“…Still, even if apparent specificity is observed in given cell types, many of these compounds appear to be intrinsically polypharmacological (Sievers et al, 2018). For instance, growing out the isoindolinone scaffold of lenalidomide led to the pleiotropic ZF/GSPT1 degrader CC-885 (Matyskiela et al, 2016), and later yielded the more GSPT1-selective compounds CC-90009 (Surka et al, 2020) and ZXH-1-161 (Powell et al, 2020). Small changes in compound structure strongly alter neosubstrate degradation specificity (Figure 2), with a recent report on 5-hydroxythalidomide, a thalidomide metabolite, illustrating how the presence of a single hydroxyl leads to a striking change in degradation selectivity from IKZF1 to SALL4, possibly explaining the ll teratogenicity of thalidomide (Donovan et al, 2018;Furihata et al, 2020).…”