scholarly journals Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity

2021 ◽  
Author(s):  
Satomi Imaide ◽  
Kristin M. Riching ◽  
Nikolai Makukhin ◽  
Vesna Vetma ◽  
Claire Whitworth ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Functional Outcomes ◽  
Ternary Complex ◽  
High Avidity ◽  
Bet Inhibitor ◽  
Anti Cancer ◽  
Work Drive ◽  
Cancer Activity ◽  
In Vivo Pharmacokinetics

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.

scholarly journals Trivalent PROTACs enhance protein degradation through cooperativity and avidity

2020 ◽  
Author(s):  
Alessio Ciulli ◽  
Satomi Imaide ◽  
Kristin Riching ◽  
Vesna Vetma ◽  
Claire Whitworth ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Conformational Changes ◽  
Ternary Complex ◽  
High Avidity ◽  
Proof Of Concept ◽  
Complex Interactions ◽  
Anti Cancer ◽  
Sufficient Stability ◽  
Bet Protein ◽  
Molecular Recognition Features

Abstract Bivalent small-molecule degraders, or proteolysis targeting chimeras (PROTACs), work by simultaneously binding a target protein and E3 ubiquitin ligase to produce a ternary complex. To drive target ubiquitination and degradation at low catalytic concentrations, degraders must form appropriately positioned complexes of sufficient stability, aided by intra-complex interactions. We hypothesized these molecular recognition features could be enhanced by increasing binding valency. Here we present trivalent PROTACs as a strategy to boost protein degradation. Our design for a trivalent PROTAC consisted of two BET bromodomain inhibitors and an E3 ligase ligand, each separately tethered via a branched linker. In screening, we identified SIM1, a VHL-based PROTAC, as a highly potent BET degrader, capable of low picomolar degradation for all family members, with preference for BRD2. In functional comparison studies to bivalent PROTACs or inhibitors, SIM1 showed more sustained anti-cancer activity across numerous therapeutically relevant cell lines. Biophysical, biochemical, and cellular mechanistic studies showed SIM1 induces conformational changes upon binding to the BET protein to simultaneously engage with high avidity both its bromodomains in a cis intramolecular fashion. The resulting 1:1:1 complex showed positive cooperativity, high stability and prolonged cellular residence time. We provide proof-of-concept for augmenting the binding valency of proximity-induced modalities as a strategy to leverage both cooperativity and avidity within the ternary complex to advance functional outcomes.

scholarly journals Trivalent PROTACs Enhance Protein Degradation Through Cooperativity and Avidity

2020 ◽  
Author(s):  
Satomi Imaide ◽  
Kristin M. Riching ◽  
Vesna Vetma ◽  
Claire Whitworth ◽  
Scott J. Hughes ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Conformational Changes ◽  
Ternary Complex ◽  
High Avidity ◽  
Proof Of Concept ◽  
Complex Interactions ◽  
Anti Cancer ◽  
Sufficient Stability ◽  
Bet Protein ◽  
Molecular Recognition Features

<p><b>Bivalent small-molecule degraders, or proteolysis targeting chimeras (PROTACs), work by simultaneously binding a target protein and E3 ubiquitin ligase to produce a ternary complex. To drive target ubiquitination and degradation at low catalytic concentrations, degraders must form appropriately positioned complexes of sufficient stability, aided by intra-complex interactions. We hypothesized these molecular recognition features could be enhanced by increasing binding valency. Here we present trivalent PROTACs as a strategy to boost protein degradation. Our design for a trivalent PROTAC consisted of two BET bromodomain inhibitors and an E3 ligase ligand, each separately tethered via a branched linker. In screening, we identified SIM1, a VHL-based PROTAC, as a highly potent BET degrader, capable of low picomolar degradation for all family members, with preference for BRD2. In functional comparison studies to bivalent PROTACs or inhibitors, SIM1 showed more sustained anti-cancer activity across numerous therapeutically relevant cell lines. Biophysical, biochemical, and cellular mechanistic studies showed SIM1 induces conformational changes upon binding to the BET protein to simultaneously engage with high avidity both its bromodomains in a cis intramolecular fashion. The resulting 1:1:1 complex showed positive cooperativity, high stability and prolonged cellular residence time. We provide proof-of-concept for augmenting the binding valency of proximity-induced modalities as a strategy to leverage both cooperativity and avidity within the ternary complex to advance functional outcomes.</b></p>

scholarly journals Trivalent PROTACs Enhance Protein Degradation Through Cooperativity and Avidity

