Craig Crews

PROTAC-mediated Protein Degradation: A New Therapeutic Modality

Abstract

Enzyme inhibition has proven to be a successful paradigm for pharmaceutical development, however, it has several limitations.  As an alternative, for the past 20 years, my lab has focused on developing Proteolysis Targeting Chimera (PROTAC), a new ‘controlled proteolysis’ technology that overcomes the limitations of the current inhibitor pharmacological paradigm. Based on an ‘Event-driven’ paradigm, PROTACs offer a novel, catalytic mechanism to irreversibly inhibit protein function, namely, the intracellular destruction of target proteins. This approach employs heterobifunctional molecules capable of recruiting target proteins to the cellular quality control machinery, thus leading to their degradation.   We have demonstrated the ability to degrade a wide variety of targets (kinases, transcription factors, epigenetic readers) with PROTACs at picomolar concentrations.  Moreover, the PROTAC technology has been demonstrated with multiple E3 ubiquitin ligases, included pVHL and cereblon. The first PROTAC-based drugs have entered clinical trials for breast and prostate cancer.

 


Biography

Dr. Crews is the John C. Malone Professor of Molecular, Cellular and Developmental Biology and holds joint appointments in the departments of Chemistry and Pharmacology at Yale University. He graduated from the U.Virginia with a B.A. in Chemistry and received his Ph.D. from Harvard University in Biochemistry.

Dr. Crews has a foothold in both the academic and biotech arenas; on the faculty at Yale since 1995, his laboratory has pioneered the use of small molecules to control intracellular protein levels. In 2003, he co-founded Proteolix, Inc., whose proteasome inhibitor, Kyprolis™ received FDA approval for the treatment of multiple myeloma.

Since Proteolix’s purchase by Onyx Pharmaceuticals in 2009, Dr. Crews has focused on a new drug development technology, which served as the founding intellectual property for his latest New Haven-based biotech venture, Arvinas, Inc.

Currently, Dr. Crews serves on several editorial boards and was Editor of Cell Chemical Biology (2008-2018). In addition, he has received numerous awards and honors, including the 2013 CURE Entrepreneur of the Year Award, 2014 Ehrlich Award for Medicinal Chemistry, 2015 Yale Cancer Center Translational Research Prize, a NIH R35 Outstanding Investigator Award (2015),  the AACR Award for Chemistry in Cancer Research (2017), Khorana Prize from the Royal Society of Chemistry (2018), Pierre Fabre Award for Therapeutic Innovation (2018), and the Pharmacia-ASPET Award for Experimental Therapeutics (2019). In 2019, he was named an American Cancer Society Professor.

Bio

Yale

John C. Malone Professor of Molecular, Cellular and Developmental Biology

Professor of Chemistry, Pharmacology and Management

Executive Director Yale Center for Molecular Discovery

Research interests:
Targeted protein degradation