A kinetic proofreading model for bispecific protein degraders
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ORIGINAL PAPER
A kinetic proofreading model for bispecific protein degraders Derek W. Bartlett1
· Adam M. Gilbert2
Received: 3 June 2020 / Accepted: 21 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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. Keywords Mechanistic modeling · Targeted protein degradation · Kinetic proofreading · Translational pharmacology
Introduction Cellular systems are dynamic reactors that orchestrate a finely tuned balance of the production and degradation of intracellular biomolecules to maintain normal cellular function. An imbalance in this homeostatic regulation can lead to cellular dysfunction that results in human diseases such as cancer. Therefore, recent drug discovery efforts have focused on the design of molecules that can leverage the cell’s endogenous protein degradation pathways to induce the selective degradation of disease-causing proteins [1–5]. Bispecific protein degraders (BPDs), also known as proteolysis-targeting chimeras (PROTACs), are molecules that can engage the ubiquitin–proteasome
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10928-020-09722-z) contains supplementary material, which is available to authorized users. & Derek W. Bartlett [email protected] 1
Pharmacokinetics, Dynamics, & Metabolism, Pfizer Worldwide Research and Development, Pfizer Inc., San Diego, CA, USA
2
Discovery Sciences, Pfizer Worldwide Research and Development, Pfizer Inc., Groton, CT, USA
system, or UPS, to catalytically degrade intracellular proteins through the formation of ternary complexes with the target protein and E3 ubiquitin ligases [6, 7]. The eventdriven pharmacology resulting from this catalytic degradation mechanism challenges the traditional drug development paradigms used for occupancy-driven therapeutics [8, 9]. Instead of relying upon occupancy and equilibrium endpoints as metrics for ef
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