To qualify XL01126 as both a cellular and in vivo suitable degrader probe, and to assess its drug development potential, we next evaluated the physicochemical and ADME properties (Table and Figure ), as well as the in vivo pharmacokinetic profiles of XL01126 (Figure ). Due to the high molecular weight and lipophilicity, XL01126 has low solubility in PBS and moderate solubility in Fed State Simulated Intestinal Fluid (FeSSIF) (Table ), which, however, are all well above its DC50 values (14 -72 nM). The high stability (half-life at 108.29 min) of XL01126 in mouse plasma indicates XL01126 might be suitable for in vivo studies and we reasoned that plasma protein binding may account for its stability as protein binding can decrease the amount of free compound available for enzymatic metabolism. The protein binding also affects the potency of XL01126 in cells as shown by the significant potency shift of XL01126 in MEFs in the presence and absence of 10% fetal bovine serum (FBS) in the culture media (Figure ). To further qualify XL01126 as appropriate for in vivo studies, we assessed its PK profiles in mice (Figure and Table ). Following a single dose of XL01126 via intravenous (IV, 5 mg/Kg), intraperitoneal (IP, 30 mg/Kg), and oral gavage (PO, 30 mg/Kg), the concentrations of XL01126 in plasma, brain tissue, and cerebrospinal fluid (CSF) were determined. XL01126 showed fast absorption in both IP and PO injection with Cmax (7700 ng/mL and 3620 ng/mL for IP and PO separately) reached at 0.25 min and 2h for IP and PO dosing, respectively. High plasma concentrations were achieved in all routes of administration and were maintained at levels way above the DC50 values for XL01126 in the experimental time period. The metabolism of XL01126 seems slow in all administration routes, probably because of high protein binding. Strikingly, XL01126 was also detected in brain tissues and CSF (Figure and 14C), suggesting that XL01126 is capable of penetrating the BBB regardless of its unfavorable in vitro ADME properties and violation of Ro5 and/or RoCNS 76 . To the best of our knowledge, this is the first-time report of a VHL-based PROTAC that is both oral bioavailable (F=15%) and BBB permeable. Further investigation of XL01126 will focus on its in vivo pharmacodynamics and PD-related functional studies.