To analyze the selectivity profile of the best degrader 1g in more detail, a global quantitative proteomics screen was conducted in MM.1S cells after 6 h treatment with 1g (0.5 µM). The analysis was performed using diaPASEF-based mass spectrometry and more than 5700 proteins could be identified. As presented in Figure , the results indicated moderate but significant HDAC1 and 2 degradation by 1g. Interestingly, KDM1A (LSD1), RCOR1, RCOR3, SIN3A, NCOR1, and MIER1 showed an even more pronounced degradation. All mentioned proteins represent family members of multi-subunit complexes (CoREST, SMRT/NCoR, SIN3, and MIER) which contain HDAC1/2 or 3. The phenomenon of degraded proteins within multi-subunit complexes that contain the POI can be explained by E3 ligase recruitment and ternary complex formation. This process not only leads to the polyubiquitination of the POI but also of other members within the entire complex. This socalled collateral degradation (or bystander effect) has been previously observed for other degraders and can occur to neighboring members within multi-protein complexes containing the POI. As degradation can be very cell line specific, we confirmed that HDAC1 degradation is not restricted to MM.1S cells but also occurs in MV4-11, MDA-MB-231 and U-87MG cells. These results suggest that FEM1B-based TPD could be extended to other cancer entities. Furthermore, we demonstrated that HDAC degradation translates into antiproliferative activity, even in the triple negative breast cancer cell line MDA-MB-231. This short-term anti-cancer activity was further validated by analysis of the log-term efficacy, as seen in clonogenic growth assays with MDA-MB-231 cells. Additionally, the cytotoxicity in MM.1S was shown to result from cell cycle arrest and the induction of apoptosis. Finally, through a global proteomics screen, we were able to show that treatment of MM.1S cells with FF2049 resulted in collateral degradation of neighboring proteins within HDAC1-3-containing multi-protein complexes. These results highlight the broader impact of the FEM1B-recruiting HDAC PROTACs on cellular protein networks.