ArticleProceedings of the National Academy of Sciences of the United States of America2026
Rebinding drives cellular retention of small-molecule drugs with abundant targets.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Abstract
Many small-molecule antitumor drugs are administered far less frequently than would be predicted from their plasma half-lives, in part because their efficacy is driven by prolonged retention within tumors. Drug retention can be caused by nonspecific protein binding, low membrane permeability, sequestration in acidic compartments, slow target dissociation, and rebinding to empty target sites, but the field has lacked a quantitative framework and preclinical assays for discriminating these mechanisms and predicting retention in vivo. We developed a theoretical framework and a simple two-drug assay for quantifying retention mechanisms in cell-based models. Application to 13 drugs with 8 distinct intracellular targets revealed diverse retention mechanisms. Rebinding emerged as a potent driver of retention whose magnitude was predicted by the target-to-affinity ratio ([Target]/
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