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Structure-Based Design of a Macrocyclic PROTAC

revised on 12.11.2019, 05:11 and posted on 20.11.2019, 12:10 by Andrea Testa, Scott J. Hughes, Xavier Lucas, Jane E. Wright, Alessio Ciulli
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.


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University of Dundee, School of Life Sciences


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Declaration of Conflict of Interest

The Ciulli laboratory receives or has received sponsored research support from Boehringer Ingelheim, Eisai Inc., Nurix Inc., and Ono Pharma. A.C. is a scientific founder, director and shareholder of Amphista Therapeutics, a company that is developing targeted protein degradation therapeutic platforms.

Version Notes

second version of the article