Cancer remains a challenging disease with an urgent need for new therapeutic strategies. One emerging new pharmacology aiming to address this demand is termed targeted protein degradation. Instead of inhibiting the disease-causing protein, the drugs of this class lead to its removal. Despite this strategy coming with multiple advantages, the design of so-called degrader molecules has been challenging. On the one side, the implementation of PROTACs, or proteolysis targeting chimeras, suffers from large unfavorable molecular weights, leading to suboptimal pharmacological properties such as cell penetration. On the other side, smaller degrader molecules do exist, e.g. molecular glue degraders, but their discovery has often been quite serendipitous. We hypothesized that an untapped resource may be hidden in the already developed molecules that fall under this inhibitory-centric paradigm. Indeed, for these inhibitors sporadic reports already exemplified that these can lead to target (here the disease causing protein) destabilization. A quantitative and qualitative understanding of these processes is, however, largely lacking and hampers any translation efforts. In this project we thus explored these non-obvious inhibitor-induced protein destabilization events for one major drug target class: the protein kinases. This work thus aids closing the gap of our understanding how small molecules which were initially designed to inhibit a protein can also lead to their degradation. This may thus provide an alternative route to engineer degrader molecules and could pave the way towards novel, alternative therapeutic strategies in the battle against cancer.
