrations.
