A plot of the enrichment/depletion in the templated library of the initially synthesized symmetric Homo-PROTACs as well as H2-H4 against the degradation level induced at 1 µM, shows a clear correlation between degrader potency and amplification observed in the templated DCL (Figure ). Similarly, the amplification in the templated DCL informs about the ability of the Homo-PROTAC to induce ternary complex formation (Figure ). We observed significant depletion of monomeric species in the templated DCL, which is consistent with enrichment in the DCC experiment being derived from thermodynamic stabilization of Homo-PROTAC species via induced VHL dimerization rather than binary binding of monomeric species or DCC-Homo-PROTACs to only one templating VHL. Besides confirming previously identified Homo-PROTACs (SH2, MeSH2) as hits and demonstrating the envisioned correlation between signal amplification in a templated DCL with degrader potency, two additional and novel, asymmetric DCC-Homo-PROTACs were identified in this second DCC experiment, namely MeH2-MeH3 and H2-MeH3, showing strong enhancement in the templated DCL. As validation of our ternary-complex directed DCC approach, we independently synthesized one of the hits, MeH2-MeH3 (Figure , see synthesis overview in Scheme S3), of this expanded DCC experiment for further evaluation. As before, native gel electrophoresis was utilized to assess the capability of MeH2-MeH3 in prompting VCB2:MeH2-MeH3 ternary complex formation in vitro. Following incubation of VCB with MeH2-MeH3 for 30 min, partial formation of the ternary complex was observed at the initial ratios of 1:1 to 1:4, and full conversion was observed with increasing excess of MeH2-MeH3 (Figure &). Based on the in vitro findings suggesting the compound's ability to induce ternary complex formation -albeit to a less extent than SH2 -MeH2-MeH3 was tested in cells and shown to induce degradation of pVHL30 after 8 hours in a dose-dependent treatment with DC50 = 1.32 μM and full degradation at 10 μM (Figure ). The evidenced activities of MeH2-MeH3, though not as potent as SH2 or H2-H4, further validates the DCC approach in expediting the identification of dimerizers as active degraders.