Mechanisms that matter: unbiased cellular screening for degraders

Recent discoveries have highlighted that small monovalent molecules can leverage a variety of cellular mechanisms to induce degradation of a specific target protein. This perspective exemplifies and contextualizes these mechanisms within drug discovery, with a focus on identification of novel monovalent degraders via cell-based high-throughput screening (HTS) methodologies. Considerations for screening strategies, assay technologies and mechanistic deconvolution are discussed, with emphasis on identification of degrader compounds from diverse compound collections.