一种测定小分子诱导泛素化动力学的方法。
A Method for Determining the Kinetics of Small-Molecule-Induced Ubiquitination.
作者信息
Vieux Ellen F, Agafonov Roman V, Emerson Lydia, Isasa Marta, Deibler Richard W, Simard Jeffrey R, Cocozziello David, Ladd Brendon, Lee Linda, Li Heng, Archer Stephen, Fitzgerald Mark, Michael Ryan, Nasveschuk Christopher G, Park Eunice S, Kern Gunther, Proia David A, Phillips Andrew J, Fisher Stewart L
机构信息
C4 Therapeutics Inc., Watertown, MA, USA.
出版信息
SLAS Discov. 2021 Apr;26(4):547-559. doi: 10.1177/24725552211000673.
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.
靶向蛋白质降解领域的最新进展使得能够通过化学手段劫持泛素-蛋白酶体系统来治疗疾病。依赖于cereblon（CRBN）的双功能降解激活化合物（BiDAC）可将CRBN招募至选定的靶蛋白，导致其泛素化和蛋白酶体降解，其催化速率是药物研发过程中需要考虑的重要参数。在这项工作中，开发了一种体外系统，通过将基本激活剂动力学模型拟合到这些数据来测量BRD4溴结构域1（BD1）的泛素化动力学。对二元复合物、三元复合物和完全泛素化复合物中BiDAC、BD1和CRBN之间的亲和力进行了表征。这项工作共同提供了一个新工具，用于理解和优化BiDAC的催化和热力学性质。
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