Influential biochemist Craig M. Crews, PhD, who pioneered the pharmaceutical field of targeted protein degradation, delivered the second Kimberly Prize in Biochemistry and Molecular Genetics Lecture to a full auditorium of Feinberg faculty, staff, fellows and students on April 15.
Crews, the John C. Malone Professor of Molecular, Cellular and Developmental Biology and a professor of Chemistry, Pharmacology, and Management at Yale University, was selected to receive the prize for leading the development of the anti-cancer drug carfilzomib (Kyprolis), used in the treatment of relapsed or refractory multiple myeloma.
Crews also spearheaded the development of PROTAC (proteolysis-targeting chimeras) drugs, which use heterobifunctional molecules — molecular homing devices fused to cellular protein adapters — to target specific proteins for destruction by the cell’s proteasome. Crews is credited with bringing PROTAC-based drugs into clinical trials, which could be used to treat an array of human diseases, including cancer.
Ali Shilatifard, PhD, the Robert Francis Furchgott Professor and chair of Biochemistry and Molecular Genetics and director of the Simpson Querrey Institute for Epigenetics, introduced Crews during the event.
“Now, we are able to go inside the cell, tag a specific protein, remove it, and ask what happened to those cellular processes. This has revolutionized biology,” Shilatifard said of Crews’s discoveries.
During his lecture, Crews detailed PROTAC therapies and outlined the future of the technology.
“What we’ve learned with PROTACs is now being applied to many other areas and new modalities,” said Crews, who is also executive director of the Yale Center for Molecular Discovery. “We know in this post-genomic era every conceivable drug target. The question is: ‘How do we naturally drug these 20,000-plus proteins?’”
Building off PROTAC technology, Crews and his laboratory developed PhosTACs, small molecule drugs able to mediate protein phosphorylation, a critical biological process which often goes awry in cancer. By utilizing ultra-targeted PhosTACs, the drug can kill cancer cells without inducing widespread side effects in healthy cells.
Similarly, Crews’s laboratory has also developed RIPTACs (Regulated Induced Proximity Targeting Chimeras), which target and kill tumor cells utilizing protein interactions without affecting non-tumor cells.
Because traditional theories of pharmacology require excess of a drug to be circulating, potentially causing damage to non-target cells, Crews argued the field requires a new, more precise model.
“What I would like to do is change the paradigm of pharmacology to what I call ‘event-driven pharmacology,’ whereby any nook or cranny on the surface of a protein could now be the attachment point for a new class of drugs that will recruit quality control machinery of the cell to now tag that protein for destruction, and once eliminated, the drugs then can do it again, and again, and again.”
About the Kimberly Prize
The Kimberly Prize in Biochemistry and Molecular Genetics, the largest biochemistry award offered in the U.S., is given by Kimberly Querrey in honor of her late husband, Lou Simpson, a Northwestern trustee, alumnus and benefactor.
The award is given each year to a scientist who has made outstanding research contributions to understanding the molecular basis of life with a direct demonstrated link of their discovery into clinic for the betterment of humankind.
The inaugural prize was awarded in 2023 to Jennifer A. Doudna, PhD, the Li Ka Shing Chancellor’s Chair in Biomedical and Health Sciences and professor of Biochemistry, Biophysics and Structural Biology at the University of California, Berkeley. Doudna, a co-winner of the Nobel Prize in Chemistry, was recognized for her fundamental biochemical research providing molecular insight into the function of CRISPR/Cas9 systems as tools for genome editing and the application of her work to science and medicine.
Prize recipients are nominated and reviewed by the dean of Northwestern University Feinberg School of Medicine, the director of Simpson Querrey Institute for Epigenetics and other luminaries. The annual prize of $250,000 is given by the Simpson Querrey Institute for Epigenetics and administered by the Feinberg School of Medicine.
“When Lou passed away two years ago, Dean Neilson, Kimberly and I discussed how to celebrate his memory, and honor both Kimberly and Lou’s contributions and impact they have had on Northwestern and Northwestern Medicine,” Shilatifard said. “We decided to award this prize in his honor that celebrates their vision of excellence and impactful contribution to science, medicine and community, which they’re both very passionate about.”