2020 ◽  
Author(s):  
Satomi Imaide ◽  
Kristin M. Riching ◽  
Vesna Vetma ◽  
Claire Whitworth ◽  
Scott J. Hughes ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Conformational Changes ◽  
Ternary Complex ◽  
High Avidity ◽  
Proof Of Concept ◽  
Complex Interactions ◽  
Anti Cancer ◽  
Sufficient Stability ◽  
Bet Protein ◽  
Molecular Recognition Features

<p><b>Bivalent small-molecule degraders, or proteolysis targeting chimeras (PROTACs), work by simultaneously binding a target protein and E3 ubiquitin ligase to produce a ternary complex. To drive target ubiquitination and degradation at low catalytic concentrations, degraders must form appropriately positioned complexes of sufficient stability, aided by intra-complex interactions. We hypothesized these molecular recognition features could be enhanced by increasing binding valency. Here we present trivalent PROTACs as a strategy to boost protein degradation. Our design for a trivalent PROTAC consisted of two BET bromodomain inhibitors and an E3 ligase ligand, each separately tethered via a branched linker. In screening, we identified SIM1, a VHL-based PROTAC, as a highly potent BET degrader, capable of low picomolar degradation for all family members, with preference for BRD2. In functional comparison studies to bivalent PROTACs or inhibitors, SIM1 showed more sustained anti-cancer activity across numerous therapeutically relevant cell lines. Biophysical, biochemical, and cellular mechanistic studies showed SIM1 induces conformational changes upon binding to the BET protein to simultaneously engage with high avidity both its bromodomains in a cis intramolecular fashion. The resulting 1:1:1 complex showed positive cooperativity, high stability and prolonged cellular residence time. We provide proof-of-concept for augmenting the binding valency of proximity-induced modalities as a strategy to leverage both cooperativity and avidity within the ternary complex to advance functional outcomes.</b></p>

scholarly journals Evaluation of the anti-cancer activity of the triterpenoidal saponin fraction isolated from the traditional Chinese medicine Conyza blinii H. Lév.

RSC Advances ◽  
2017 ◽  
Vol 7 (6) ◽  
pp. 3408-3412 ◽  
Author(s):  
Long Ma ◽  
Haiyan Liu ◽  
Lingpei Meng ◽  
Ping Qin ◽  
Botao Zhang ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Anti Cancer ◽  
Saponin Fraction ◽  
Cancer Activity

Triterpenoidal saponins fraction isolated from a traditional Chinese medicine Conyza blinii H. Lév. demonstrates anti-cancer activity both in vitro and in vivo.

scholarly journals Mechanism of action of the third generation benzopyrans and evaluation of their broad anti-cancer activity in vitro and in vivo

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Alexander J. Stevenson ◽  
Eleanor I. Ager ◽  
Martina A. Proctor ◽  
Dubravka Škalamera ◽  
Andrew Heaton ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Third Generation ◽  
The Third ◽  
Anti Cancer ◽  
Cancer Activity

scholarly journals Phospho-ibuprofen (MDC-917) incorporated in nanocarriers: anti-cancer activity in vitro and in vivo

2012 ◽  
Vol 166 (3) ◽  
pp. 991-1001 ◽  
Author(s):  
T Nie ◽  
CC Wong ◽  
N Alston ◽  
P Aro ◽  
PP Constantinides ◽  
...  
Keyword(s):  
Anti Cancer ◽  
Cancer Activity

In vitro and in vivo anti-cancer activity of tangeretin against colorectal cancer was enhanced by emulsion-based delivery system

2015 ◽  
Vol 15 ◽  
pp. 264-273 ◽  
Author(s):  
Yuwen Ting ◽  
Yi-Shiou Chiou ◽  
Min-Hsiung Pan ◽  
Chi-Tang Ho ◽  
Qingrong Huang
Keyword(s):  
Colorectal Cancer ◽  
Delivery System ◽  
Anti Cancer ◽  
Cancer Activity
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