PROTACs go macrocyclic: Check our latest paper published in Angewandte

  • ToC graphics
  • Figure 1. Structure‐based design of macrocyclic PROTAC 1.
  • Scheme 1. Synthesis of trifunctional linker 13.
  • Scheme 2. Macrolactamization and completion of the synthesis of macroPROTAC‐1.
  • Figure 2. Binding affinity and cooperativity of ternary complex formation.
  • Figure 3. Crystal structure of ternary complex VHL:1:Brd4BD2.
  • Figure 4. Cellular activity of macroPROTAC‐1.

Closing the circle: A macrocyclic PROTAC has been designed and synthesized by adding a cyclizing linker to MZ1, a PROTAC targeting the bromodomain of the BET protein, Brd4. A co‐crystal structure of macroPROTAC‐1 bound in a ternary complex with E3 ligase VHL and the second bromodomain of Brd4 validated the rational design. This macrocyclization strategy enhanced the target specificity and cellular activity of the PROTAC.

Read the Article open access here.

Read the SLS News piece here.