While consisting of successful drugs, the current pharmacopeia also has inherent limitations based on its 'Occupancy-based' paradigm of pharmaceutical control. These limitations include: 1) the need to achieve/maintain high systemic exposure to insure sufficient in vivo protein inhibition, 2) the 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.  As an alternative pharmaceutical strategy, 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).  For the past decade, the Crews lab has focused on developing different strategies for inducing protein degradation, including the PROTAC (Proteolytic Targeting Chimera) and HyT (Hydrophobic Tagging) technologies. These heterodimeric ligand approaches offer the potential to selectively knock down intracellular levels of specific proteins, irrespective of protein class, thus allowing one to target those proteins that are currently not 'pharmacologically vulnerable'.

Breaking bad:  Advantages of protein degradation over inhibition

248th National Meeting (2014)

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