A quantitative approach for defining the degradability landscape of protein degraders.

TitleA quantitative approach for defining the degradability landscape of protein degraders.
Publication TypeJournal Article
Year of Publication2026
AuthorsDu W, De Boni L, Hopkins BDavid, Elemento O
JournalNat Commun
Date Published2026 Jul 13
ISSN2041-1723
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-1, 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.

DOI10.1038/s41467-026-75591-8
Alternate JournalNat Commun
PubMed ID42443212