UM171 glues asymmetric CRL3–HDAC1/2 assembly to degrade CoREST corepressors

Abstract UM171 is a potent agonist of ex vivo human haematopoietic stem cell self-renewal 1 . By co-opting KBTBD4, a substrate receptor of the CUL3–RING E3 ubiquitin ligase (CRL3) complex, UM171 promotes the degradation of the LSD1–CoREST corepressor complex, thereby limiting haematopoietic stem cell attrition 2,3 . However, the direct target and mechanism of action of UM171 remain unclear. Here we show that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1/2 to promote corepressor degradation. Through proteomics and chemical inhibitor studies, we identify the principal target of UM171 as HDAC1/2. Cryo-electron microscopy analysis of dimeric KBTBD4 bound to UM171 and…