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Small-molecule degraders are a novel chemical modality enabling immediate, selective and direct loss of targeted proteins. While the majority of proteins in the proteome lack selective pharmacological agents or chemical probes, hybrid chemical–genetic degradation approaches have emerged as complementary and versatile strategies to modulate the stability of specific proteins. These broadly applicable degradation-based strategies use small molecules or antibodies to recruit the degradation machinery to dispose of target proteins and are highly complementary to widely used gene-directed approaches. Moreover, these approaches offer improved target selectivity profiles and enable functional studies with temporal resolution that is not possible with genetic approaches. In this chapter, we summarize the development and utility of the degradation tag (dTAG) system for engineering target-specific protein degradation. The dTAG technology platform uses hetero-bifunctional small-molecule degraders to co-opt the endogenous cellular degradation machinery to rapidly and reversibly deplete FKBP12F36V-tagged target proteins. We expect that the dTAG system and related tag-based degradation strategies will become essential tools for pre-clinical target validation and mechanistic biological investigation in cellular and mouse models of development and disease.

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