While the paper discusses the advantages of PROTACs over traditional small-molecule inhibitors, could the authors elaborate on potential limitations regarding selectivity? Given that PROTACs rely on E3 ligases, how do variations in ligase expression across tissues impact target specificity and potential off-target effects? Moreover, the review touches on the clinical progress of PROTACs, but were there any major challenges in pharmacokinetics or bioavailability that have hindered their transition from preclinical to clinical stages?
