Structure-Based Design of a Macrocyclic PROTAC

Andrea Testa, Scott J. Hughes, Xavier Lucas, Jane E. Wright, Alessio Ciulli (Lead / Corresponding author)

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Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Here, we report the design and synthesis of a first macrocyclic PROTAC by adding a second cyclizing linker to the BET degrader MZ1. A co-crystal structure of macroPROTAC-1 bound in a ternary complex with VHL and the second Brd4 bromodomain validated the rational design. Biophysical studies revealed enhanced discrimination between the second and the first bromodomains of BET proteins. Despite a 12-fold loss of binary binding affinity for Brd4, macroPROTAC-1 exhibited cellular activity comparable to MZ1. Our findings support macrocyclization as an advantageous strategy to enhance PROTAC degradation potency and selectivity between homologous targets.
Original languageEnglish
Number of pages9
JournalAngewandte Chemie International Edition
Early online date19 Nov 2019
Publication statusE-pub ahead of print - 19 Nov 2019


  • proteolysis targeting chimeras (PROTACs)
  • macrocycles
  • drug design
  • protein-protein interactions
  • protein structures

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