Weinstein Foundation award lecturer describes groundbreaking PROTAC research
Craig M. Crews, PhD, presented the AACR-Irving Weinstein Foundation Distinguished Lecture on Sunday, April 10, at the AACR Annual Meeting 2022. Crews was honored for his groundbreaking research that spearheaded new and revolutionary therapeutic approaches, including the development of novel proteasome inhibitors and proteolysis targeting chimera (PROTAC) technology, which enabled the drugging of cancer targets previously considered undruggable.
PROTACs offer a new approach to control protein function that harnesses chemistry and biology, Crews explained during his lecture, which can be viewed on the virtual platform by registered meeting participants through July 13, 2022.
PROTACs engage an E3 ubiquitin ligase and a disease-causing protein—protein of interest (POI) —to be degraded. The E3 ligase recruiting element and the POI are joined by a linker, whose composition and length can affect the PROTAC activity. The PROTAC works by inducing target protein ubiquitination, Crews explained. Ubiquitin marks the protein for destruction.
“When I developed this concept more than 20 years ago, it was an interesting approach but remained in the realm of chemical biology and academia,” Crews said. “We initially didn’t have a clear path for therapeutic development.”
Working with Arvinas, a biotech company that Crews founded in 2013, Crews and his research colleagues continued developing the PROTAC technology to improve its pharmaceutical potential. The newer PROTACs they developed possess improved drug-like properties, including oral bioavailability. The newer generation of PROTACs have been used to degrade several proteins by hijacking various E3 ligases, such as von Hippel Lindau (VHL) and cereblon (CRBN), thus launching the field of targeted protein degradation as a new therapeutic modality.
By degrading receptors rather than inhibiting them, PROTACs may allow for the treatment of patients who have become resistant to inhibitor-based drugs, Crews said. PROTACs deliver on the power of monoclonal antibodies, RNA interference, and CRISPR, but with small-molecule, orally available drug-like compounds, he added.
The two initial PROTACs in development—ARV-110, an androgen receptor-targeting molecule, and ARV-471, an estrogen receptor-targeting molecule—are in phase II trials for prostate and breast cancer, respectively. It’s theorized that this biological approach could allow for targeting of proteins previously thought to be undruggable.
“It’s exciting as we see this modality play out in the clinic and, hopefully, helping cancer patients in the future,” said Crews, who is the John C. Malone Professor of Molecular, Cellular, and Developmental Biology, a professor of chemistry, pharmacology, and management, and the executive director of the Yale Center for Molecular Discovery at Yale University.
The AACR-Irving Weinstein Foundation Distinguished Lectureship was established in 2004 to honor an individual whose outstanding scientific innovation and thought leadership has inspired creative thinking and new directions in cancer research. The recipient of the award is selected annually by the AACR President.
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