Given the high levels of on-target potency and specificity, we were interested to evaluate the performance of some of our compounds with respect to their in vitro and in vivo pharmacokinetic profiles. 21, 22, KH1 (24), 25 and KH2 (26) were all tested for liver microsome stability and kinetic solubility (RealSol, pH 7.4) (Supplementary Table ). As is often the case for bifunctional molecules, solubility was low but detectable in the low micromolar range for compounds 21, KH1 (24) and KH2 (26). Liver microsome data was variable across the compound set, wherein 22, KH1 (24) and KH2 (26) showed low-to-moderate scaled microsomal clearance across species (Supplementary Table ). We therefore moved forward to investigate in vivo clearance in a mouse cassette PK experiment using the better performing compounds KH2 (26) and). KH1 (24) displayed low, but measurable, oral bioavailability of 1.6% and a total mean plasma concentration above 65 nM for up to 4 hours following i.v. dosing at 0.37 mg/kg. Whilst we measured exposure up to 24 hours, due to the rapid degradation kinetics of KH1 (24), we were particularly interested to understand compound exposures at the shorter time points. Notably, we also observed some penetration of compound KH1 (24) into the brain, a total concentration of 16 nM at 2 hours and a brain: plasma ratio of 0.18 at this time point (Supplementary Tables ).