GSK215

Protein inhibition via the traditional drug-designing approach has been shown to be an effective method for developing numerous small-molecule-based therapeutics. In the last decade, small inhibitors-guided protein degradation has arisen as an alternative method with the potential to fulfill the drug requirement for undruggable targets. Focal adhesion kinase (FAK) is a crucial modulator of the growth and spread of tumors, apart from it also acts as a scaffold for signaling of other proteins. FAK inhibitors have thus far had unsatisfactory results in clinical trials for cancer applications. Unlike prior attempts to control FAK expression, which were restricted to kinase domain inhibition with limited success in clinical research, protein degradation has the potential to concurrently disrupt FAK's kinase and scaffolding function. Recently, several FAK degraders were reported based on FAK Type I inhibitors using complex chemical synthesis approaches. Interestingly, recently a ternary complex was published revealing the binding mode of the FAK-PROTAC-E3 complex. This complex opens an avenue for the development of rational PROTAC design against FAK protein. Therefore, in the present study, we selected the most active Type I FAK inhibitor GSK2256098. The binding mode of the inhibitor prompted us to identify the most suitable analog for PROTAC design. We have identified a high-affinity analog that is suitable for PTOTAC design through the application of molecular docking (MD) and molecular dynamics simulations (MDS). Further based on the ternary FAK-PROTAC-E3 complex we build a binary complex FAK-Hit-E3-VHL between both proteins. Using the structure-based approach ten different potential FAK PROTACs candidates were designed. The stability of the complexes was analyzed using MDS and binding free energies were used to predict the binding affinity. Finally, based on desirable intermolecular interactions with the target and E3 ligase ProTAC4 was selected as the best candidate when compared with known FAK PROTAC GSK215.