Journal
NATURE CHEMICAL BIOLOGY
Volume 17, Issue 11, Pages 1157-1167Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41589-021-00878-4
Keywords
-
Categories
Ask authors/readers for more resources
Tri-valent PROTACs with increased binding valency enhance protein degradation efficacy and anti-cancer activity, forming highly stable ternary complexes with positive cooperativity. SIM1 engages with both BET bromodomains with high avidity and forms a productive 1:1:1 complex with VHL, demonstrating prolonged residence time and improved functional outcomes.
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. Trivalent PROTACs are reported as a strategy to increase protein degradation efficacy and therapeutic window by combining avidity of target engagement with cooperativity to form highly favorable and productive ternary complexes.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available