All synthesized Homo-PROTACs were subsequently tested in both cellular degradation and biophysical ternary complex formation assays. First, VHL levels were determined via Western Blot after compound treatment for 8 h in two different cell lines (HEK 293 and HeLa) and compared to the degradation induced by reference compound CM11 (Figures and). Efficient degradation of the long isoform of VHL (pVHL30) was observed at 1 µM concentration for four compounds (SH1, SH2, MeSH1, MeSH2), featuring -like CM11 -18-atom linkers. In line with previous reports, degradation efficacy decreased with shorter linkers. Interestingly unprecedented degradation of the short isoform of VHL (pVHL19) was induced by compound SH2. Comparison with the degradation behavior of the disulfide-free analog alCM11 inducing only < 35% degradation of pVHL19 (Figure ), and SH1 with a disulfide-alkoxy linker inducing 11% degradation of pVHL19, suggested that combination of the disulfide motif and the alkyl linker leads to the cooperative improvement in pVHL19 degradation observed with SH2.