The potent and fast degradation of LRRK2 and inhibition of the Rab substrate phosphorylation by XL01126 prompted us to question if our PROTAC could surpass its warhead (HG-10-102-01) in dephosphorylating the substrate of LRRK2 and how much of the substrate dephosphorylation results from the protein degradation. This is of particular relevance for this project because the warhead ligand itself is a strong LRRK2 inhibitor with nanomolar kinase inhibition activities (Figure ) , and is a general challenge with PROTACs against protein kinase. As expected, the warhead HG-10-102-01 did not degrade LRRK2, but potently inhibited LRRK2 phosphorylation and Rab10 phosphorylation (EC50 = 110 nM on G2019S LRRK2 MEFs, EC50 = 214 nM on WT MEFs) (Figure and Figure ). In contrast, XL01126 dose-dependently degraded both WT LRRK2 (Figure ) and G2019S LRRK2 (Figure ).