2. Academic Validation
  3. A Method for Determining the Kinetics of Small-Molecule-Induced Ubiquitination

A Method for Determining the Kinetics of Small-Molecule-Induced Ubiquitination

  • SLAS Discov. 2021 Apr;26(4):547-559. doi: 10.1177/24725552211000673.
Ellen F Vieux 1,  Roman V Agafonov 1,  Lydia Emerson 1,  Marta Isasa 1,  Richard W Deibler 1,  Jeffrey R Simard 1,  David Cocozziello 1,  Brendon Ladd 1,  Linda Lee 1,  Heng Li 1,  Stephen Archer 1,  Mark Fitzgerald 1,  Ryan Michael 1,  Christopher G Nasveschuk 1,  Eunice S Park 1,  Gunther Kern 1,  David A Proia 1,  Andrew J Phillips 1,  Stewart L Fisher 1
Affiliations

Affiliation

  • 1 C4 Therapeutics Inc., Watertown, MA, USA.
PMID: 33780296 DOI: 10.1177/24725552211000673
Abstract

Recent advances in targeted protein degradation have enabled chemical hijacking of the ubiquitin-proteasome system to treat disease. The catalytic rate of Cereblon (CRBN)-dependent bifunctional degradation activating compounds (BiDAC), which recruit CRBN to a chosen target protein, resulting in its ubiquitination and proteasomal degradation, is an important parameter to consider during the drug discovery process. In this work, an in vitro system was developed to measure the kinetics of BRD4 bromodomain 1 (BD1) ubiquitination by fitting an essential activator kinetic model to these data. The affinities between BiDACs, BD1, and CRBN in the binary complex, ternary complex, and full ubiquitination complex were characterized. Together, this work provides a new tool for understanding and optimizing the catalytic and thermodynamic properties of BiDACs.

Keywords

BiDAC; kinetics; targeted protein degradation; ubiquitination.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-182577
    BRD4 BD1降解剂
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