A quantitative approach for defining the degradability landscape of protein degraders.
basic_science · Level V
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- Record sourced from PubMed, PMID 42443212.
- Also identified by DOI 10.1038/s41467-026-75591-8.
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Abstract
Targeted protein degradation (TPD) is an emerging therapeutic modality, but how multiple factors jointly determine degradation efficacy remains poorly understood. Here we present a quantitative framework for modeling the cellular mechanism of action of TPD, allowing for prediction of cellular efficacy with practically obtainable parameters. Applying this model to published data on 41 targets reveals a common range of degradation rate between 0.1 and 10 min<sup>-1</sup>, reflecting a characteristic efficiency of the TPD process. We define the degradability landscape, which provides a holistic characterization of the degradation propensity of a target of interest and serves as a roadmap for degrader optimization. We show how degradability is influenced by key factors such as target half-life and E3 level. We further quantify functional inhibition for kinase targets, enabling direct comparison between degrader and small molecule inhibitors. Finally, we uncover degrader discovery opportunities by systematically identifying targets with the potential to achieve superior degradation to facilitate TPD translational development.