The Tale Of Proteolysis Targeting Chimeras (Protacs) For Leucine-Rich Repeat Kinase 2 (Lrrk2)

Here we present the rational design and synthetic methodologies towards proteolysis‐targeting chimeras (PROTACs) for the recently‐emerged target leucine‐rich repeat kinase 2 (LRRK2). Two highly potent, selective, brain‐penetrating kinase inhibitors were selected, and their structure was appropriately modified to assemble a cereblon‐targeting PROTAC. Biological data show strong kinase inhibition and the ability of the synthesized compounds to enter the cells. However, data regarding the degradation of the target protein are inconclusive. The reasons for the inefficient degradation of the target are further discussed.
Here, we present our efforts for developing LRRK2‐targeting PROTACs, starting from two highly‐potent LRRK2 inhibitors. Although the synthesized PROTACs showed cell permeability and interacted with the target, they failed to induce target degradation. This work highlights the challenges of PROTAC design for multidomain protein targets where the structure is not fully known and the dynamics are not fully understood.