Article

Disrupting linearity of PROTAC scaffolds prevents off-target complex I inhibition

2026-02-14

Abstract excerpt

Chemical inducers of proximity have transformed small-molecule pharmacology, but the large, bifunctional architectures they often employ introduce new and poorly understood off-target risks. During a targeted protein degrader synthesis project, we identified a subset of compounds that cause rapid and unexpected ATP depletion in cells. Mechanistic studies traced this effect to inhibition of mitochondrial complex I,...

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Identifiers and source

Literature Corpus work: 718891bc-a498-5baa-a91c-06ba92c22025
DOI: 10.64898/2026.02.13.702718

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