The current ‘inhibitor/binder-based’ paradigm of pharmaceutical control has inherent limitations: 1) the need to achieve/maintain high systemic exposure to insure sufficient in vivo protein inhibition, 2) potential off-target side effects due to high in vivo concentrations, and 3) the need to bind to an active site, thus limiting the potential ‘drug target space’ to a fraction of the proteome. Alternatively, induced protein degradation lacks these limitations. Based on an ‘Event-driven’ paradigm, this approach offers a novel, catalytic mechanism to irreversibly inhibit protein function, namely, the intracellular destruction of target proteins. This is achieved via recruitment of target proteins to the cellular quality control machinery, i.e., the Ubiquitin/Proteasome System (UPS) using PROTACs (Proteolysis Targeting Chimeras) that can achieve ‘degradation concentrations’ (DC50 values) in the picomolar range. This knockdown technology has been shown to effectively decrease intracellular levels of a variety of target protein classes, including kinases, transcription factors and epigenetic readers.

PROTACS: Induced protein degradation as a therapeutic strategy

253rd National Meeting (2017)

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