PROTAC is an emerging drug discovery modality, yet the development of an active and efficient degrader is still a laborious and unguided process. Structure-guided PROTAC design is an attractive strategy, but solving the crystal structure of a target protein:PROTAC:E3 ligase ternary complex is a challenging feat. The step-by-step PROTAC development strategy we used here provides an empirical and generalized roadmap for developing PROTACs against LRRK2 and other challenging targets. The ternary binding affinity assay and ternary complex formation assay we developed here successfully circumvented the use of recombinant full-length LRRK2 protein which is challenging to express and purify. These two assays can potentially be applied to PROTAC or molecular glue development for other challenging targets as well.