Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity

Satomi Imaide, Kristin M. Riching, Nikolai Makukhin, Vesna Vetma, Claire Whitworth, Scott J. Hughes, Nicole Trainor, Sarah D. Mahan, Nancy Murphy, Angus Cowan, Kwok-Ho Chan, Conner Craigon, Andrea Test, Chiara Maniai, Marjeta Urh, Danette L. Daniels, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

103 Citations (Scopus)
133 Downloads (Pure)

Abstract

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.]

Original languageEnglish
Pages (from-to)1157-1167
Number of pages11
JournalNature Chemical Biology
Volume17
Issue number11
Early online date21 Oct 2021
DOIs
Publication statusPublished - Nov 2021

Keywords

  • Mechanism of action
  • Pharmacology
  • Small molecules

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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