To assess the degradation selectivity of XL01126 and identify potential off-targets at the proteome level, we performed unbiased quantitative tandem mass tag (TMT)-based global proteomic profiling in WT MEFs. Over 8000 proteins were quantified in the cell lysate samples from WT MEFs that were treated with 300 nM XL01126, cis-XL01126, or DMSO for 4h (Figure ). The data corroborate a significant chemical knockdown of LRRK2, as validated by Western blotting (Figure ). LRRK1, the closest homologue of LRRK2, and other LRRK2-related proteins such as VPS35 and Rab-specific phosphatase PPM1H remained unaffected. The proteomic data also revealed a small (~30%) depletion in protein levels of phosphodiesterase 6 (PDE6D) (Figure ). PDE6D has a deep hydrophobic ligand-binding pocket, and has been shown to be degradable via PROTACs . Curiously, PDE6D was also found as adventitious off-target degradation of PTK2 PROTACs previously . Inspection of chemical structures highlighted that the PTK2 PROTAC and XL01126 share a similar aminopyrimidine warhead at the target ligand end, a moiety known to be critical to the high binding affinity in PDE6D inhibitor Deltasonamide , suggesting a potential off-target degradation due to adventitious PROTAC binding to PDE6D. Dose-dependent degradation of PDE6D in both WT MEFs and LRRK2 KO MEFs as shown via Western blotting (Figure ) indicated that XL01126 induced PDE6D degradation is LRRK2-independent and excluded it being a downstream consequence of LRRK2 degradation. A study examining the mechanism of LRRK2 degradation demonstrated that degradation by XL01126 is mediated by the ubiquitin-proteasome system as XL01126-induced degradation can be blocked by VHL ligand (VH101), neddylation inhibitor (MLN4924), and proteasome inhibitor (MG132) pretreatments in both WT MEFs (Figure ) and G2019S LRRK2 MEFs (Figure ). However, the LRRK2 dephosphorylation and Rab10 dephosphorylation are not completely rescued by VH101, MLN4924, and MG132 pretreatments owing to the kinase inhibition effect of XL01126 as also evidenced in our kinase inhibition assay (Figure ).