Structure‐Guided Optimization of a Molecular Glue Targeting the KBTBD4‐HDAC1/2 Complex
TL;DR
Optimization of UM171, a molecular glue initiating the degradation of neosubstrate HDAC1/2–CoREST–LSD1 through a multiprotein complex formed with KBTBD4, resulted in a 20‐fold improvement in glue activity, demonstrated by the stability of its ternary complex with KBTBD4‐HDAC2.
Abstract
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.
