ePrints

Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity

Lookup NU author(s): Dr Chiara ManiaciORCiD

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.

Abstract

© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.Bivalent proteolysis-targeting chimeras (PROTACs) drive protein degradation by simultaneously binding a target protein and an E3 ligase and forming a productive ternary complex. We hypothesized that increasing binding valency within a PROTAC could enhance degradation. Here, we designed trivalent PROTACs consisting of a bivalent bromo and extra terminal (BET) inhibitor and an E3 ligand tethered via a branched linker. We identified von Hippel–Lindau (VHL)-based SIM1 as a low picomolar BET degrader with preference for bromodomain containing 2 (BRD2). Compared to bivalent PROTACs, SIM1 showed more sustained and higher degradation efficacy, which led to more potent anticancer activity. Mechanistically, SIM1 simultaneously engages with high avidity both BET bromodomains in a cis intramolecular fashion and forms a 1:1:1 ternary complex with VHL, exhibiting positive cooperativity and high cellular stability with prolonged residence time. Collectively, our data along with favorable in vivo pharmacokinetics demonstrate that augmenting the binding valency of proximity-induced modalities can be an enabling strategy for advancing functional outcomes. [Figure not available: see fulltext.]

Publication metadata

Author(s): Imaide S, Riching KM, Makukhin N, Vetma V, Whitworth C, Hughes SJ, Trainor N, Mahan SD, Murphy N, Cowan AD, Chan K-H, Craigon C, Testa A, Maniaci C, Urh M, Daniels DL, Ciulli A

Publication type: Article

Publication status: Published

Journal: Nature Chemical Biology

Year: 2021

Volume: 17

Pages: 1157-1167

Print publication date: 01/11/2021

Online publication date: 21/10/2021

Acceptance date: 10/08/2021

ISSN (print): 1552-4450

ISSN (electronic): 1552-4469

Publisher: Nature Research

URL: https://doi.org/10.1038/s41589-021-00878-4

DOI: 10.1038/s41589-021-00878-4

Altmetrics

Share