Craig M. Crews (born June 1, 1964) is an American scientist at Yale University known for his contributions to chemical biology. He is known for his contributions to the field of induced proximity through his work in creating heterobifunctional molecules that "hijack" cellular processes by inducing the interaction of two proteins inside a living cell.[1] His initial work focused on the discovery of PROteolysis-TArgeting Chimeras (PROTACs) to trigger degradation of disease-causing proteins, a process known as targeted protein degradation (TPD), and he has since developed new versions of -TACs to leverage other cellular processes and protein families to treat disease.[2]
Crews graduated from the University of Virginia in 1986 with a bachelor's degree in chemistry, after which he performed research at the University of Tübingen as a German Academic Exchange Service (DAAD) Fellow.[6] As a graduate student in the laboratory of Raymond Erikson at Harvard University, Crews was the first to purify and clone the MAP kinase kinase MEK1,[7][8] a key signaling molecule controlling cancer-driving cellular processes including proliferation and survival.[9][10] Targeting MEK1 for the treatment of cancer has since been pursued by several biotechnology companies.[11]
He subsequently worked in the research group of Stuart Schreiber as a Cancer Research Institute Fellow before joining the faculty of Yale University as an assistant professor in Molecular, Cellular, and Developmental Biology in 1995.[6]
Research
Crews studies controlled proteostasis, i.e., the pharmacological modulation of protein turnover.[12] In 2001, Crews developed, in collaboration with Ray Deshaies, proteolysis targeting chimeras (PROTACs),[13][14] a new technology to induce proteolysis.[12] PROTACs are dimeric molecules that recruit specific intracellular proteins to the cellular quality control machinery (i.e., an E3 ubiquitin ligase) in a catalytic manner for subsequent removal by the proteasome.[15] This technology has the potential to allow pharmacological targeting of proteins previously thought "undruggable" including many responsible for drug resistance in cancer.[16] Excitement around the field has resulted in much private and public investment in therapeutic approaches based on targeted protein degradation.[17] Prior to its work on PROTACs, the Crews lab's synthesis and mode of action studies of the natural product epoxomicin revealed that it is a potent and selective proteasome inhibitor.[18] Subsequent medicinal chemistry efforts produced the epoxyketone containing proteasome inhibitor YU101,[19] which served as the basis for the multiple myeloma drug carfilzomib.[20][21]
Crews’ initial research at Yale explored the synthesis and mode of action of the natural product epoxomicin, which revealed itself to be a potent and selective proteasome inhibitor via its epoxyketone pharmacophore.[22][23] Subsequent medicinal chemistry efforts by Crews produced the epoxyketone-containing proteasome inhibitor, YU101.[24]
Crews’ work on proteasome inhibitors ultimately inspired the concept of induced proximity, beginning with using heterobifunctional molecules, now known as PROTACs, to hijack the cell’s degradation machinery to induce degradation of target proteins.[29]
Crews’ work in the field of induced proximity has led to the development of a number of investigational therapeutic candidates aimed at drugging proteins that are difficult to target using existing small molecule technology.[16][17] A clinically advanced PROTAC, ARV-471, is being developed by Crews’ company Arvinas and is the first induced heterobifunctional proximity molecule to demonstrate clinical proof-of-concept.[30]
He and collaborator Ray Deshaies first developed the PROTAC concept in 2001.[31]PROTACs are heterobifunctional molecules that initiate proteasome-dependent removal of specific proteins by simultaneously binding the protein and a ubiquitin ligase (i.e., an E3 ubiquitin ligase). The induced proximity of target and ligase catalyzes ubiquitination of the target protein, tagging the target protein for recognition by the proteasome.[32]PROTACs have the potential to allow pharmacological targeting of proteins previously thought "undruggable", such as those with inaccessible or non-selective active sites, including many responsible for drug resistance in cancer.[16]
Biotechnology companies
Crews has founded three biotechnology companies to develop TACs discovered in his Yale research lab, each of which induces protein-protein interactions within distinct target classes to achieve a therapeutic effect.
In 2013, Crews founded New Haven-based Arvinas, which uses the PROTAC technology discovered in his lab to develop drugs to treat cancer, neurodegeneration, and other diseases.[33] Notably, Arvinas’ PROTAC drugs have successfully demonstrated oral availability in clinical trials, overcoming a key challenge faced by PROTACs-based drug development since conception, owing to their atypically large size and pharmacological properties.[34]
As of 2023, Arvinas has three PROTAC therapies in clinical trials.[35] The most advanced is vepdegestrant (ARV-471), a PROTAC targeting the Estrogen Receptor, in Phase 3 trials to treat metastatic breast cancer. In 2021, Arvinas and Pfizer, Inc. partnered to co-develop vepdegestrant.[36] Phase 1/2 data have shown promising safety, tolerability, and pharmacokinetics for both drugs, and both drugs appeared to be well tolerated .[34][37] Moreover, ongoing clinical trials have demonstrated evidence of efficacy.[37][38]
In 2019, Crews founded Halda Therapeutics, a venture-backed biotech company that is developing RIPTACs, or Regulated Induced Proximity Targeting Chimeras, for the treatment of cancer.[39] Unlike PROTACs, RIPTACs do not directly elicit degradation of a target protein.[40] Instead, RIPTACs induce the formation of a stable complex between a target protein selectively expressed in cancer tissue and a more widely expressed protein essential for cell survival.[41] The resulting cooperative protein:protein interaction (PPI) abrogates the function of the essential protein, thus leading to the death of cancer cells expressing the target protein.
In 2021, Crews founded Siduma Therapeutics to advance other novel heterobifunctional concepts with broad utility in drug development.[42]
