Potency assay, off target (cells):
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 4 h. LRRK1, the closest homologue of LRRK2, and other LRRK2-related proteins such as VPS35 and Rab-specific phosphatase PPM1H remained unaffected. PDE6D ~30% degradation
XL01126-induced PDE6D degradation is LRRK2-independent and excluded it being a downstream consequence of LRRK2 degradation.
