The superior activity of SIM1 on the viability of 22Rv1 cells was evidenced in a colonyformation assay, where only SIM1-treated cells showed significant cytotoxicity as compared to vehicle control or cells treated with bivalent counterparts at the same concentration of 10nM (Fig. ). Substantial cell death was observed after 24h treatment with 10nM SIM1, as shown by PARP cleavage assays (Fig. and Extended Data Fig. ). In contrast, 10nM MT1 or MZ1 did not cause observable PARP cleavage even up to 48h, and 1µM concentration was needed to induce levels of PARP cleavage similar to 10nM SIM1 (Extended Data Fig. ). Cells died of apoptosis as indicated by prevented cleavage of PARP upon co-treatment with QVD-OPh, a pancaspase inhibitor, and not of necroptosis, as shown by co-treatment with Necrostatin-1 (Fig. and Extended Data Fig. ). Caspase-Glo assays confirmed the more potent activity of SIM1 (EC50 2nM) compared to MZ1 or ARV-771 (EC50 150 and 90nM, respectively), with much greater maximal signal than non-degraders cis-SIM1 and MT1 (Fig. ), and apoptosis was blocked by co-treatment with the VH298 and QVD-OPh (Extended Data Fig. ).