The stem cell-supporting small molecule UM171 triggers Cul3-KBTBD4-mediated degradation of ELM2 domain- harboring proteins

To chemically modulate the ubiquitin-proteasome system for the degradation of specific target proteins is currently emerging as an alternative therapeutic modality. Earlier, we discovered such properties of the stem cell-supporting small molecule UM171 and identified that members of the CoREST complex (RCOR1 and LSD1) are targeted for degradation. UM171 supports the in vitro propagation of hematopoietic stem cells by transiently perturbing the differentiation-promoting effects of CoREST. Here, we employed global pro-teomics to map the UM171-targeted proteome and identified the additional target proteins, namely RCOR3, RREB1, ZNF217, and MIER2. Further, we discovered that critical ele-ments recognized by Cul3KBTBD4 ligase in the presence of UM171 are located within the EGL-27 and MTA1 homology 2 (ELM2) domain of the substrate proteins. Subsequent experi-ments identified conserved amino acid sites in the N-terminus of the ELM2 domain that are essential for UM171-mediated degradation. Overall, our findings provide a detailed account on the ELM2 degrome targeted by UM171 and identify critical sites required for UM171-mediated degradation of specific substrates. Given the target profile, our results are highly relevant in a clinical context and point towards new thera-peutic applications for UM171.