Structure‐Guided Optimization of a Molecular Glue Targeting the KBTBD4‐HDAC1/2 Complex

Optimization of UM171, a molecular glue initiating the degradation of neosubstrate HDAC1/2-CoREST-LSD1 through a multiprotein complex formed with KBTBD4, was carried out using the cryo-EM structure of its KBTBD4-HDAC2 complex. Structural modifications resulted in a 20-fold improvement in glue activity, demonstrated by the stability of its ternary complex with KBTBD4-HDAC2. These improvements were also accompanied by a robust degradation of LSD1 and the CoREST1 protein. Our results, although promising, also highlight the complexity of structure-guided glue design. The effect of the developed glues on the viability of HepG2 cells revealed a varying level of toxicity, which was disconnected from the glue activity. These observations highlight the potential impact of off-target effects on the biological activity of these glues.