Structure-Based Design of a Macrocyclic PROTAC

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

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)
123 Downloads (Pure)

Abstract

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. Herein, we report the design and synthesis of a macrocyclic PROTAC by adding a cyclizing linker to the BET degrader MZ1. A co-crystal structure of macroPROTAC-1 bound in a ternary complex with VHL and the second bromodomain of Brd4 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
Pages (from-to)1727-1734
Number of pages8
JournalAngewandte Chemie International Edition
Volume59
Issue number4
Early online date19 Nov 2019
DOIs
Publication statusPublished - 20 Jan 2020

Keywords

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

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