Pharmacokinetics, Dynamics, & Metabolism, Pfizer Worldwide Research and Development, Pfizer Inc., San Diego, CA, USA.
Discovery Sciences, Pfizer Worldwide Research and Development, Pfizer Inc., Groton, CT, USA.
J Pharmacokinet Pharmacodyn. 2021 Feb;48(1):149-163. doi: 10.1007/s10928-020-09722-z. Epub 2020 Oct 22.
Bispecific protein degraders (BPDs) engage the ubiquitin-proteasome system (UPS) to catalytically degrade intracellular proteins through the formation of ternary complexes with the target protein and E3 ubiquitin ligases. Here, we describe the development of a mechanistic modeling framework for BPDs that includes the reaction network governing ternary complex formation and degradation via the UPS. A critical element of the model framework is a multi-step process that results in a time delay between ternary complex formation and protein degradation, thereby balancing ternary complex stability against UPS degradation rates akin to the kinetic proofreading concept that has been proposed to explain the accuracy and specificity of biological processes including protein translation and T cell receptor signal transduction. Kinetic proofreading likely plays a central role in the cell's ability to regulate substrate recognition and degradation by the UPS, and the model presented here applies this concept in the context of a quantitative pharmacokinetic (PK)-pharmacodynamic (PD) framework to inform the design of potent and selective BPDs.
双特异性蛋白降解剂（BPD）通过与靶蛋白和 E3 泛素连接酶形成三元复合物，利用泛素-蛋白酶体系统（UPS）催化降解细胞内蛋白。本文描述了一种用于 BPD 的机制建模框架的开发，该框架包括通过 UPS 进行三元复合物形成和降解的反应网络。模型框架的一个关键要素是一个多步骤过程，该过程导致三元复合物形成和蛋白降解之间存在时间延迟，从而在 UPS 降解率下平衡三元复合物的稳定性，类似于已被提出用于解释包括蛋白质翻译和 T 细胞受体信号转导在内的生物过程的准确性和特异性的动力学校对概念。动力学校对可能在细胞调节 UPS 底物识别和降解的能力中发挥核心作用，本文提出的模型将这一概念应用于定量药代动力学（PK）-药效动力学（PD）框架中，为设计有效和选择性的 BPD 提供信息。
