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Structure-based design of a macrocyclic PROTAC

DOI: 10.1002/anie.201914396 DOI Help

Authors: Alessio Ciulli (University of Dundee) , Andrea Testa (University of Dundee) , Scott J. Hughes (University of Dundee) , Xavier Lucas (University of Dundee) , Jane E. Wright (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: November 2019
Diamond Proposal Number(s): 14980

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. 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.

Journal Keywords: proteolysis targeting chimeras (PROTACs); macrocycles; drug design; proteinprotein interactions; protein structures

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography