Exploring PI3Ks and related kinases for targeted protein degradation

Our group has been interested in targeted protein degradation (where a small molecule induces the degradation of a protein), particularly in areas where classical inhibitors have failed. We were led to a set of kinases involved in cellular growth and the DNA damage response pathway, which are important in cancer, but where classical inhibitors failed due to toxicity. The specific targets we selected were ATR, ATM, and the lipid kinase PI3KCA. We reasoned that degrading these proteins could allow better dosing and/or tissue-specific degradation, which might mitigate toxicity. The thesis begins with a discussion of these kinases and why they are important in cancer. Also included in the introduction is an overview of that concept of small-molecule mediated protein degradation and when it is useful. Next is a presentation and discussion of the data followed by conclusions and outlook.
Section 2.1: The project around the targets ATR and ATM began with small structure-activity relationship (SAR) studies to identify suitable exit vectors on the chosen inhibitors. For ATR the conclusive investigation led to the design, synthesis, and exploration of bifunctional molecules aiming for target degradation. However, the efforts did not result in the discovery of a functional degrader molecule but the experience acquired in the field contributed to the success of the following approach.
Section 2.2: Based on the previously gained knowledge we chose to pursue a strategy that would allow a broader consideration of the PI3K and PI3K-related kinases (PIKK) active pockets. By selecting a pan-PI3K ligand for our CRBN-targeting PROTACs, and applying a structure-based method for the design of the molecules, we hoped to gain insights into the structural features needed and drive selectivity through degradation. Indeed, our work resulted in the creation of WJ112 14, a PI3Kα-specific nanomolar degrader that should serve as an important research tool for studying PI3K biology. Given the toxicities observed in the clinic with unselective PI3Kα inhibitors, the results here offer a new approach toward selectively targeting this frequently mutated oncogenic driver.