Ternary Complex-Templated Dynamic Combinatorial Chemistry for the Selection and Identification of Homo-PROTACs.

Autor: Diehl CJ; Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, 1 James Lindsay Place, DD1 5JJ, Dundee, Scotland, U.K., Salerno A; Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, 1 James Lindsay Place, DD1 5JJ, Dundee, Scotland, U.K., Ciulli A; Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, 1 James Lindsay Place, DD1 5JJ, Dundee, Scotland, U.K.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Jun 17; Vol. 63 (25), pp. e202319456. Date of Electronic Publication: 2024 May 16.
DOI: 10.1002/anie.202319456
Abstrakt: Dynamic combinatorial chemistry (DCC) leverages a reversible reaction to generate compound libraries from constituting building blocks under thermodynamic control. The position of this equilibrium can be biased by addition of a target macromolecule towards enrichment of bound ligands. While DCC has been applied to select ligands for a single target protein, its application to identifying chimeric molecules inducing proximity between two proteins is unprecedented. In this proof-of-concept study, we develop a DCC approach to select bifunctional proteolysis targeting chimeras (PROTACs) based on their ability to stabilize the ternary complex. We focus on VHL-targeting Homo-PROTACs as model system, and show that the formation of a VHL 2  : Homo-PROTAC ternary complex reversibly assembled using thiol-disulfide exchange chemistry leads to amplification of potent VHL Homo-PROTACs with degradation activities which correlated well with their biophysical ability to dimerize VHL. Ternary complex templated dynamic combinatorial libraries allowed identification of novel Homo-PROTAC degraders. We anticipate future applications of ternary-complex directed DCC to early PROTAC screenings and expansion to other proximity-inducing modalities beyond PROTACs.
(© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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