Craig M. Crews, September 1

SciLifeLab The Svedberg seminar series September 1

Craig M. Crews

Departments of Molecular, Cellular and Developmental Biology; Chemistry; and Pharmacology, Yale University, New Haven, CT USA

Craig Crews received his PhD degree in Biochemistry at Harvard in 1993 with Ray Erik- son, working on the purification/cloning of MEK1. He subsequently performed postdoctor- al research at Harvard with Stuart Schreiber for two years before joining the faculty at Yale Univer- sity in 1995. His lab’s research at the interface of chemistry and biology has led to both innovative chemical approaches to the study of cell biology as well as the development of a FDA approved anti-cancer drug.

Making the Problem Go Away: Induced Protein Degradation as a Therapeutic Strategy

The current ‘inhibitor/binder-based’ pharmacopeia has inherent limitations due to its ‘Occupancy-based’ paradigm of pharmaceutical control: 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. 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). My lab has developed different strategies 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’.

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