Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity

20 October 2021, Version 2

Abstract

Bivalent PROTACs work 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 enhanced degradation. Here, we designed trivalent PROTACs consisting of a bivalent BET inhibitor and an E3 ligand, tethered via a branched linker. We identified VHL-based SIM1 as a low picomolar BET degrader, with preference for BRD2. Compared to bivalent PROTACs, SIM1 showed more sustained and higher degradation efficacy, which led to more potent anti-cancer 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.

Keywords

Targeted Protein Degradation
PROTACs
multivalency
Trivalent
Ternary Complex Formation
Avidity
BET proteins
BRD2
BRD3
BRD4
Degraders
trifunctional core
pVHL protein
E3 Ligase

Supplementary materials

Title
Description
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Title
Supporting Information trivalent pgs
Description
The authors declare that all data supporting the findings of this study are available within the paper and its supplementary information files.
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Title
proteomics supporting data SIM1 cisSIM1
Description
proteomics dataset
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